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•
•
•
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numbered
CONFIDENTIAL
The GlaxoSmithKline group of companies
RM2010/00132/00
ADC111114
Division: Worldwide Development
Information Type: Clinical Study Report
Control: other
Title:
A Randomized, Double-Blind, Parallel-Group, 24-Week Study
to Evaluate the Efficacy and Safety of ADVAIR™ DISKUS™
(Fluticasone Propionate/Salmeterol Combination Product
250/50mcg Inhalation Powder) BID Plus Spiriva HandiHaler
(Tiotropium Bromide Inhalation Powder 18mcg) QD Versus
Spiriva QD Plus Placebo DISKUS BID in Subjects with Chronic
Obstructive Pulmonary Disease (COPD)
Phase:
IV
Compound Number: CCI18781+GR33343
Effective Date:
28-APR-2010
Subject: Chronic Obstructive Pulmonary Disease, Lung Function, Quality of Life,
Tiotropium
Author(s):
Indication Studied: COPD
Initiation Date:
01Dec2008
Completion Date:
08Dec2009
Early Termination Date:
N/A
Date of Report:
April 2010
Earlier CSRs
N/A
This study was performed in compliance with Good Clinical Practices and
GlaxoSmithKline Standard Operating Procedures for all processes involved, including
the archiving of essential documents.
Copyright 2010 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.
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TABLE OF CONTENTS
Page
LIST OF FIGURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
LIST OF TABLES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
ETHICS AND GOOD CLINICAL PRACTICE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
2. STUDY OBJECTIVE(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
3. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE . . . . . . . . . . .
12
4. INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Discussion of Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Protocol Amendment(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. Selection of Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4.1. Inclusion/Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4.2. Withdrawal Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5. Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5.1. Investigational Product(s) and Reference Therapy . . . . . . . . . . . . . .
4.5.2. Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5.3. Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5.4. Prior and Concomitant Medications and Non-Drug Therapies . . . . .
4.5.5. Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6. Study Assessments and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.1. Efficacy Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.2. Primary Efficacy Measure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.3. Secondary Efficacy Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.4. Other Efficacy Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.5. Exploratory Efficacy Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.6. Safety Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.7. Data Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.8. Statistical Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5. STUDY POPULATION RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Subject Disposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2. Protocol Deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3. Populations Analyzed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4. Demographics and Baseline Characteristics . . . . . . . . . . . . . . . . . . . . . . . .
5.4.1. Demographics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5.4.2. Disease Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.3. Screening Pulmonary Function Tests . . . . . . . . . . . . . . . . . . . . . . . .
5.4.4. Current Medical Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5. Prior and Concomitant Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5.1. Prior COPD Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5.2. COPD Concomitant Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5.3. Non-COPD Concomitant Medications . . . . . . . . . . . . . . . . . . . . . . . .
5.6. Exposure and Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.1. Exposure to Study Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.2. Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
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30
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6. EFFICACY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1. AM Pre-Dose FEV1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2. 2 Hour Post-Dose FEV1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3. AM Pre-Dose FVC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4. 2 Hour Post-Dose FVC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.5. AM Pre-Dose IC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.6. CRQ-SAS Domain Scores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.7. Albuterol Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.8. HCU for COPD Exacerbations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.9. QIDS-SR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.10. HADS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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7. SAFETY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1.1. Run-In . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1.2. During Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1.3. Summary of Drug-Related Adverse Events Post Randomization . . .
7.1.4. Adverse Events Leading to Withdrawal from the Study . . . . . . . . . .
7.1.5. Post-Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2. Serious and Other Significant Adverse Events . . . . . . . . . . . . . . . . . . . . . .
7.2.1. Deaths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.2. Other Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.3. Other Significant Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3. Other Safety Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.4. Medical Device Incidents, Near-Incidents, Malfunctions and Remedial
Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.5. Pregnancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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8. SUBANALYSIS OF >50% FEV1 PREDICTED AT BASELINE POPULATION
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1. Demographic and Baseline Characteristics . . . . . . . . . . . . . . . . . . . . . . . . .
8.2. Disease Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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8.3. Screening Pulmonary Function Tests (PFTs) . . . . . . . . . . . . . . . . . . . . . . .
8.3.1. Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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9. DISCUSSION AND CONCLUSIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.1. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.2. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
57
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10. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60
11. CASE NARRATIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
STUDY POPULATION DATA SOURCE TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
EFFICACY DATA SOURCE FIGURES AND TABLES . . . . . . . . . . . . . . . . . . . . . . .
285
SAFETY DATA SOURCE TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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LIST OF FIGURES
Page
Figure 1 AM Pre-Dose FEV1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 2 2 Hour Post-Dose FEV1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 3 Pre-Dose FVC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 4 2 Hour Post-Dose FVC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 5 AM Pre-Dose IC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
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LIST OF TABLES
Page
Table 1 Time and Events Table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 2 Summary of Subject Disposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 3 Summary of Protocol Deviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 4 Demographic Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 5 Disease Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6 Summary of Screening Pulmonary Function Tests . . . . . . . . . . . . . . . . . . . .
Table 7 Non-COPD Concomitant Medications for Greater than or equal to Five
Percent of Subjects in any group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8 AM Pre-Dose FEV1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 9 2 Hour Post-Dose FEV1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 10 Pre-Dose FVC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 11 2 Hour Post-Dose FVC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 12 AM Pre-Dose IC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 13 CRQ-SAS Domain Scores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 14 HCU for COPD Exacerbations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 15 Scores on the QIDS-SR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 16 HADS Depression and Anxiety Scale Scores . . . . . . . . . . . . . . . . . . . . . . .
Table 17 Adverse Events Occurring in Greater than Two Percent of Subjects in
Any Group During Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 18 Pneumonia Adverse Events Post-Randomization . . . . . . . . . . . . . . . . . . .
Table 19 Demographic Characteristics [>50% FEV1 at Baseline Population] . . . . . .
Table 20 Disease Characteristics [>50% FEV1 at Baseline Population] . . . . . . . . . .
Table 21 Summary of Screening Pulmonary Function Tests [>50% FEV1 at
Baseline Population] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 22 2 Hour Post-Dose FEV1 [>50% FEV1 at Baseline Population] . . . . . . . . .
6
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Abbreviations
AE
ANCOVA
ATS
AUC
BID
BMI
CD-ROM
COPD
CRQ-SAS
CT
ECG
eCRF
FEV1
FSC
FVC
GCSP
GOLD
GSK
HADS
HCU
IC
ICS
ITT
IUD
IVRS
LABA
LAMA
LTOT
mcg
MDI
MedDRA
mL
mMRC
OCS
PDF
QIDS-SR
QD
QOL
RAP
SAE
sGAW
SGRQ
SOC
SPM
sRAW
TDI
US
Adverse Event
Analysis of Covariance
American Thoracic Society
Area Under the Curve
Twice-Daily
Body Mass Index
Compact Disk-Read Only Memory
Chronic Obstructive Pulmonary Disease
Chronic Respiratory Questionnaire-Self-Administered Standardized
Computerized Tomography
Electrocardiogram
Electronic Case Report Form
Forced Expiratory Volume in One Second
Fluticasone Propionate/Salmeterol Combination
Forced Vital Capacity
Global Clinical Safety and Pharmacovigilance
Global Initiative for Obstructive Lung Disease
GlaxoSmithKline
Hospital Anxiety and Depression Scale
Health Care Utilization
Inspiratory Capacity
Inhaled Corticosteroid
Intent-to-Treat
Intrauterine Device
Interactive Voice Recognition System
Long-Acting Bronchodilator
Long-Acting Muscarinic Antagonist
Long-Term Oxygen Therapy
Microgram
Metered Dose Inhaler
Medical Dictionary for Regulatory Activities
Milliliter
Modified Medical Research Council
Oral Corticosteroid
Portable Document Format
Quick Inventory of Depressive Symptomatology-Self Report
Once-Daily
Quality of Life
Reporting and Analysis Plan
Serious Adverse Event
Specific Airways Conductance
St. George’s Respiratory Questionnaire
System Organ Class
Study Procedures Manual
Specific Airways Resistance
Transitional Dyspnea Index
United States
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Trademark Information
Trademarks of the GlaxoSmithKline
group of companies
Trademarks not owned by the
GlaxoSmithKline group of companies
ADVAIR
DISKUS
HandiHaler
InForm
SAS
Spiriva
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ETHICS AND GOOD CLINICAL PRACTICE
The study protocol, any amendments, the informed consent, and other information that
required pre-approval were reviewed and approved by a national, regional, or
investigational center ethics committee or institutional review board meeting the
definition in 21 CFR 312.3(b).
This study was conducted in accordance with "good clinical practice" (GCP) and all
applicable subject privacy requirements, and, the guiding principles of the Declaration of
Helsinki.
Written informed consent was obtained from each subject prior to the performance of any
study-specific procedures. Case report forms were provided for each subject’s data to be
recorded.
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INTRODUCTION
Chronic Obstructive Pulmonary Disease (COPD) is one of the leading causes of
morbidity and mortality worldwide. Currently, COPD is the fifth leading cause of death
worldwide; and by the year 2020, it is estimated that COPD will become the third leading
cause of death worldwide [Urbano, 2005]. The most distinguishing feature of COPD is
dyspnea which can be related to airflow obstruction as documented by spirometric
evaluation. Exacerbations of COPD are also an important cause of the mortality and
morbidity associated with COPD and frequent exacerbations are associated with quality
of life impairment and frequent hospitalizations [Seemungal, 1998; Andersson, 2002].
Smoking cessation is the only therapy that has been shown to slow the rate of decline in
lung function in COPD [Anzueto, 2006]. However, effective treatments to manage
symptoms and improve health status are available. Long-acting bronchodilators are
among the most effective medications for COPD and are recommended for moderate to
very severe COPD [Global Initiative for Obstructive Lung Disease [GOLD, 2007].
Tiotropium (Spiriva) is a long-acting bronchodilator which acts by antagonism of
muscarinic (particularly M3) receptors (long-acting muscarinic antagonist, LAMA).
Tiotropium is indicated for the long-term maintenance treatment of bronchospasm
associated with COPD including chronic bronchitis and emphysema [Spiriva Product
Information, 2007]. Tiotropium has been shown to be effective in improving trough
forced expiratory volume in one second (FEV1), dyspnea, health status, and exacerbations
compared to placebo after 1 year of treatment [Casaburi, 2002]. Also, in a 6-month
study, tiotropium significantly reduced the number of and health care utilization for
exacerbations [Niewoehner, 2005].
Salmeterol, a long-acting beta-agonist (LABA) is another effective bronchodilator for
COPD, but is most commonly prescribed for COPD as a component of a dry powder
inhaler consisting of the inhaled corticosteroid (ICS) fluticasone propionate and
salmeterol (FSC) DISKUS™. Randomized trials have shown treatment with FSC at
strengths of 250/50mcg and 500/50mcg BID results in greater improvement in lung
function and dyspnea compared with the individual components in patients with COPD
[Mahler, 2002; Hanania, 2003; Calverley, 2003]. Recent studies have also demonstrated
that both the 500/50 and 250/50 strengths of FSC statistically significantly reduced the
rate of exacerbations in COPD [Calverley, 2007; Ferguson, 2008; Anzueto, 2009]. In the
United States (US), only the 250/50 strength of FSC is indicated for the twice-daily
maintenance treatment of airflow obstruction in patients with COPD associated with
chronic bronchitis or emphysema.
Recent COPD guidelines have recommended that combining bronchodilators with
different mechanisms and durations of action may increase the degree of bronchodilation
for equivalent or lesser side effects [GOLD, 2007]. In effect, combining different
treatments can potentially produce greater improvements in COPD than individual
treatments alone. The bronchodilator component of FSC (salmeterol) and the
bronchodilator tiotropium each have different effects on bronchodilation and may work
synergistically to improve bronchodilation when given together. The ICS component of
FSC (fluticasone propionate) works through a different mechanism by reducing
inflammation in COPD.
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Tiotropium and FSC are the two most prescribed medications for the treatment of COPD,
and are frequently co-prescribed in clinical practice. While intuitively, the combination
of FSC with tiotropium would provide additional benefit in COPD compared to a single
bronchodilator (i.e, tiotropium) alone, there are only a few empirical studies to support
this. A 3-month pilot study of treatment of FSC 500/50 plus placebo, tiotropium plus
placebo, or FSC 500/50 plus tiotropium showed that all groups had statistically
significant improvements in trough FEV1 at the end of the study compared to baseline.
However, the greatest difference occurred in the FSC 500/50 plus tiotropium group
[Cazzola, 2007]. Another recent study [Aaron, 2007] compared the effect of FSC 250/25
plus tiotropium, tiotropium plus salmeterol, and tiotropium plus placebo. The study was
not adequately powered to show a statistically significant difference among groups on the
primary endpoint of exacerbations. However, the FSC plus tiotropium group improved
lung function, hospitalizations for exacerbations and St. George’s Respiratory
Questionnaire (SGRQ) scores compared to tiotropium plus placebo. Of note, the
tiotropium plus salmeterol group did not improve these endpoints compared to tiotropium
plus placebo which suggests that dual bronchodilator therapy was no better than a single
bronchodilator in this study. This finding, along with the aforementioned studies
indicating the benefit of FSC versus the individual components alone, may indicate the
further benefit achieved when an ICS is added to bronchodilator therapy compared to
dual bronchodilatory therapy alone. A recent GlaxoSmithKline (GSK) study
[Singh, 2008] examined the effect of FSC 500/50 plus tiotropium compared with either
treatment alone. This study showed that the triple therapy was superior to either agent
alone in area under the curve (AUC)0-4hr spirometry, specific airway conductance
(sGAW) and specific airway resistance (sRAW) at 14 days and other lung function
measurements as well as improvement in symptomatic endpoints such as the Transition
Dyspnea Index (TDI) and the use of rescue medication.
Of note, the triple combination studies mentioned above all showed statistically
significant differences with triple combination therapy on a variety of lung function and
symptomatic endpoints in COPD. In addition, the patient populations in these studies
ranged from moderate (FEV1 ≤75% predicted normal) to severe (FEV1 <50% predicted
normal) indicating that a wide range of COPD severities do benefit from triple
combination therapy compared to dual or single bronchodilator therapy alone. However,
larger and adequately powered studies are needed to confirm these results.
The addition of FSC 250/50 to tiotropium may also indirectly improve other endpoints
which are considered exploratory for this study. It has been well-documented that
patients with COPD have co-morbidities such as depression and anxiety which adds to
the economic burden associated with COPD [Mannino, 2007]. Recent guidelines
[GOLD, 2007] suggest that these comorbidities are frequent in COPD patients and should
be actively identified. These co-morbidities are associated with poorer survival and
quality of life [Ng, 2007]. Furthermore, studies in COPD have shown significant
associations between depression and physical symptoms of COPD such as dyspnea
[Katon, 2007]. In addition, one study found that treatment with an antidepressant
decreased comorbid depression in COPD but had no effect on physical symptoms such as
dyspnea and lung function [Borson, 1992]. A non-pharmacological, non-antidepressant
treatment (pulmonary rehabilitation) also resulted in improvement in depression, anxiety,
and dyspnea in COPD patients [Diaz, 2007].
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We hypothesize that improving respiratory symptoms in COPD with the addition of a
pharmacological regimen of FSC 250/50 plus tiotropium may also lead to an
improvement in those subjects who demonstrate depression and/or anxiety as assessed by
validated psychometric questionnaires.
The purpose of this study is to evaluate the effects on lung function and quality of life
with FSC 250/50 plus tiotropium compared with tiotropium plus placebo. In addition,
these treatments will be evaluated to determine their effect on the exploratory endpoints
of depression and anxiety. The aim is to examine the effect of the 250/50 strength of
FSC which is the only approved dosage for COPD treatment in the US plus tiotropium
compared with tiotropium plus placebo. The results of this study may support the use of
triple therapy in COPD patients to augment the benefits of tiotropium alone.
2.
STUDY OBJECTIVE(S)
The primary objective was to evaluate the effectiveness and safety of FSC 250/50mcg
plus tiotropium 18mcg compared to tiotropium 18mcg alone in patients with COPD.
3.
INVESTIGATORS AND STUDY ADMINISTRATIVE
STRUCTURE
This was a multi-center study. Thirty-three centers in the United States (US) enrolled at
least one subject. The first subject was enrolled on 01Dec2008, and the last subject
completed the study on 08Dec2009.
There was no steering committee or independent data monitoring board for this study.
Two external advisors including
and
advised on the design of the study.
Centralized spirometry services were provided by
US.
4.
INVESTIGATIONAL PLAN
4.1.
Study Design
This was a multicenter, randomized, double-blind, parallel group study. Subjects
completed a 4-week run-in period in which open-label tiotropium only was given.
Albuterol was supplied as rescue medication during run-in and throughout the rest of the
study. Following run-in, only subjects who had an modified Medical Research Council
(mMRC) dyspnea scale score of ≥2 were eligible for randomization. The run-in period
was followed by a 24 week treatment period. Subjects were randomized 1:1 to open-label
tiotropium 18mcg once-daily plus double-blind FSC 250/50 mcg BID or open-label
tiotropium 18mcg once daily plus double-blind matching Placebo DISKUS BID.
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There were a total of 6 study visits Screening, Randomization, and after 4, 8, 16, and 24
weeks of treatment. A follow-up phone contact for collection of adverse event (AE) and
pregnancy (if applicable) information was conducted approximately 14 days following
the last study visit. Study completion was defined as completion of the follow-up phone
call.
The magnitude of bronchodilator response to FSC DISKUS 250/50 is generally larger in
subjects with COPD who demonstrate FEV1 reversibility to albuterol compared with nonreversible subjects [Hanania, 2003]. Therefore, the treatment groups were stratified by
albuterol reversibility assessed at Visit 1 to ensure the proportion of reversible to nonreversible subjects is similar across groups.
Supplementary study conduct information not mandated to be present in the protocol was
provided in the accompanying Study Procedures Manual (SPM). The SPM provided the
site personnel with administrative and detailed technical information that did not impact
subject safety.
4.2.
Discussion of Study Design
Both tiotropium and FSC 250/50 are approved as maintenance treatment for
bronchospasm associated with COPD. No placebo group was chosen as the value of addon therapy (FSC 250/50) to an existing therapy (tiotropium) was assessed. The 18mcg
dose is the only approved dose of tiotropium. While a few studies have been conducted
combining tiotropium with FSC500/50, no studies have been conducted with the 250/50
dose of FSC which is the only dose currently approved for COPD in the US. The 6
month duration of treatment is consistent with other studies and allows enough of a
treatment period to evaluate the effects of FSC 250/50 added to tiotropium therapy
compared with tiotropium alone.
4.3.
Protocol Amendment(s)
There were no protocol amendments for this study.
4.4.
Selection of Study Population
4.4.1.
Inclusion/Exclusion Criteria
The study inclusion and exclusion criteria were chosen to identify subjects with an age
and smoking history consistent with COPD. In addition, since one objective was to study
the effects of triple therapy across a wide range of disease severities (especially GOLD
stage II), the post-bronchodilator FEV1 criteria was ≥40% to ≤80% percent predicted.
Subjects also had to have a confirmed diagnosis of COPD. Exclusion criteria included
potential confounders such as other respiratory disorders other than COPD.
In addition, two randomization criteria were required. One of these was that prior to
randomization, subjects had to have an mMRC score of ≥2 indicating at least a moderate
degree of dyspnea. This was to ensure that after 4 weeks of treatment on open-label
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Tiotropium only, the patients were severe enough (at least in terms of dyspnea) to
warrant potential randomization to triple therapy. The other randomization criterion was
that patients could not have experienced a COPD exacerbation or respiratory tract
infection that required treatment with antibiotics, systemic corticosteroids, or
hospitalization during the run-in period (including Visit 2). This criterion was to ensure
that subjects were stable enough to enter the study.
4.4.2.
Withdrawal Criteria
Reasons for subject withdrawal from the study included the following: AE, lost-to follow
up, lack of efficacy, protocol violation, non-compliance, subject decided to withdraw
from the study, Investigator decision, or other.
The reason for subject withdrawal was recorded in the electronic Case Report Form
(eCRF) and study source documents.
Study drug should not have been discontinued for >14 days. If a subject discontinued use
of blinded study medication for >14 consecutive days or had a calculated compliance to
study medication of <75.0% at any study visit, the study sponsor/site monitor must have
been contacted to discuss subject eligibility for continued participation in the study.
Subjects prematurely withdrawn from the study were not replaced.
Any female who became pregnant during the study was withdrawn.
4.5.
Treatments
4.5.1.
Investigational Product(s) and Reference Therapy
The following double-blind study medication was used in this study:
•
Fluticasone propionate/salmeterol 250/50mcg per inhalation via DISKUS
(formulated with lactose) twice-daily
•
Matching Placebo DISKUS (formulated with lactose) DISKUS one inhalation twicedaily
The following open-label study medication was used in this study:
•
Tiotropium Bromide (18mcg) per inhalation via the HandiHaler device once-daily
Double-blind study medication was manufactured by GSK. Clinical Trial Supplies of
GSK Research and Development provided the FSC 250/50 DISKUS and Placebo
DISKUS. Sites were supplied with Spiriva (Tiotropium Bromide Inhalation Powder)
HandiHaler 18mcg manufactured by Boehringer Ingelheim (Ingelheim, Germany).
All subjects received albuterol as relief medication. GSK Clinical Trial Supplies
provided each investigative site with a bulk supply of albuterol Metered Dose Inhaler
(MDI) and nebules.
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Each subject was instructed to self administer blinded study drug during the double-blind
treatment period as follows:
•
Each morning (approximately 6-9AM) take 1 inhalation from the DISKUS followed
by 1 inhalation from the Spiriva HandiHaler Device. Each evening (approximately
6-9PM), approximately 12 hours after morning dosing with the DISKUS, take 1
inhalation from the DISKUS
In order to obtain accurate pre-dose FEV1 assessments, subjects were instructed to
withhold their morning dose of study drug at study Visits 3, 4, 5, and 6 corresponding to
weeks 4, 8, 16, and 24 respectively. The first dose of study drug was administered in the
clinic at Visit 2, and the morning dose of study drug was administered in the clinic for all
other visits (Visits 3 through 6) following completion of pre-dose pulmonary function
tests. Study visits must have been re-scheduled if the subjects did not withhold their
morning dose of study drug.
Subjects recorded the total number of inhalations administered from the DISKUS and
HandiHaler each day in their diary card.
All subjects received supplemental albuterol as relief medication. Albuterol must have
been withheld for at least 6 hours prior to all visits. If a subject had taken albuterol
within 6 hours prior to a visit, the visit must have been rescheduled.
4.5.2.
Treatment Assignment
After obtaining written informed consent and completing at least one additional screening
procedure [including making any change in subject medication use (e.g., drug washout)],
a unique subject identifier was assigned for each subject and was used to identify
individual subjects during the course of the study.
Subjects were assigned to study treatment in accordance with a randomization schedule.
This study utilized an interactive voice recognition service (IVRS) which provided a
means for central allocation of drug. Each Investigator was supplied with sufficient
supplies to conduct the trial. Additional treatment packs were supplied as needed to the
sites. Each subject was assigned a unique randomization number. Once a randomization
number had been assigned it was not re-assigned.
All study medication was supplied by GSK. After all appropriate regulatory and ethical
approval documents had been received and approved by GSK, study medication was sent
to the site.
Subjects were stratified based on FEV1 reversibility to albuterol. Within each stratum
(reversible or non-reversible), subjects were randomly assigned to FSC 250/50 DISKUS
twice daily plus tiotropium once-daily or Placebo DISKUS twice-daily plus tiotropium
once-daily at a ratio of 1:1.
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Blinding
The investigator or treating physician may have unblinded a subject’s treatment
assignment only in the case of an emergency, when knowledge of the study treatment
was essential for the appropriate clinical management or welfare of the subject.
Whenever possible, the investigator must have first discussed options with the GSK
Medical Monitor or appropriate GSK study personnel before unblinding the subject’s
treatment assignment. If this was impractical, the investigator must have notified GSK as
soon as possible, but without revealing the treatment assignment of the unblinded subject,
unless that information was important for the safety of subjects currently in the study.
The date and reason for the unblinding must have been recorded in the appropriate data
collection tool.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may have unblinded
the treatment assignment for any subject with a Serious Adverse Event (SAE). If the
SAE required that an expedited regulatory report be sent to one or more regulatory
agencies, a copy of the report, identifying the subject’s treatment assignment, may have
been sent to clinical investigators in accordance with local regulations and/or GSK
policy.
If a subject’s treatment assignment was unblinded, the subject must have been
prematurely discontinued from the study.
4.5.4.
Prior and Concomitant Medications and Non-Drug Therapies
All COPD medications taken ≤ 30 days prior to Visit 1 were recorded in the eCRF.
All concomitant medications (COPD and other) taken during the study were recorded in
the eCRF. The minimum requirements were that drug name and the dates of
administration were to be recorded.
4.5.4.1.
Permitted Medications
•
Inhaled albuterol
•
Systemic corticosteroids for the acute treatment of a COPD exacerbation not to
exceed 10 days
•
Systemic corticosteroids for non-respiratory-related medical treatment; however,
GSK or designee must have been notified if this occurred to determine subject
eligibility
•
Systemic antibiotics for treatment of a COPD exacerbation or treatment of an upper
or lower respiratory tract infection not to exceed 10 days
•
Systemic antibiotics for non-respiratory related medical treatment
•
Antihistamines, nasal decongestants and/or other intranasal medications including
intranasal corticosteroids for the treatment of rhinitis
•
Leukotriene modifiers/ receptor antagonists
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•
Beta-blocker eye drops
•
Systemic beta-blockers were allowed for those subjects who had been on a stable
regimen for at least 30 days prior to Visit 1 and judged capable to continue this
regimen until discharged from the study. Initiation of systemic beta-blocker
medications within 30 days prior to Visit 1 and during the study was not allowed.
•
Immunotherapy for the treatment of allergies provided that the subject had received a
constant dose for 30 days prior to Visit 1 and the dose was maintained during the
study
•
Treatment for smoking cessation
•
Mucolytics
•
Flu shots
•
Monoamine oxidase inhibitors and tricyclic antidepressants were permitted but
should have been used with extreme caution as these may potentiate the effects of
fluticasone/salmeterol 250/50 or salmeterol on the vascular system.
Participation in a pulmonary rehabilitation program was permitted provided subjects had
not begun or discontinued enrolment in a pulmonary rehabilitation program within 60
days of Visit 1 or during the study. Subjects who were enrolled in a pulmonary
rehabilitation program at study start should have maintained participation in the program
for the duration of the study.
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4.5.4.2.
Prohibited Medications and Non-Drug Therapies
The following medications were not permitted during the study and must not have been
taken for the indicated times prior to Visit 1 (Screening):
Medication
Exclusion Period
Ritonavir (Norvir)
No use at any time during the study
Long-acting beta-agonist/inhaled corticosteroid
compounds (e.g., ADVAIR or Symbicort)
30 days prior to Visit 1 and no use at
any time during the study
Inhaled corticosteroids
30 days prior to Visit 1 and no use at
any time during the study
Oral or parenteral corticosteroids
30 days prior to Visit 1 and no use
during the study except for treatment of
COPD exacerbations
Any Investigational drug
30 days prior to Visit 1 and no use at
any time during the study
Theophylline preparations
48 hours prior to Visit 1 and no use at
any time during the study
Tiotropium
48 hours prior to Visit 1 and no use at
any time during the study
Salmeterol and formoterol
24 hours prior to Visit 1 and no use
during the study
Oral beta-agonists
12 hours prior to Visit 1 and no use
during the study
Ipratropium and ipratropium/albuterol combination
products (e.g., Atrovent or Combivent)
6 hours prior to Visit 1 and no use during
the study
Initiation of systemic beta-blocker medications within 30 days prior to Visit 1 was not
allowed.
Use of nocturnal positive pressure devices [e.g., continuous positive airway pressure or
bi-level positive airway pressure] was not allowed.
Long-term oxygen therapy (LTOT) was not allowed.
If a prohibited medication was used by a study subject, the study Sponsor must have been
contacted to discuss the subject’s eligibility for continued participation in the study.
4.5.5.
Compliance
Treatment compliance with blinded study drug was evaluated at Visits 3, 4, 5, and 6.
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Treatment compliance with the study HandiHaler and DISKUS was determined by
dividing total number of inhalations recorded in the subject diary card by the total
number of inhalations prescribed X 100.
Study drug should not have been discontinued for greater than 14 consecutive days. If a
subject discontinued use of blinded study drug for >14 consecutive days or had a
calculated compliance to study drug of <75.0% at any study visit, the study Sponsor must
have been contacted to discuss subject eligibility for continued participation in the study.
4.6.
Study Assessments and Procedures
The Time and Events Table is provided in Table 1.
Table 1
Time and Events Table
Procedures
Screen/
Run-in
Randomization
Week
Visit
Written Informed
Consent1
Subject Demography
Medical History/Smoking
History
Smoking Status
Medication History2
Concomitant Medication
Review
Physical Examination
Chest x-ray or review3
ECG4
Inclusion/Exclusion
Criteria
Albuterol Reversibility
Issue Diary Card
Collect/Review Diary
Card
Issue Albuterol
MMRC5
Efficacy Assessments
CRQ-SAS6
QIDS6
HADS6
Pre/Post-Dose PFTs
Trough IC
Safety Assessments
Adverse Events
Serious Adverse Events
Incidence/Type of
Pneumonia7
Visit 1
Double-Blind Treatment
Early
Withdrawal
Week
4
Visit
3
Week
8
Visit 4
Week
16
Visit
5
Week
24
Visit
6
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Visit 2
Followup
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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x
x
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Procedures
Screen/
Run-in
Randomization
Week
Visit
Visit 1
Laboratory
Assessments
PGx Sampling8
Visit 2
Double-Blind Treatment
Week
4
Visit
3
Week
8
Visit 4
Week
16
Visit
5
Early
Withdrawal
Followup
Week
24
Visit
6
PGx sample to be taken any time after obtaining the PGx informed consent and
after randomization. It is recommended that the PGx sample be collected at
Visit 3
x
x
x
x
x
x
Pregnancy Test
x
Investigational product
Dispense Invest.
x
x
x
x
Product.
Collect Invest. Product
x
x
x
x
x
Assess Invest. Product
x
x
x
x
x
compliance
IVRS9
x
x
x
x
x
x
x
x
Review DISKUS and
x
x
x
x
x
HandiHaler Inhalation
Technique
Follow-up phone call10
X
1. Written informed consent for study participation was obtained before performing any study procedures or making
any study-related changes in subject medication use.
2. Recorded all COPD medications used ≤ 30 days prior to Visit 1
3. Chest X-ray must have been taken if a subject has not had one within 6 months of Visit 1
4. The Investigator determined the clinical significance of any ECG abnormality and determine if a subject is
precluded from entering the study
5. Subjects must have had a score of ≥2 on the MMRC at Visit 2 to be eligible for randomization.
6. Questionnaires must have been completed prior to any other study assessments.
7. Pneumonia diagnosis must have been confirmed by chest x-ray.
8. A separate pharmacogenetics (PGx) specific written informed consent must been obtained before PGx sampling.
9. Subjects were randomized to blinded study drug using a telephone based IVRS system (RAMOS) which will be
used by the investigator or designate to register the subject, randomize the subject and provide medication
assignment information.
10. The follow-up phone contact was for collection of post-treatment AE and pregnancy information
4.6.1.
Efficacy Assessment
4.6.2.
Primary Efficacy Measure
The primary efficacy measure was AM pre-dose FEV1 at Endpoint.
4.6.3.
Secondary Efficacy Measures
Secondary efficacy measures were as follows:
•
2 hour post-dose FEV1 at Endpoint
•
AM Pre-dose FVC at Endpoint
•
2 hour post-dose FVC at Endpoint
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•
AM Pre-Dose IC at Endpoint
•
Scores on the CRQ-SAS at Endpoint
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Other Efficacy Measures
Other efficacy measures were as follows:
•
Supplemental albuterol use
•
Rate of HCU for COPD exacerbations (i.e., use of systemic corticosteroids and/or
antibiotics, unscheduled or urgent care physician /clinic office visits, and/or
emergency room visits)
•
HCU (i.e., hospitalization) for COPD
4.6.5.
Exploratory Efficacy Measures
Exploratory efficacy measures were as follows:
•
Scores on the QIDS-SR scale
•
Scores on the HADS
4.6.6.
Safety Assessments
Safety assessments included the following:
•
Type and incidence of adverse events (AEs)
•
Type and incidence of pneumonia
4.7.
Data Management
This study used Phase Forward’s InForm system. InForm is a web-based clinical trials
data management system that provides investigational sites a standardised and validated,
remote, electronic data capture system for the collection of clinical trial data. Activities
performed using InForm include data entry, modification, review and validation. Each
activity performed carries a unique user identification code and a date-time stamp.
InForm training for this study was provided to site staff at the Investigator meeting.
Study-specific Electronic Case Report Form (eCRF) training for the monitors was
provided prior to the Investigator meeting by GSK Data Management. Additionally, an
InForm interactive training database was available to site staff and study monitors for
independent follow-up training.
The application was fully validated using test data, prior to distributing the url for site
use.
Encrypted clinical trial data was transmitted from the site via the internet to a firewallprotected network server, and then via an application server into the clinical database
(e.g., InForm puts data into a shared drive).
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An electronic audit trail of all changes made to the eCRF was kept within the InForm
system. This audit trail identified the user making the change by userid, and date and time
of change.
Pre-defined data validation checks were run within the eCRF as the data were entered and
submitted by authorised site staff. The resulting data queries were then resolved.
Additional queries were generated within the eCRF by authorized GSK staff as a result of
data review (e.g., source document review, external data reconciliation).
In addition to InForm eCRF data, electronic spirometry data was delivered to GSK by an
external vendor. Also in addition to InForm eCRF data, paper diary and questionnaire
data were delivered by and external vendor. This data was validated and reconciled with
the eCRF data.
Adverse events and concomitant medications were coded by the autoencoder using
company standard dictionaries (GSK Drug) and industry standard dictionaries
(MedDRA).
Serious adverse event (SAE) data were documented according to standard GSK practice
in the GSK standard InForm eCRF. Upon submission of the SAE entry, a systemgenerated e-mail was sent to the GSK GCSP department to facilitate rapid reporting as
outlined in the study protocol.
The principal investigator electronically signed and dated each InForm casebook attesting
to his/her responsibility for the quality of all data included therein, and that the data
represented a complete and accurate record of each subject's participation in the study. At
the end of the study once all data queries were resolved, a compact disk-read only
memory (CD-ROM) containing eCRF portable document formats (PDFs-the PDF
contained all of the patient's eCRF data, the data queries, and a copy of the audit trail)
was sent to the site along with a letter explaining how to view the data on the PDF. Upon
delivery of the CD-ROM, the study site notified GSK of receipt of the CD.
After data management procedures were completed the database was released on
18FEB2010. Following release the database was frozen on 25FEB2010.
The original validated data (eCRFs, etc.) will be archived according to company standard
procedures.
4.8.
Statistical Analyses
Full details of all statistical analyses conducted for this study are provided in the
Reporting and Analysis Plan (RAP).
The study was powered to demonstrate superiority of FSC250/50 plus tiotropium over
tiotropium in pre-dose FEV1 change from baseline at Endpoint. Data from a 24-week
GSK COPD study (SFCA3007) indicated that a reasonable estimate of the standard
deviation of change in AM pre-dose FEV1 is 250 mL. It was estimated that 133 subjects
per treatment group would provide 90% power for detection of a significant difference of
100 mL in pre-dose FEV1 change from baseline at Endpoint between the two treatment
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groups based on a two-sample two-sided t-test with a significance level of 0.05.
Approximately 350 subjects were to be randomized to allow for a 30% study withdrawal
rate.
The primary analysis population was the ITT population which included all subjects
randomized to double-blind study drug. The Screen Failure population included all
subjects screened for inclusion in the study but were discontinued from the study at
Screening (Visit 1). The Run-In Failure population included all subjects screened for
inclusion in the study but were discontinued from the study after screening and prior to
randomization to blinded study drug at Visit 2. Adverse events and reasons for study
withdrawal were summarized for these populations. The Safety population included all
subjects screened in the study (screen failures, run-in failures and randomized subjects)
and was used for summarizing subject disposition and SAEs. One subgroup was defined
for analysis: subjects with baseline FEV1 predicted values >50%. Demographics,
background disease characteristics and efficacy endpoints were summarized for this
subgroup.
Statistical tests of all efficacy measures were two-sided alternative hypothesis tests
conducted at the 0.05 significance level. For interpretation of results and to control
overall type I error rate, step-down principles for testing of efficacy measures were
implemented. The primary efficacy measure acted as gatekeeper for analysis of the
secondary efficacy measures. Other efficacy measures were also nested under a
secondary efficacy measure and the secondary efficacy measure served as a gatekeeper
for the other measures. Additionally, the Hochberg method was used at the 0.05
significance level to control the type I error rate across the secondary efficacy measures.
The primary efficacy analysis was mean change from baseline in pre-dose FEV1
compared between the two treatment groups at Endpoint. Endpoint was defined as the
last scheduled measurement of pre-dose FEV1 during the 24-week treatment period (from
Visits 3-6, Weeks 4, 8, 16 and 24, respectively) and baseline was defined as the pre-dose
FEV1 measure from Visit 2 (Randomization). An Analysis of Covariance (ANCOVA)
model with terms for treatment group, pooled investigator, reversibility stratum and
baseline was used to test statistical differences between treatment groups in pre-dose
FEV1 mean change from baseline at Endpoint. Treatment group differences from the
ANCOVA model were presented as least squares means and standard errors with the
corresponding 95% confidence intervals. Treatment group differences were also
summarized for each clinic visit.
Secondary efficacy measures were pre-dose FVC and IC, 2-hour post-dose FEV1 and
FVC, and CRQ-SAS scores. Other efficacy measures were supplemental albuterol use
and HCU for COPD exacerbations and were nested under the secondary efficacy measure
of pre-dose IC. Exploratory measures were QIDS-SR and HADS scores.
The secondary efficacy measures of 2-hour post-dose FEV1 and FVC and pre-dose FVC
and IC were compared between treatment groups in the same manner as pre-dose FEV1.
CRQ-SAS domain change from baseline scores were compared between treatment groups
with an ANCOVA model with terms for treatment group, pooled investigator,
reversibility stratum and baseline scores. The primary analysis of the CRQ-SAS was at
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Endpoint (last questionnaire collected during the 24-week treatment period or at Early
Withdrawal). Baseline CRQ-SAS scores were the assessments from Visit 2
(Randomization).
Supplemental albuterol use was compared between treatment groups using ANCOVA
with terms for treatment group, pooled investigator, reversibility stratum and baseline in
the model. Mean change from baseline values for the overall 24-week treatment period,
each 4-week treatment period interval and Endpoint were compared. Endpoint was the
primary analysis time point and was defined as the last week of the treatment period for
which a subject provided data. Baseline week was determined from the 7-day period
immediately prior to Randomization (Visit 2).
The analysis of COPD exacerbations compared the rate of exacerbations per subject per
the 24-week treatment period between treatment groups. The protocol and RAP specified
use of a negative binomial regression model as it was assumed that the exacerbation data
would be overdispersed. (Poisson modeled data are overdispersed if the variance exceeds
the mean). However, analysis of the exacerbation data showed that this model could not
be used as the data were underdispersed. (Poisson modeled data are underdispersed if the
variance is less than the mean). The negative binomial distribution differs from the
Poisson distribution in that it includes a dispersion parameter that must be ≥ 0. (The
negative binomial distribution approaches a Poisson distribution as the dispersion
parameter approaches 0). Underdispersion would require a negative value of the
dispersion parameter, which is not possible. Therefore, a Poisson regression model with
generalized estimating equations to account for underdispersion was used for analysis of
the COPD exacerbations. The model included terms for treatment group, pooled
investigator, reversibility stratum and baseline severity (baseline FEV1 percent
predicted), with log (time of treatment) as an offset variable. Healthcare utilization was
summarized by treatment group in terms of the frequency of healthcare contacts
(physician office visits, urgent care visits, emergency room visits and hospitalizations) as
related to exacerbations during the 24-week study.
QIDS-SR scores and HADS anxiety and depression scores were summarized in the same
manner as the CRQ-SAS. The QIDS-SR and HADS were summarized for the ITT
population as well as for subjects meeting depression criteria (score of ≥6 indicating at
least mild disease state at baseline) as determined by the QIDS-SR scale and depression
and anxiety criteria (scores of ≥8 indicating at least mild disease state at baseline) as
determined by the HADS depression and anxiety scales, respectively.
The proportion of subjects reporting AEs was tabulated for each treatment group by
MedDRA system organ class and preferred term. All AEs occurring during the study,
AEs leading to study withdrawal, drug-related AEs, SAEs and pneumonia AEs were
summarized.
Statistical programming was performed in a UNIX environment using SAS Version 9.1.
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5.
STUDY POPULATION RESULTS
5.1.
Subject Disposition
A total of 33 investigative sites enrolled at least one subject. Enrollment by site ranged
from 1 (<1%) to 37 (11%) subjects (Table 5.1). A total of 342 subjects were enrolled of
whom 264 (77%) completed the study. A total of 78 subjects (23%) did not complete all
procedures and were considered prematurely withdrawn from the study (Table 5.2). A
listing of study withdrawals is provided in Table 5.18. The treatmentblind was not
broken for any subject (Table 5.19). A summary of subject disposition is provided in
Table 2.
Table 2
Summary of Subject Disposition
Completion Status, n (%)
Completed
Withdrawn
Primary reason for withdrawal, n (%)
Adverse event
Lack of efficacy
Protocol deviation
Lost to follow-up
Investigator discretion
Withdrew consent
Missing
FSC + Tio
N=173
Tio
N=169
Total
N=342
137 (79)
36 (21)
127 (75)
42 (25)
264 (77)
78 (23)
12 (7)
0
10 (6)
8 (5)
2 (1)
4 (2)
0
10 (6)
1 (<1)
10 (6)
5 (3)
3 (2)
13 (8)
0
22 (6)
1 (<1)
20 (6)
13 (4)
5 (1)
17 (5)
0
Data Source: Table 5.2
5.2.
Protocol Deviations
Protocol deviations including inclusion/exclusion criteria deviations are shown in
Table 5.3, Table 5.4, and Table 3; a listing of subjects with these deviations is shown in
Table 5.20 and Table 5.21, respectively. A total of 16 (5%) subjects had any protocol
deviation. The most common deviation was the use of a prohibited medication. A total
of 1 (<1%) subject in the Tiotropium group had an inclusion criteria deviation.
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Table 3
Summary of Protocol Deviations
Any protocol deviation, n (%)
Inclusion criteria violation
Noncompliance with study drug
Use of prohibited medication
Inclusion criteria deviation, n (%)
Post-albuterol FEV1/FVC and FEV1 %
predicted
FSC + Tio
N=173
3 (2)
0
1 (<1)
2 (1)
0
Tio
N=169
13 (8)
1 (<1)
4 (2)
8 (5)
1 (<1)
Total
N=342
16 (5)
1 (<1)
5 (1)
10 (3)
1 (<1)
0
1 (<1)
1 (<1)
Data Source: Table 5.3 and Table 5.4
5.3.
Populations Analyzed
The primary analysis population was the ITT population which included all subjects
randomized to double-blinded study drug (342 [54%] subjects). The Screen Failure
population included all subjects screened for inclusion in the study but were discontinued
from the study at Screening (Visit 1). The Screen Failure population included 228 (36%)
subjects, and the most common reason for screen failure in this population was not
meeting inclusion/exclusion criteria (220 [96%] subjects). The most common eligibility
criterion not met in this population was the inclusion criterion of post-albuterol
FEV1/FVC and FEV1 percent predicted (207 [91%] subjects). The Run-In Failure
population included all subjects screened for inclusion in the study but were discontinued
from the study after screening and prior to randomization to blinded study drug at Visit 2
(63 [10%] subjects). The most common reason for run-in failure was AE (14 [22%]
subjects). Adverse events and reasons for study withdrawal were summarized for these
populations. The Safety population (633 subjects) included all subjects screened in the
study (screen failures, run-in failures and randomized subjects) and was used for
summarizing subject disposition and SAEs. A summary of analysis populations is
provided in Table 5.5., and a summary of inclusion/exclusion criteria not met for the
Screen Failure population is provided in Table 5.6 One subgroup was defined for
analysis: subjects with baseline FEV1 predicted values >50%. Demographics,
background disease characteristics, and efficacy endpoints were summarized for this
subgroup.
5.4.
Demographics and Baseline Characteristics
5.4.1.
Demographics
Demographic characteristics and race /racial combinations are provided in Table 5.7,
Table 5.8, and Table 5.9, and summarized in Table 4. Age was similar across the two
groups with a mean age of 61.3 and 61.0 years for the FSC + Tio and Tio groups,
respectively. There were slightly more males enrolled in the FSC + Tio group (50%)
compared with the Tio group (43%). Most of the subjects were of non-Hispanic/Latino
ethnicity (100% and >99%) in the FSC + Tio and Tio groups, respectively and White
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(95% and 96% in the FSC + Tio and Tio groups, respectively). A total of 4% of subjects
in each group were of African American/African heritage. Listings of individual
demographic characteristics and race are located in Table 5.22 and Table 5.23,
respectively.
Table 4
Demographic Characteristics
Age, yrs
Mean (Range)
Sex, Male, n %
Ethnicity, n %
Hispanic/Latino
Not Hispanic/Latino
Race, n %
African American/
African Heritage
American Indian or
Alaska Native
Asian
Native Hawaiian or other
Pacific Islander
White
FSC + Tio
N=173
Tio
N=169
Total
N=342
61.3 (41-80)
87 (50)
61.0 (40-84)
73 (43)
61.2 (40-84)
160 (47)
0
173 (100)
1 (<1)
168 (>99)
1 (<1)
341 (>99)
7 (4)
7 (4)
14 (4)
1 (<1)
0
0
0
1 (<1)
0
0
165 (95)
0
162 (96)
0
327 (96)
Data Source: Table 5.7 and Table 5.8
5.4.2.
Disease Characteristics
Disease characteristics are provided in Table 5.10 and summarized in Table 5. The mean
duration of COPD was for similar for the two groups (6.88 and 6.36 years in the FSC +
Tio and Tio groups, respectively). Over 50% of subjects had emphysema as the
predominant COPD type. Over 50% of subjects in each group were also current smokers
and had a similar mean pack-year smoking history. The majority of subjects in each
group did not have a COPD exacerbation in the past 12 months requiring hospitalization
(95% and 96% of subjects in the FSC + Tio and Tio groups, respectively. The majority
of subjects in each group also did not have a COPD exacerbation in the past 12 months
requiring OCS and/or antibiotics. However, a portion of subjects in each group did have
at least one COPD exacerbation in the past 12 months requiring OCS/antibiotics (32%
and 26% in the FSC + Tio and Tio groups, respectively). The mMRC scores were similar
between both groups (2.4 and 2.5 in the FSC + Tio and Tio groups, respectively).
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Table 5
Disease Characteristics
COPD Duration, yrs
Mean (Range)
COPD Type, n %
Chronic bronchitis
Emphysema
Both
Smoking Status, n %
Current smoker
Former smoker
Pack-Years
Mean
(Range)
COPD Exacerbations in the past 12 months
Requiring hospitalization
0
1
≥2
COPD Exacerbations in the past 12 months
Requiring OCS/antibiotic
0
1
2
≥3
mMRC Score
Mean
(Range)
FSC + Tio
N=173
Tio
N=169
Total
N=342
6.88 (0.1-35)
6.36 (0.1-29)
6.62 (0.1-35)
49 (29)
85 (50)
37 (22)
48 (28)
88 (52)
33 (20)
97 (29)
173 (51)
70 (21)
102 (59)
71 (41)
96 (57)
73 (43)
198 (58)
144 (42)
55.4
(10-192)
54.7
(10-175)
55.1
(10-192)
165 (95)
8 (5)
0
162 (96)
6 (4)
1 (<1)
327 (96)
14 (4)
1 (<1)
117 (68)
45 (26)
7 (4)
4 (2)
125 (74)
35 (21)
6 (4)
3 (2)
242 (71)
80 (23)
13 (4)
7 (2)
2.4
(1-4)
2.5
(2-4)
2.5
(1-4)
Data Source: Table 5.10
5.4.3.
Screening Pulmonary Function Tests
Pre- and post-bronchodilator FEV1 and FVC, post-bronchodilator FEV1/FVC ratios, and
reversibility for both treatment groups are provided in Table 5.11 and summarized in
Table 6. Mean pre- and post-bronchodilator FEV1 and FVC were similar between
groups. Mean post-bronchodilator FEV1 percent predicted values were 56.0% and 57.4%
for the FSC + Tio and Tio groups, respectively. The mean post-bronchodilator
FEV1/FVC ratios were 0.53 and 0.55 for the FSC + Tio and Tio groups, respectively.
The majority of subjects were nonreversible (63% and 64% in the FSC + Tio and Tio
groups, respectively).
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Table 6
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Summary of Screening Pulmonary Function Tests
FEV1
Pre-BD FEV1 L
Mean (Range)
Pre-BD FEV1 % predicted
Mean (Range)
Post-BD FEV1 L
Mean (Range)
Post-BD FEV1 % predicted
Mean (Range)
FVC
Pre-BD FVC, L
Mean (Range)
Post-BD FVC, L
Mean (Range)
Post-BD FEV1/FVC ratio
Mean (Range)
Nonreversible, n (%)
FSC + Tio
N=173
Tio
N=169
Total
N=342
1.50 (0.70-3.39)
1.54 (0.59-3.03)
1.52 (0.59-3.39)
49.9 (24-84)
52.2 (25-89)
51.1 (24-89)
1.67 (0.78-3.56)
1.70 (0.62-3.16)
1.69 (0.62-3.56)
56.0 (36-79)
57.4 (37-79)
56.7 (36-79)
2.89 (1.38-5.67)
2.89 (1.40-5.25)
2.89 (1.38-5.67)
3.16 (1.54-5.88)
3.12 (1.52-5.64)
3.14 (1.52-5.88)
0.53 (0.25-0.70)
109 (63)
0.55 (0.31-0.70)
108 (64)
0.54 (0.25-0.70)
217 (63)
Data Source: Table 5.11
5.4.4.
Current Medical Conditions
A total of 340 (>99%) subjects had any current medical condition. The most common
medical conditions across both treatment groups were musculoskeletal and connective
tissue disorders (69%), cardiac disorders (63%), gastrointestinal disorders (52%),
respiratory, thoracic and mediastinal disorders (46%), psychiatric disorders (44%), and
nervous system disorders (32%). All current medical conditions are provided in
Table 5.12.
5.5.
Prior and Concomitant Medications
5.5.1.
Prior COPD Medications
A total of 143 (83%) and 125 (74%) subjects in the FSC + Tio and Tio groups
respectively, took any prior COPD medication. The most common prior COPD
medications taken in the FSC + Tio and Tio groups, respectively, were salbutamol (55%
and 49%), tiotropium bromide (44% and 31%), and salmeterol xinafoate + fluticasone
propionate (13% and 7%). A summary of prior COPD medications is provided in
Table 5.13.
5.5.2.
COPD Concomitant Medications
A summary of COPD concomitant medications is provided in Table 5.14. A total of 25
(14%) and 32 (19%) subjects in the FSC + Tio and Tio groups used any concomitant
COPD medication. COPD concomitant medications reported for ≥5% of subjects in the
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FSC + Tio or Tio group, respectively were prednisone (8% and 11%), azithromycin (4%
and 5%), and salbutamol (2% and 5%). A summary of the relationship of medication
class, dictionary term, and verbatim text is provided in Table 5.24.
5.5.3.
Non-COPD Concomitant Medications
A summary of non-COPD concomitant medications is provided in Table 5.15. NonCOPD concomitant medications reported for ≥5% of subjects in any group are
summarized in Table 7.
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Table 7
Non-COPD Concomitant Medications for Greater than or equal to
Five Percent of Subjects in any group
Any medication, n %,
Nervous System, n %
Acetylsalicylic acid
Paracetamol
Ibuprofen
Parcetamol + hydrocodone bitartrate
Hydrocodone
Alprazolam
Lorazepam
Paroxetine hydrochloride
Tramadol
Zolpidem tartrate
Gabapentin
Trazodone
Alimentary Tract and Metabolism, n %
Vitamin NOS
Omeprazole
Esomeprazole magnesium
Ascorbic acid
Calcium
Pantoprazole
Vitamin D NOS
Tocopherol
Cardiovascular System, n %
Simvistatin
Linsinopril
Atorvastatin calcium
Hydrochlorothiazide
Atenolol
Furosemide
Fish oil
Rosuvastatin calcium
Omega -3 marine triglycerides
Muscoloskeletal System, n %
Naproxen sodium
Blood and Blood Forming Organs, n %
Clopidogrel bisulfate
Cyanocobalamin
Systemic Hormonal Preparations,
excluding Sex Hormones and Insulins, n %
Levothyroxine sodium
Levothyroxine
Data Source: Table 5.15
31
FSC + Tio
N=173
159 (92)
Tio
N=169
156 (92)
54 (31)
32 (18)
24 (14)
17 (10)
12 (7)
10 (6)
8 (5)
8 (5)
5 (3)
6 (3)
8 (5)
9 (5)
43 (25)
33 (20)
26 (15)
12 (7)
15 (9)
12 (7)
6 (4)
6 (4)
9 (5)
8 (5)
5 (3)
4 (2)
35 (20)
18 (10)
9 (5)
8 (5)
8 (5)
8 (5)
12 (7)
8 (5)
28 (17)
17 (10)
11 (7)
10 (6)
10 (6)
9 (5)
3 (2)
4 (2)
22 (13)
13 (8)
14 (8)
13 (8)
8 (5)
10 (6)
11 (6)
9 (5)
8 (5)
18 (11)
25 (15)
15 (9)
14 (8)
10 (6)
8 (5)
5 (3)
6 (4)
1 (<1)
9 (5)
8 (5)
7 (4)
9 (5)
11 (7)
2 (1)
8 (5)
3 (2)
9 (5)
8 (5)
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5.6.
Exposure and Treatment Compliance
5.6.1.
Exposure to Study Drug
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A summary of exposure to open-label Tiotropium and double-blind DISKUS is provided
in Table 5.16. Exposure to open-label Tiotropium was similar in both groups with a
mean of 173.8 days and 171.7 days for the FSC + Tio and Tio groups, respectively.
Exposure to double blind DISKUS was also similar in both groups with a mean exposure
of 146.4 and 144 days in the FSC + Tio and Tio groups, respectively. A listing of subject
exposure to double-blind study drug is provided in Table 5.25.
5.6.2.
Treatment Compliance
A summary of treatment compliance for the Tiotropium HandiHaler and DISKUS is
provided in Table 5.17. Tiotropium HandiHaler compliance was similar in both groups
with mean values of 98.6% and 98% in the FSC + Tio and Tio groups, respectively.
Compliance with the DISKUS device was also similar between groups with mean values
of 98.2% and 97.2% in the FSC + Tio group and Tio group, respectively.
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6.
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EFFICACY RESULTS
The primary efficacy endpoint was AM pre-dose FEV1 at Endpoint. Secondary
endpoints included 2 hour post-dose FEV1 at Endpoint, AM pre-dose FVC at Endpoint, 2
hour post-dose FVC at Endpoint, AM pre-dose IC at Endpoint, and domain scores on the
CRQ-SAS at Endpoint.
Other endpoints included supplemental albuterol use, rate of HCU for COPD
exacerbations (ie, use of systemic corticosteroids and/or antibiotics, unscheduled or
urgent care physician/clinic office visits, and/or emergency room visits), and HCU
(hospitalizations) for COPD exacerbations.
Exploratory endpoints included scores on the QIDS-SR and the HADS.
6.1.
AM Pre-Dose FEV1
The FSC + Tio group had a statistically significant increase from baseline AM pre-dose
FEV1 at Endpoint compared with the Tio group (LS mean difference of 115 mL,
p<0.001). The FSC + Tio group also resulted in statistically significant improvements on
this Endpoint compared to the Tio group at Weeks 4, 8, 16, and 24, Table 6.1 A
summary of these results are provided in Table 8 and displayed graphically in Figure 1.
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Table 8
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AM Pre-Dose FEV1
Mean BL FEV1
n
Mean, mL (SE)
Endpoint
n
Mean, mL (SE)
Change from BL
n
Mean, mL (SE)
LS Mean Difference, (SE)
p value
Week 4
LS Mean Difference, (SE)
p value
Week 8
LS Mean Difference, (SE)
p value
Week 16
LS Mean Difference, (SE)
p value
Week 24
LS Mean Difference, (SE)
p value
FSC + Tio
N=173
Tio
N=169
170
1597 (44.4)
168
1640 (42.3)
154
1695 (45.6)
155
1598 (44.7)
152
101 (21.8)
155
-16 (20.4)
115 (29.5)
<0.001
138 (25.5)
<0.001
128 (24.5)
<0.001
156 (28.1)
<0.001
108 (31.0)
<0.001
Data Source: Table 6.1
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Figure 1
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AM Pre-Dose FEV1
Data Source: Figure 6.1
Vertical bars represent standard errors
6.2.
2 Hour Post-Dose FEV1
The FSC + Tio group had a statistically significant increase from baseline 2 hour postdose FEV1 at Endpoint compared to the Tio group (LS mean difference of 154 mL,
p<0.001). The FSC + Tio group also resulted in statistically significant improvements on
this Endpoint compared to the Tio group at Weeks 4, 8, 16, and 24, Table 6.2. A
summary of these results are provided in Table 9 and displayed graphically in Figure 2.
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Table 9
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2 Hour Post-Dose FEV1
Mean BL FEV1
n
Mean, mL (SE)
Endpoint
n
Mean, mL (SE)
Change from BL
n
Mean, mL (SE)
LS Mean Difference, (SE)
p value
Week 4
LS Mean Difference, (SE)
p value
Week 8
LS Mean Difference, (SE)
p value
Week 16
LS Mean Difference, (SE)
p value
Week 24
LS Mean Difference, (SE)
p value
FSC + Tio
N=173
Tio
N=169
170
1597 (44.4)
168
1640 (42.3)
154
1829 (44.8)
154
1690 (45.5)
152
233 (23.1)
154
77 (20.6)
154 (30.1)
<0.001
158 (26.4)
<0.001
131 (26.6)
<0.001
178 (28.4)
<0.001
140 (32.7)
<0.001
Data Source: Table 6.2
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Figure 2
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2 Hour Post-Dose FEV1
Data Source: Figure 6.2
Vertical bars represent standard errors
6.3.
AM Pre-Dose FVC
The FSC + Tio group had a statistically significant increase from baseline in pre-dose
FVC at Endpoint compared to the Tio group (LS mean difference of 122 mL, p=0.006).
The FSC + Tio group also resulted in statistically significant improvements on this
Endpoint compared to the Tio group at Weeks 4, 8, 16, and 24, Table 6.3. A summary of
these results are provided in Table 10 and displayed graphically in Figure 3.
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Table 10
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Pre-Dose FVC
Mean BL FEV1
n
Mean, mL (SE)
Endpoint
n
Mean, mL (SE)
Change from BL
n
Mean, mL (SE)
LS Mean Difference, (SE)
p value
Week 4
LS Mean Difference, (SE)
p value
Week 8
LS Mean Difference, (SE)
p value
Week 16
LS Mean Difference, (SE)
p value
Week 24
LS Mean Difference, (SE)
p value
FSC + Tio
N=173
Tio
N=169
170
3024 (66.8)
168
3019 (69.4)
154
3101 (70.8)
155
2959 (69.7)
152
95 (32.7)
155
-28 (30.6)
122 (44.0)
0.006
141 (38.2)
<0.001
113 (36.7)
0.002
181 (43.2)
<0.001
108 (47.5)
0.024
Data Source: Table 6.3
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Figure 3
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Pre-Dose FVC
Data Source: Figure 6.3
Vertical bars represent standard errors
6.4.
2 Hour Post-Dose FVC
The FSC + Tio group had a statistically significant increase from baseline in 2 hour postdose FVC at Endpoint compared to the Tio group (LS mean difference of 175 mL,
p<0.001). The FSC + Tio group also resulted in statistically significant improvements on
this Endpoint compared to the Tio group at Weeks 4, 8, 16, and 24, Table 6.4. A
summary of these results are provided in Table 11 and displayed graphically in Figure 4.
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Table 11
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2 Hour Post-Dose FVC
Mean BL FEV1
n
Mean, mL (SE)
Endpoint
n
Mean, mL (SE)
Change from BL
n
Mean, mL (SE)
LS Mean Difference, (SE)
p value
Week 4
LS Mean Difference, (SE)
p value
Week 8
LS Mean Difference, (SE)
p value
Week 16
LS Mean Difference, (SE)
p value
Week 24
LS Mean Difference, (SE)
p value
FSC + Tio
N=173
Tio
N=169
170
3024 (66.8)
168
3019 (69.4)
154
3273 (71.8)
154
3072 (72.4)
152
265 (35.9)
154
87 (31.2)
175 (46.4)
<0.001
178 (40.2)
<0.001
117 (39.7)
0.004
237 (46.2)
<0.001
151 (50.9)
0.003
Data Source: Table 6.4
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Figure 4
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2 Hour Post-Dose FVC
Data Source: Figure 6.4
Vertical bars represent standard errors
6.5.
AM Pre-Dose IC
The FSC + Tio group had a statistically significant increase from baseline in AM predose IC at Endpoint compared to the Tio group (LS mean difference of 141 mL,
p<0.001). The FSC + Tio group also resulted in statistically significant improvements on
this Endpoint compared to the Tio group at Weeks 4, 8, 16, and 24, Table 6.5. A
summary of these results are provided in Table 12 and displayed graphically in Figure 5.
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Table 12
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AM Pre-Dose IC
Mean BL FEV1
n
Mean, mL (SE)
Endpoint
n
Mean, mL (SE)
Change from BL
n
Mean, mL (SE)
LS Mean Difference, (SE)
p value
Week 4
LS Mean Difference, (SE)
p value
Week 8
LS Mean Difference, (SE)
p value
Week 16
LS Mean Difference, (SE)
p value
Week 24
LS Mean Difference, (SE)
p value
FSC + Tio
N=173
Tio
N=169
169
2233 (52.2)
167
2240 (52.4)
154
2327 (59.5)
156
2180 (53.5)
151
107 (28.4)
154
-8 (28.1)
141 (41.0)
<0.001
151 (37.7)
<0.001
96 (41.8)
0.022
128 (43.3)
0.003
132 (44.9)
0.004
Data Source: Table 6.5
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Figure 5
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AM Pre-Dose IC
Data Source: Figure 6.5
Vertical bars represent standard errors
6.6.
CRQ-SAS Domain Scores
A summary of CRQ-SAS scores is provided in Table 6.6 and summarized in Table 13.
Scores on each domain ranged from 1 (maximum impairment) to 7 (no impairment). The
Minimal Clinically Important Difference (MCID) is 0.5 for each domain. Baseline scores
on each domain (mastery, fatigue, emotional function, and dyspnea) indicated mild
impairment in each group. However, there were no statistically significant changes on
any domain score between the two groups.
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Table 13
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CRQ-SAS Domain Scores
Mastery
n
BL Mean Score (SE)
Endpoint
n
Mean Score (SE)
Change from BL
n
Mean Score (SE)
LS Mean Difference, (SE)
p value
Fatigue
n
BL Mean Score (SE)
Endpoint
n
Mean Score (SE)
Change from BL
n
Mean Score (SE)
LS Mean Difference, (SE)
p value
Emotional Function
n
BL Mean Score (SE)
Endpoint
n
Mean Score (SE)
Change from BL
n
Mean Score (SE)
LS Mean Difference, (SE)
p value
Dyspnea
n
BL Mean Score (SE)
Endpoint
n
Mean Score (SE)
Change from BL
n
Mean Score (SE)
LS Mean Difference, (SE)
FSC + Tio
N=173
Tio
N=169
171
4.98 (0.107)
167
5.05 (0.107)
163
5.23 (0.115)
165
5.09 (0.107)
162
0.28 (0.078)
164
0.04 (0.090)
0.20 (0.112)
0.069
171
3.91 (0.095)
167
3.82 (0.103)
163
4.10 (0.114)
165
3.97 (0.108)
162
0.23 (0.094)
164
0.17 (0.091)
0.09 (0.123)
0.470
171
4.59 (0.100)
167
4.56 (0.101)
163
4.81 (0.103)
165
4.71 (0.102)
162
0.24 (0.072)
164
0.16 (0.073)
0.08 (0.096)
0.394
171
4.72 (0.109)
167
4.66 (0.111)
162
4.88 (0.115)
165
4.85 (0.115)
161
0.21 (0.091)
164
0.19 (0.091)
0.02 (0.119)
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FSC + Tio
N=173
p value
0.879
Tio
N=169
Data Source: Table 6.6
6.7.
Albuterol Use
Mean baseline values for albuterol use were 2.3 puffs/day in both the FSC + Tio and Tio
groups. At Endpoint, albuterol use was reduced to 1.8 puffs/day in the FSC + Tio group
and increased to 2.4 puffs/day in the Tio group with a LS mean difference (SE) of -0.6
(0.24), p=0.010. Albuterol use was statistically significantly reduced in the FSC + Tio
group compared to the Tio group when evaluated over 1-24 weeks and over 4 week
periods throughout the study except at Weeks 17-20 when the difference between groups
was not statistically significant. A summary of supplemental albuterol use is provided in
Table 6.7.
6.8.
HCU for COPD Exacerbations
There were 25 (14%) and 26 (15%) subjects in the FSC + Tio and Tio groups who
experienced 26 and 30 exacerbations, respectively (Table 6.8). The primary cause of the
exacerbations in both groups was tobacco smoke (Table 6.8). The mean exacerbation rate
was 0.14 and 0.17 in the FSC + Tio and Tio groups, respectively, p=0.531 (Table 6.9).
The rate of HCU for exacerbations could not be calculated due to the low number of
events in each group. A summary of HCU for exacerbations is summarized in Table 6.10
and Table 14. Most of the exacerbations resulted in 1 office visit (20 [77%] and 18
[60%]) in the FSC + Tio and Tio groups, respectively. One exacerbation in the FSC +
Tio group resulted in a 4 day stay in the general ward of the hospital. Three
exacerbations in the Tio group resulted in a general ward hospital stay of 3 days or
longer. A listing of subjects with COPD exacerbations is provided in Table 6.11.
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Table 14
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HCU for COPD Exacerbations
FSC + Tio
N=173
Subjects with an exacerbation, n (%)
Exacerbations, n
Office visits, n %
0
1
2
≥3
Urgent care visits, n %
0
1
≥2
ER visits, n %
0
1
≥2
Days in general ward, n %
0
1
2
3
4
5
6
≥7
Days in ICU, n %
0
≥1
Tio
N=169
25 (14)
26
26 (15)
30
3 (12)
20 (77)
3 (12)
0
7 (23)
18 (60)
4 (13)
1 (3)
25 (96)
1 (4)
0
27 (90)
3 (10)
0
26 (100)
0
0
26 (87)
4 (13)
0
24 (96)
0
0
0
1 (4)
0
0
0
26 (90)
0
0
1 (3)
1 (3)
0
0
1 (3)
26 (100)
0
29 (100)
0
Data Source: Table 6.10
6.9.
QIDS-SR
A summary of scores on the QIDS-SR is provided in Table 6.12 and summarized in
Table 15. There were no statistically significant differences between groups on the
QIDS-SR scores at Endpoint (LS mean difference of 0.0 and SE of 0.37, p=0.947). A
total of 70 and 71 subjects in the FSC + Tio and Tio groups, respectively, met the criteria
of having at least mild depression (score of ≥6 at baseline). When the analysis was
performed with subjects who met the criteria of at least mild depression at baseline, there
was also no statistically significant difference between groups, p=0.681, Table 6.13.
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Table 15
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Scores on the QIDS-SR
QIDS-SR
n
BL Mean Score (SE)
Endpoint
n
Mean Score (SE)
Change from BL
n
Mean Score (SE)
LS Mean Difference, (SE)
p value
FSC + Tio
N=173
Tio
N=169
163
5.9 (0.31)
155
6.6 (0.38)
152
6.2 (0.35)
157
6.8 (0.37)
144
0.3 (0.28)
145
0.1 (0.28)
0.0 (0.37)
0.947
Data Source: Table 6.12
6.10.
HADS
A summary of scores on the HADS is provided in Table 6.14 and summarized in
Table 16. There were no statistically significant differences between groups on the
HADS depression scale at Endpoint (LS mean difference of -0.1 and SE of 0.28,
p=0.789). A total of 35 and 40 subjects in the FSC + Tio and Tio groups, respectively,
met the criteria of having at least mild depression on the HADS (score of ≥8 at baseline).
When the analysis was performed with subjects who met the criteria of at least mild
depression at baseline, there was also no statistically significant difference between
groups, p=1.000, Table 6.15.
There were no statistically significant differences between groups on the HADS anxiety
scale at Endpoint (LS mean difference of 0.3 and SE of 0.32, p=0.438, Table 6.14). A
total of 42 and 49 subjects in the FSC + Tio and Tio groups, respectively, met the criteria
of having at least mild anxiety on the HADS (score of ≥8 at baseline). When the analysis
was performed with subjects who met the criteria of at least mild anxiety at baseline,
there was also no statistically significant difference between groups, p=0.564, Table 6.16.
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Table 16
HADS Depression and Anxiety Scale Scores
Depression Scale
n
BL Mean Score (SE)
Endpoint
n
Mean Score (SE)
Change from BL
n
Mean Score (SE)
LS Mean Difference, (SE)
p value
Anxiety Scale
n
BL Mean Score (SE)
Endpoint
n
Mean Score (SE)
Change from BL
n
Mean Score (SE)
LS Mean Difference, (SE)
p value
FSC + Tio
N=173
Tio
N=169
168
4.6 (0.29)
163
4.8 (0.30)
157
4.6 (0.31)
163
4.8 (0.31)
154
-0.1 (0.22)
158
-0.1 (0.19)
-0.1 (0.28)
0.789
169
4.9 (0.31)
164
5.5 (0.33)
155
5.1 (0.34)
161
5.1 (0.35)
153
-0.0 (0.26)
158
-0.4 (0.23)
0.3 (0.32)
0.438
Data Source: Table 6.14
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7.
SAFETY RESULTS
7.1.
Adverse Events
7.1.1.
Run-In
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A summary of all of the AEs that occurred in the Run-In Failure population (ie, subjects
not randomized) is provided in Table 7.1. A total of 19 (30%) subjects experienced any
AE in this population. Two events (bronchitis and COPD) occurred in 5% of this
population. All other events occurred in 2% of subjects.
A summary of all AEs that occurred during Run-In in the ITT population is provided in
Table 7.2. The most common AE that occurred during Run-In was headache (3% and
4% of subjects in the FSC + Tio and Tio groups, respectively). All other AEs occurred in
≤2% of subjects.
7.1.2.
During Treatment
A summary of all AEs that occurred during treatment is provided in Table 7.3. A
summary of the most common AEs (>2% of subjects in either group) that occurred
during treatment is provided in Table 7.4 and summarized in Table 17. A total of 97
(56%) and 85 (50%) subjects in the FSC + Tio and Tio groups, respectively had any AE
during treatment. The most common AE during treatment in both groups was COPD
occurring in 14% of subjects in both treatment groups. A listing of all AEs is provided in
Table 7.10, and a listing of subjects numbers for individual AEs is provided in
Table 7.11. A listing of the relationship of AE System Organ Class (SOC), preferred
term, and verbatim text is provided in Table 7.12.
Table 17
Adverse Events Occurring in Greater than Two Percent of Subjects
in Any Group During Treatment
Any event n, %
Chronic obstructive pulmonary disease
Headache
Back pain
Nasopharyngitis
Oropharyngeal pain
Bronchitis
Oral candidiasis
Dyspnea
Data Source: Table 7.4
49
FSC + Tio
N=173
97 (56)
Tio
N=169
85 (50)
24 (14)
11 (6)
5 (3)
5 (3)
6 (3)
6 (3)
5 (3)
0
24 (14)
9 (5)
9 (5)
6 (4)
4 (2)
3 (2)
1 (<1)
5 (3)
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7.1.3.
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Summary of Drug-Related Adverse Events Post Randomization
A summary of drug-related AEs that occurred post-randomization (includes all AEs that
occurred after randomization through the follow-up period) is provided in Table 7.5. A
total of 21 (12%) and 12 (7%) subjects in the FSC + Tio and Tio groups, respectively,
had an AE that was considered related to study drug by the Investigator. The most
common drug-related AE in the FSC + Tio group was oral candidiasis experienced by 5
(3%) subjects. All other drug-related AEs in the FSC + Tio group were experienced by
≤2% of subjects. In the Tio group, the most common drug-related AE was cough
experienced by 2 (1%) subjects. All other drug-related AEs in the Tio group were
experienced by <1% of subjects.
7.1.4.
Adverse Events Leading to Withdrawal from the Study
A summary of AEs leading to withdrawal from the study is provided in Table 7.6. A
total of 12 (7%) and 10 (6%) subjects in the FSC + Tio and Tio groups, respectively, had
an AE leading to study withdrawal. The most common AE leading to study withdrawal
in both groups was COPD which occurred in 3 (2%) subjects in each group. All other
AEs leading to study withdrawal occurred in <1% of subjects in each group. A listing of
AEs leading to withdrawal is provided in Table 7.13.
7.1.5.
Post-Treatment
A summary of all AEs occurring post-treatment (after the last dose of study drug) is
provided in Table 7.7. A total of 8 (5%) subjects in each group had an AE that occurred
post-treatment. The most common AE that occurred post-treatment in the FSC + Tio
group was nasopharyngitis occurring in 2 (1%) subjects. All other AEs occurring posttreatment in the FSC + Tio group occurred in <1% of subjects. In the Tio group, the
most common AE occurring post-treatment was COPD in 3 (2%) subjects. All other AEs
occurring post-treatment in the Tio group occurred in ≤1% of subjects.
7.2.
Serious and Other Significant Adverse Events
7.2.1.
Deaths
A listing of fatal SAEs is provided in Table 7.14. There was one death in the study.
This section has been excluded to protect patient privacy
A case narrative for this event is provided in Section 11.
7.2.2.
Other Serious Adverse Events
A summary of SAEs occurring post-randomization is provided in Table 7.8, and a listing
of non-fatal SAEs is provided in Table 7.15. A total of 7 (4%) and 13 (8%) subjects in
the FSC + Tio and Tio groups, respectively experienced an SAE. The most frequent SAE
was COPD occurring in 5 (3%) subjects in the Tio group. All other SAEs occurred in
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<1% of subjects in each group. Case narratives for all non-fatal SAEs are provided in
Section 11.
7.2.3.
Other Significant Adverse Events
A summary of pneumonia AEs occurring post-randomization is provided in Table 7.9
and summarized in Table 18. Listings of pneumonia AEs, pneumonia chest x-rays,
pneumonia chest x-rays with cultures and clinical findings, and a listing of pneumonia
chest x-rays with treatment and outcomes are provided in Table 7.16, Table 7.17,
Table 7.18, and Table 7.19, respectively.
Two subjects in the FSC + Tio group experienced a pneumonia during treatment.
This section has been excluded to protect patient privacy
The event was considered moderate but not serious, and the event resolved.
The study drug was not changed, and the subject continued in the study. A chest x-ray
was performed. Although no infiltrates or other notable findings were recorded, the chest
x-ray diagnosis was listed as “pneumonia.” Culture results were not obtained. The
subject was treated with a quinolone for the pneumonia.
This section has been excluded to protect patient privacy
The event was considered moderate but not serious, and the
event resolved. The study drug was not changed, and the subject continued in the study.
A chest x-ray was inadvertently not done in error by the site. The subject was treated
with a cephalosporin for the pneumonia.
Table 18
Pneumonia Adverse Events Post-Randomization
FSC + Tio
N=173
2 (1)
1 (<1)
1 (<1)
Any event n, %
Pneumonia
Pneumonia bacterial
Tio
N=169
0
0
0
Data Source: Table 7.9
Two subjects randomized to the FSC + Tio group each experienced an episode of
pneumonia during the run-in period (Table 7.16).
7.3.
Other Safety Evaluations
7.4.
Medical Device Incidents, Near-Incidents, Malfunctions and
Remedial Action
No medical device(s) manufactured or marketed, by GSK or by a third party for GSK,
were used in this study.
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7.5.
Pregnancies
There were no pregnancies reported during the conduct of this study (Table 7.20).
8.
SUBANALYSIS OF >50% FEV1 PREDICTED AT
BASELINE POPULATION RESULTS
A sub-analysis was performed on subjects with an FEV1 >50% predicted at baseline. A
total of 104 and 107 subjects in the FSC + Tio and Tio groups met this criterion,
respectively. Demographic and baseline characteristics as well as primary and all
secondary endpoints were summarized in this population.
8.1.
Demographic and Baseline Characteristics
Demographic characteristics and race /racial combinations are provided in Table 8.1 and
Table 8.2, and summarized in Table 19. Age was similar across the two groups with a
mean age of 59.9 and 60.6 years for the FSC + Tio and Tio groups, respectively. There
were more males enrolled in the FSC + Tio group (53%) compared to the Tio group
(43%). Most of the subjects were of non-Hispanic/Latino ethnicity (100% and >99%) in
the FSC + Tio and Tio groups, respectively and White (93% and 96% in the FSC + Tio
and Tio groups, respectively). A total of 6% and 4% of subjects in the FSC + Tio and
Tio groups were of African American/African heritage. These demographic
characteristics are similar to those for the ITT population.
Table 19
Demographic Characteristics [>50% FEV1 at Baseline Population]
Age, yrs
Mean (Range)
Sex, Male, n %
Ethnicity, n %
Hispanic/Latino
Not Hispanic/Latino
Race, n %
African American/
African Heritage
American Indian or
Alaska Native
Asian
Native Hawaiian or other
Pacific Islander
White
FSC + Tio
N=104
Tio
N=107
Total
N=211
59.9 (41-79)
55 (53)
60.6 (40-82)
46 (43)
60.3 (40-82)
101 (48)
0
104 (100)
1 (<1)
106 (>99)
1 (<1)
210 (>99)
6 (6)
4 (4)
10 (5)
1 (<1)
0
0
0
1 (<1)
0
0
97 (93)
0
103 (96)
0
200 (95)
Data Source: Table 8.1 and Table 8.2
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8.2.
Disease Characteristics
Disease characteristics are provided in Table 8.3 and summarized in Table 20. The mean
duration of COPD was for similar for the two groups (6.94 and 6.40 years in the FSC +
Tio and Tio groups, respectively). Over half of the subjects in each group had
emphysema as the predominant COPD type, and >60% of subjects in each group were
current smokers. Each group also had a >50 pack-year smoking history. The majority of
subjects in each group did not have a COPD exacerbation in the past 12 months requiring
hospitalization (95% and 97% of subjects in the FSC + Tio and Tio groups, respectively).
The majority of subjects in each group also did not have a COPD exacerbation in the past
12 months requiring OCS and/or antibiotics. However, a portion of subjects in each
group did have at least one COPD exacerbation in the past 12 months requiring
OCS/antibiotics (33% and 21% in the FSC + Tio and Tio groups, respectively). The
mean mMRC scores were similar between both groups (2.4 and 2.5 in the FSC + Tio and
Tio groups, respectively). These disease characteristics are similar to those of the ITT
population.
Table 20
Disease Characteristics [>50% FEV1 at Baseline Population]
COPD Duration, yrs
Mean (Range)
COPD Type, n %
Chronic bronchitis
Emphysema
Both
Smoking Status, n %
Current smoker
Former smoker
Pack-Years
Mean
(Range)
COPD Exacerbations in the past 12
months
Requiring hospitalization
0
1
≥2
COPD Exacerbations in the past 12
months
Requiring OCS/antibiotic
0
1
2
≥3
mMRC Score
Mean
(Range)
FSC + Tio
N=104
Tio
N=107
Total
N=211
6.94 (0.135.0)
6.40 (0.2-29.0)
6.66 (0.1-35.0)
30 (29)
57 (55)
16 (16)
31 (29)
56 (52)
20 (19)
61 (29)
113 (54)
36 (17)
69 (66)
35 (34)
64 (60)
43 (40)
133 (63)
78 (37)
53.9
(11-192)
53.0
(10-175)
53.5
(10-192)
99 (95)
5 (5)
0
104 (97)
2 (2)
1 (<1)
203 (96)
7 (3)
1 (<1)
70 (67)
28 (27)
4 (4)
2 (2)
85 (79)
18 (17)
2 (2)
2 (2)
155 (73)
46 (22)
6 (3)
4 (2)
2.4
(1-4)
2.5
(2-4)
2.5
(1-4)
Data Source: Table 8.3
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8.3.
Screening Pulmonary Function Tests (PFTs)
Pre- and post-bronchodilator FEV1 and FVC, post-bronchodilator FEV1/FVC ratios, and
reversibility for both treatment groups are provided in Table 8.4 and summarized in
Table 21. Mean screening pre- and post-bronchodilator FEV1 and FVC were similar
between groups. Mean post-bronchodilator FEV1 percent predicted values were 61.1%
and 62.5% for the FSC + Tio and Tio groups, respectively. The mean postbronchodilator FEV1/FVC ratio was 0.57 in both groups. The majority of subjects were
nonreversible (62% and 68% in the FSC + Tio and Tio groups, respectively). These
screening PFTs were similar to those of the ITT population. As expected, the mean postbronchodilator FEV1 percent predicted values were slightly higher than for the ITT
population.
Table 21
Summary of Screening Pulmonary Function Tests [>50% FEV1 at
Baseline Population]
FEV1
Pre-BD FEV1 L
Mean (Range)
Pre-BD FEV1 % predicted
Mean (Range)
Post-BD FEV1 L
Mean (Range)
Post-BD FEV1 % predicted
Mean (Range)
FVC
Pre-BD FVC, L
Mean (Range)
Post-BD FVC, L
Mean (Range)
Post-BD FEV1/FVC ratio
Mean (Range)
Nonreversible, n (%)
FSC + Tio
N=104
Tio
N=107
Total
N=211
1.69 (0.76-3.39)
1.72 (0.76-3.03)
1.70 (0.76-3.39)
55.1 (34-84)
57.8 (34-89)
56.5 (34-89)
1.87 (0.82-3.56)
1.86 (0.87-3.16)
1.86 (0.82-3.56)
61.1 (45-79)
62.5 (39-79)
61.8 (39-79)
3.08 (1.38-5.67)
3.07 (1.40-5.25)
3.08 (1.38-5.67)
3.30 (1.54-5.88)
3.27 (1.52-5.64)
3.28 (1.52-5.88)
0.57 (0.37-0.70)
64 (62)
0.57 (0.37-0.70)
73 (68)
0.57 (0.37-0.70)
137 (65)
Data Source: Table 8.4
8.3.1.
Efficacy
8.3.1.1.
AM Pre-Dose FEV1
There was no statistically significant difference between the two subgroups on AM predose FEV1 at Endpoint (LS mean diff of 50 mL, p=0.178, Table 8.5).
8.3.1.2.
2 Hour Post-Dose FEV1
The FSC + Tio group had a statistically significant increase from baseline 2 hour postdose FEV1 at Endpoint compared to the Tio group (LS mean difference of 82 mL,
p=0.026). The FSC + Tio group also resulted in statistically significant improvements on
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this Endpoint compared to the Tio group at Weeks 4, 8, and 16 but not at Week 24. A
summary of these results are provided in Table 8.6 and Table 22.
Table 22
2 Hour Post-Dose FEV1 [>50% FEV1 at Baseline Population]
Mean BL FEV1
n
Mean, mL (SE)
Endpoint
n
Mean, mL (SE)
Change from BL
n
Mean, mL (SE)
LS Mean Difference, (SE)
p value
Week 4
LS Mean Difference, (SE)
p value
Week 8
LS Mean Difference, (SE)
p value
Week 16
LS Mean Difference, (SE)
p value
Week 24
LS Mean Difference, (SE)
p value
FSC + Tio
N=104
Tio
N=107
104
1873 (54.1)
107
1865 (48.8)
93
2005 (59.3)
97
1887 (55.7)
93
145 (27.1)
97
54 (25.3)
82 (36.6)
0.026
119 (32.9)
<0.001
89 (33.7)
0.009
129 (33.9)
<0.001
68 (39.8)
0.092
Data Source: Table 8.6
8.3.1.3.
Pre-Dose FVC
There was no statistically significant difference between the two subgroups on pre-dose
FVC at Endpoint (LS mean difference of 40 mL, p=0.431, Table 8.7).
8.3.1.4.
2 Hour Post-Dose FVC
There was no statistically significant difference between the two subgroups on 2 hour
post-dose FVC at Endpoint (LS mean difference of 84 mL, p=0.081, Table 8.8).
8.3.1.5.
Pre-Dose IC
There was no statistically significant difference between the two subgroups on pre-dose
IC at Endpoint (LS mean difference of 53 mL, p=0.286, Table 8.9).
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8.3.1.6.
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CRQ-SAS Domain Scores
There were no statistically significant differences between the two subgroups on each
domain of the CRQ-SAS at Endpoint: (mastery: LS mean difference of 0.07, p=0.623;
fatigue: LS mean difference of -0.18, p=0.257; emotional function: LS mean difference
of -0.01, p=0.942; and dyspnea: LS mean difference of -0.11, p=0.501, Table 8.10).
56
CONFIDENTIAL
9.
DISCUSSION AND CONCLUSIONS
9.1.
Discussion
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This was an interventional study designed to examine the efficacy and safety of triple
therapy with FSC + Tiotropium compared with Tiotropium alone. Triple therapy was
statistically superior to Tiotropium monotherapy on a variety of lung function endpoints
including pre-dose FEV1, 2 hour post-dose FEV1, pre-dose FVC, 2 hour post-dose FVC,
and pre-dose IC. These results are in agreement with previous studies showing
improvements in lung function with FSC 500/50 + Tiotropium on lung function
[Cazzola, 2007; Aaron, 2007]. However, this was the first study examining the effect of
the FSC 250/50 dose (which is the only approved dose of FSC in the U.S.) + Tiotropium
on endpoints in COPD patients.
The effect of triple therapy with FSC 250/50 + Tiotropium compared with Tiotropium
alone was also examined on a variety of other endpoints impacting quality of life (QOL).
The CRQ-SAS is a widely used QOL questionnaire in COPD and is similar in reliability,
validity, and response to bronchodilation as the SGRQ [Rutten-van Molken, 1999].
However, there were no differences between treatments on any of the four domain scores
on this questionnaire. Interestingly, baseline scores on each domain revealed mild
impairment in both treatment groups perhaps explaining the lack of treatment effect.
However, triple therapy did result in a statistically significant reduction of rescue
albuterol use of -0.6 puffs/day. Baseline and endpoint mean albuterol use did not change
at all (-0.0 puffs/day) in the Tiotropium only group suggesting that triple therapy does
have a positive impact on this aspect of COPD patients’ daily living.
COPD exacerbations negatively impact patients’ quality of life and represent a significant
healthcare burden [Seemungal, 1998]. This study examined the effect of HCU for
exacerbations to determine if triple therapy could positively reduce the rate of HCU for
exacerbations. However, in this study, there were too few COPD exacerbations in each
group to calculate rates of HCU (26 and 30 exacerbations in the FSC + Tio and Tio
groups, respectively).
Since depression and anxiety are frequent co-morbid conditions with COPD
[Mannino, 2007], the effect of triple therapy was examined on these endpoints via
commonly used questionnaires for depression and depression/anxiety, the QIDS-SR and
HADS, respectively. The triple therapy group did not differ statistically on either of
these endpoints compared with Tiotropium alone. This could be explained by the fact
that the baseline mean scores of the ITT population indicated patients in either group did
not have depression or anxiety as measured by these scales. When a sub-analysis of
patients who had baseline scores on these scales indicating at least mild depression and/or
anxiety was performed, statistical significance between the two groups was still not
reached. The number of patients in each group meeting the baseline score of depression
and/or anxiety was low in each group.
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One unique aspect of this study was the patient population of a post-bronchodilator FEV1
percent predicted of ≥40 to ≤80%. Most of the previous studies examining the effect of
triple therapy with FSC + Tio recruited patients with severe disease. In one triple therapy
study examining the effect of Budesonide/Formoterol plus Tiotropium compared to
Tiotropium [Welte, 2009], the patient population was ≤50% FEV1 percent predicted but
at least 25% of the patients were GOLD stage II [<80% FEV1 percent predicted]. It has
been suggested [Antoniu, 2010] that while the benefits of triple therapy have been proven
irrespective of disease severity, the effects of triple therapy should be evaluated in
subjects with less advanced COPD. In the current study, the mean post-BD FEV1 percent
predicted was 56.0% and 57.4% in the FSC + Tio and Tio groups, respectively,
indicating a GOLD stage II population. The improvements, especially on lung function
endpoints, observed with triple therapy in this moderate disease population suggest that
initiating triple therapy earlier in the disease may confer greater benefit. In the current
study, approximately 68% of patients were GOLD stage II.
A sub-analysis of patients with a post-BD FEV1 >50% did not demonstrate statistically
significant differences on the lung function endpoints of AM pre-dose FEV1, AM predose FVC, 2 hour post-dose FVC, or IC. However, triple therapy did statistically
improve 2 hour post-dose FEV1 by 82 mLs indicating a benefit on lung function in this
moderate population.
Triple therapy was well-tolerated and posed no significant safety risks. FSC is known to
increase the risk of pneumonia [ADVAIR Prescribing Information, 2009]. However,
only 2 patients developed pneumonia in the FSC + Tio group, and both events resolved
with the subjects continuing in the study. Two subjects developed pneumonia
randomized to the FSC + Tio group but both events occurred during the run-in phase
while the patients were only on open-label Tiotropium therapy; thus, these two
pneumonia events could not be attributed to FSC.
In summary, triple therapy with FSC + Tio resulted in improved lung function compared
with Tiotropium alone in a moderate disease population. Quality of life and other
endpoints affecting quality of life (depression and anxiety) were not improved with a
triple therapy regimen, but these patients had little to mild impairment on quality of life
measures upon study entry. Further research is need to determine the particular patient
characteristics that may benefit most from triple therapy including specific responder
analyses for the endpoints in this study.
9.2.
Conclusions
•
Triple therapy with FSC + Tio resulted in statistically significant improvements on
various lung function measures including AM pre-dose FEV1, 2 hour post-dose
FEV1, AM pre-dose FVC, 2 hour post-dose FVC, and pre-dose IC compared to
Tiotropium alone.
•
There were no statistically significant differences between groups on any domain
score of the CRQ-SAS.
•
Triple therapy with FSC + Tio resulted in a statistically significant reduction in
albuterol use compared with Tiotropium alone.
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•
The number of COPD exacerbations in each group was low; thus, rate of HCU for
COPD exacerbations could not be calculated.
•
There were no statistically significant differences between groups on depression or
depression/anxiety measured via the QIDS-SR and HADS, respectively.
•
Triple therapy was well-tolerated and did not result in any significant safety risks.
59
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10.
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REFERENCES
Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M,
O'Donnell D, Mclvor A, Sharma S, Bishop G, Anthony J, Cowie R, field S, Hirsch A,
Hernandez P, Rivington R, Road J, Hoffstein V, Hodder R, Marciniuk D, McCormack D,
Fox G, Cox G, Prins HB, Ford G, Bleskie D, Doucette S, Mayers I, Chapman K, Zamel
N, FitzGerald M, for the Canadian Thoracic Society/Canadian Respiratory Clinical
Research Consortium. Tiotropium in Combination with Placebo, Salmeterol, or
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ADVAIR (Fluticasone Propionate/Salmeterol) Prescribing Information, April, 2009
Andersson F, Borg S, Jansson SA, Jonsson AC, Ericsson A, Prutz C, Ronmark E,
Lundback B. The Costs of Exacerbations in Chronic Obstructive Pulmonary Disease.
Respir Med. 2002;96:700-708.
Antoniu SA, Carone M, Sampablo I. Triple inhaled therapy in stable chronic obstructive
disease: the earlier, the better? Expert Opin Pharmacother. 2010;11:1039-1042.
Anzueto A. Clinical Course of Chronic Obstructive Pulmonary Disease: Review of
Therapeutic Interventions. Am. J. Med. 2006;119:S46-S53.
Anzueto A, Ferguson GT, Feldman G, Chinsky K, Seibert A, Emmett A, Knobil K,
O'Dell D, Kalberg C, Crater G. Effect of fluticasone propionate/salmeterol (250/50) on
COPD exacerbations and impact on patient outcomes. J COPD. 2009;6:320-329.
Borson S, McDonald GJ, Gayle T, Deffebach M, Lakshminarayan S, VanTuinen C.
Improvement in Mood, Physical Symptoms, and Function with Nortriptyline for
Depression in Patients with Chronic Obstructive Pulmonary Disease. Psychosomatics.
1992;33:190-201.
Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C.
Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary
disease: a randomized controlled trial. Lancet. 2003;361:449-456.
Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates J,
Vestbo J, for the TORCH Investigators. Salmeterol and Fluticasone Propionate and
Survival in Chronic Obstructive Pulmonary Disease. New Engl J Med. 2007;356:775789.
Casaburi R, Mahler DA, Jones PW, Wanner A, San Pedro GS, ZuWallack RL, Menjoge
SS, Serby CW, Witek Jr T. A Long-Term Evaluation of Once-Daily Inhaled Tiotropium
in Chronic Obstructive Pulmonary Disease. Eur Respir J. 2002;19:217-224.
Cazzola M, Ando F, Santus P, Ruggeri P, Di Marco F, Sanduzzi A, D'Amato M. A pilot
study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium
on the airflow obstruction of patients with severe-to-very severe COPD. Pulm.
Pharmacol. Ther. 2007;20:556-561.
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Diaz PD, Montes de Oca M, Lopez JM, Celli BR. Pulmonary Rehabilitation Improves
Depression, Anxiety, Dyspnea, and Health Status in Patients with COPD. Am J Phys Med
Rehabil. 2007;86:30-36.
Ferguson GT, Anzueto A, Fei R, Emmett A, Knobil K, Kalberg C. Effect of fluticasone
propionate/salmeterol (250/50 mcg) or salmeterol (50 mcg) on COPD exacerbations.
Respir Med. 2008;102:1099-1108.
GOLD (Global Strategy for the Diagnosis, Management, and Prevention of COPD,
Global Initiative for Chronic Obstructive Lung Disease), 2007. Available from
http://www.goldcopd.org.
Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, Shah T. The Efficacy
and Safety of Fluticasone Propionate (250mcg)/Salmeterol(50mcg) Combined in the
DISKUS Inhaler for the Treatment of COPD. Chest. 2003;124:834-843.
Katon W, Lin EHB, Kroenke K. The Association of Depression and Anxiety with
Medical Symptom Burden in Patients with Chronic Medical Illness. Gen Hosp Psych.
2007;29:147-155.
Mahler DA, Wire P, Horstmann D, Chang CN, Yates J, Fischer T, Shah T. Effectiveness
of Fluticasone Propionate and Salmeterol Combination Delivered via the DISKUS
Device in the Treatment of Chronic Obstructive Pulmonary Disease. Am J Respir Crit
Care Med. 2002;166:1084-1091.
Mannino DM, Braman S. The Epidemiology and Economics of Chronic Obstructive
Pulmonary Disease. Proc Am Throac Soc. 2007;4:502-506.
Ng TP, Niti M, Tan WC, Cao Z, Ong KC, Eng P. Depressive Symptoms and Chronic
Obstructive Pulmonary Disease: Effect on Mortality, Hospital Readmission, Symptom
Burden, Functional Status, and Quality of Life. Arch Intern Med. 2007;167:60-67.
Niewoehner DE, Rice K, Cote C, Paulson D, Cooper Jr A, Korducki L, Cassino C,
Kesten S. Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with
Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator. Ann Int Med.
2005;143:317-326.
Rutten-van Molken M, Roos Bianca, Van Noord JA. An empirical comparison of the St
George's Respiratory Questionnaire (SGRQ) and the Chronic Respiratory Disease
Questionnaire (CRQ) in a clinical trial setting. Thorax. 1999;54:995-1003.
Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of
Exacerbation on Quality of Life in Patients with Chronic Obstructive Pulmonary Disease.
Respir Crit Care Med. 1998:157;157:1418-1422.
Singh D, Brooks J, Hagan G, Cahn A, O'Connor BJ. Superiority of "triple" therapy with
salmeterol/fluticasone propionate and tiotropium bromide versus individual components
in moderate to severe COPD. Thorax. 2008;63:592-598.
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Spiriva (Tiotropium Bromide Inhalation Powder) Product Information. August, 2007.
Urbano FL, Pascual RM. Contemporary Issues in the Care of Patients with Chronic
Obstructive Pulmonary Disease. J. Manag Care Pharm. 2005;11 (suppl):S2-S13.
Welte T, Miravitlles M, Hernandez P, Eriksson G, Peterson S, Polanowski T, Kessler R.
Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with
chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;180:741-750.
62
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11.
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CASE NARRATIVES
This section contained patient narratives which are textual descriptions of medical history, treatment and
outcome for individual patients who experienced a clinically important adverse event including serious
adverse events during the trial. They have been excluded to protect patient privacy. This data may be
made available subject to an approved research proposal and a determination of the ability to provide
information from the specific narratives whilst protecting the patient’s privacy. For further information
please see the Patient Level Data section of the GSK Clincal Study Register.
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STUDY POPULATION DATA SOURCE TABLES
Page
Table 5.1 Summary of Enrollment by Investigator (Intent-to-Treat Population) . . . . .
Table 5.2 Summary of End of Study Record (Intent-to-Treat Population) . . . . . . . . .
Table 5.3 Summary of Protocol Deviations (Intent-to-Treat Population) . . . . . . . . . .
Table 5.4 Summary of Inclusion/Exclusion Criteria Deviations (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 5.5 Summary of Analysis Populations (Safety Population) . . . . . . . . . . . . . . .
Table 5.6 Summary of Inclusion/Exclusion Criteria Not Met (Screen Failure
Population) (Screen failure Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 5.7 Summary of Demographic Characteristics (Intent-to-Treat Population) . .
Table 5.8 Summary of Race and Racial Combinations (Intent-to-Treat Population) .
Table 5.9 Summary of Race and Racial Combination Details (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 5.10 Summary of Disease Characteristics (Intent-to-Treat Population) . . . . . .
Table 5.11 Summary of Screening Pulmonary Function Tests (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 5.12 Summary of Current Medical Conditions (Intent-to-Treat Population) . . .
Table 5.13 Summary of Prior COPD Medication Use (Intent-to-Treat Population) . .
Table 5.14 Summary of COPD Concomitant Medications (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 5.15 Summary of Non-COPD Concomitant Medications (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 5.16 Summary of Exposure to Study Drug (Intent-to-Treat Population) . . . . .
Table 5.17 Summary of Treatment Compliance (Intent-to-Treat Population) . . . . . .
Table 5.18 Listing of End of Study Record (Intent-to-Treat Population) . . . . . . . . . .
Table 5.19 Listing of Subjects for Whom the Treatment Blind was Broken
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 5.20 Listing of Protocol Deviations (Intent-to-Treat Population). . . . . . . . . . . .
Table 5.21 Listing of Subjects with Inclusion/Exclusion Criteria Deviations
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 5.22 Listing of Demographic Characteristics (Intent-to-Treat Population) . . . .
Table 5.23 Listing of Race (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . .
Table 5.24 Relationship of Medication Class, Dictionary Term and Verbatim Text
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 5.25 Listing of Exposure to Double-Blilnd Study Drug (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.1 Summary of Demographic Characteristics - Subjects >50% Predicted at
Baseline (Baseline FEV1 % Predicted>50% Population) . . . . . . . . . . . . . . . . . .
94
96
98
99
100
101
102
103
105
106
107
109
111
112
114
118
142
143
144
149
150
151
152
184
205
265
278
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Table 8.2 Summary of Race and Racial Combinations - Subjects >50% Predicted
at Baseline (Baseline FEV1 % Predicted>50% Population) . . . . . . . . . . . . . . . .
Table 8.3 Summary of Disease Characteristics - Subjects >50% Predicted at
Baseline (Baseline FEV1 % Predicted>50% Population) . . . . . . . . . . . . . . . . . .
Table 8.4 Summary of Screening Pulmonary Function Tests - Subjects >50%
Predicted at Baseline (Baseline FEV1 % Predicted>50% Population) . . . . . . . .
95
280
281
283
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 2
Table 5.1
Summary of Enrollment by Investigator
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CONFIDENTIAL
96
Country/
FSC250/50+Tio
Tiotropium
Total
Investigator (Centre ID)
(N=173)
(N=169)
(N=342)
-------------------------------------------------------------------------------------------------United States
All investigators
173 (100%)
169 (100%)
342 (100%)
1 (<1%)
1 (<1%)
2 (<1%)
3
(2%)
5
(3%)
8
(2%)
7
(4%)
8
(5%)
15
(4%)
7
(4%)
8
(5%)
15
(4%)
2
(1%)
2
(1%)
4
(1%)
10
(6%)
10
(6%)
20
(6%)
7
(4%)
7
(4%)
14
(4%)
9
(5%)
10
(6%)
19
(6%)
12
(7%)
12
(7%)
24
(7%)
6
(3%)
2
(1%)
8
(2%)
8
(5%)
6
(4%)
14
(4%)
2
(1%)
2
(1%)
4
(1%)
3
(2%)
3
(2%)
6
(2%)
3
(2%)
3
(2%)
6
(2%)
6
(3%)
7
(4%)
13
(4%)
0
2
(1%)
2 (<1%)
4
(2%)
6
(4%)
10
(3%)
1 (<1%)
1 (<1%)
2 (<1%)
2
(1%)
3
(2%)
5
(1%)
19 (11%)
18 (11%)
37 (11%)
3
(2%)
4
(2%)
7
(2%)
1 (<1%)
2
(1%)
3 (<1%)
4
(2%)
2
(1%)
6
(2%)
11
(6%)
12
(7%)
23
(7%)
10
(6%)
9
(5%)
19
(6%)
2
(1%)
0
2 (<1%)
7
(4%)
4
(2%)
11
(3%)
6
(3%)
6
(4%)
12
(4%)
5
(3%)
5
(3%)
10
(3%)
1 (<1%)
0
1 (<1%)
6
(3%)
3
(2%)
9
(3%)
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 2
Table 5.1
Summary of Enrollment by Investigator
Country/
FSC250/50+Tio
Tiotropium
Total
Investigator (Centre ID)
(N=173)
(N=169)
(N=342)
-------------------------------------------------------------------------------1 (<1%)
2
(1%)
3 (<1%)
4
(2%)
4
(2%)
8
(2%)
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Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 5.2
Summary of End of Study Record
FSC250/50+Tio Tiotropium
Total
(N=173)
(N=169)
(N=342)
----------------------------------------------------------------------------------------------Completion Status
Completed
137 (79%)
127 (75%)
264 (77%)
Prematurely withdrawn
36 (21%)
42 (25%)
78 (23%)
12
0
10
8
2
4
0
(7%)
(6%)
(5%)
(1%)
(2%)
10 (6%)
1 (<1%)
10 (6%)
5 (3%)
3 (2%)
13 (8%)
0
22 (6%)
1 (<1%)
20 (6%)
13 (4%)
5 (1%)
17 (5%)
0
98
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CONFIDENTIAL
Primary reason for withdrawal
Adverse event
Lack of efficacy
Protocol deviation
Lost to follow-up
Investigator discretion
Withdrew consent
Missing
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 5.3
Summary of Protocol Deviations
FSC250/50+Tio Tiotropium
Total
Protocol deviation
(N=173)
(N=169)
(N=342)
----------------------------------------------------------------------------------------------------------Any protocol deviation
3 (2%)
13 (8%)
16 (5%)
Inclusion criteria violation
Noncompliance with study drug
Use of prohibited medication
0
1 (<1%)
2 (1%)
1 (<1%)
4 (2%)
8 (5%)
1 (<1%)
5 (1%)
10 (3%)
CONFIDENTIAL
99
Subjects may have had more than one protocol deviation.
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Note:
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 5.4
Summary of Inclusion/Exclusion Criteria Deviations
FSC250/50+Tio Tiotropium
Total
Criterion
(N=173)
(N=169)
(N=342)
----------------------------------------------------------------------------------------------Any criteria deviations
0
1 (<1%)
1 (<1%)
Inclusion criteria
Post-albuterol FEV1/FVC and FEV1 % predicted
0
1 (<1%)
1 (<1%)
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Protocol: ADC111114
Population: Safety
Page 1 of 1
Table 5.5
Summary of Analysis Populations
Total
(N=633)
----------------------------------------------------------------------------------------------------------Safety population
633
Screen failure population
Reason for screen failure
228 (36%)
101
Run-in failure population
Reason for run-in failure
Sub-reason for run-in failure
220
0
1
0
1
1
5
(96%)
(<1%)
(<1%)
(<1%)
(2%)
63 (10%)
Missing
Adverse event
Lack of efficacy
Protocol deviation
Lost to follow-up
Investigator discretion
Withdrew consent
3
14
0
11
8
14
13
None
COPD exacerbation
57 (90%)
6 (10%)
Note: Percentages for screen failure reasons are based on the Screen failure population.
Percentages for run-in failure reasons are based on the Run-in failure population.
All other percentages are based on the Safety population.
20APR2010 07:41
(17%)
(13%)
(22%)
(21%)
342 (54%)
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Intent-to-Treat population
(5%)
(22%)
CONFIDENTIAL
Did not meet inclusion/exclusion criteria
Adverse event
Protocol deviation
Study closed/terminated
Lost to follow-up
Investigator discretion
Withdrew consent
Protocol: ADC111114
Population: Screen failure
Page 1 of 1
Table 5.6
Summary of Inclusion/Exclusion Criteria Not Met (Screen Failure Population)
Not Randomized
Criterion
(N=228)
------------------------------------------------------------------------------------------------------Any criteria deviations
226 (>99%)
Inclusion criteria
Informed consent
Established clinical history of COPD
Post-albuterol FEV1/FVC and FEV1 % predicted
(2%)
(<1%)
(91%)
1
1
3
3
1
3
1
2
(<1%)
(<1%)
(1%)
(1%)
(<1%)
(1%)
(<1%)
(<1%)
Exclusion criteria
Use of exclusionary medication
Previously diagnosed cancer
Clinically significant disease/abnormality
Respiratory disorder other than COPD
History of alcohol or drug abuse
Clinically significant abnormal 12-lead ECG
Clinically significant abnormal chest x-ray or CT scan
BMI >=40 kg/m^2
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102
4
2
207
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 2
Table 5.7
Summary of Demographic Characteristics
FSC250/50+Tio Tiotropium
Total
(N=173)
(N=169)
(N=342)
----------------------------------------------------------------------------------------------------------Age (y)
n
173
169
342
Mean
61.3
61.0
61.2
SD
8.56
9.41
8.98
Median
63.0
61.0
62.0
Min.
41
40
40
Max.
80
84
84
Ethnicity
n
Hispanic/Latino
Not Hispanic/Latino
173
0
173 (100%)
169
1 (<1%)
168 (>99%)
342
1 (<1%)
341 (>99%)
Height (cm)
n
Mean
SD
Median
Min.
Max.
173
169.3
9.79
170.0
142
198
169
169.3
9.94
170.0
147
193
342
169.3
9.85
170.0
142
198
Weight (kg)
n
Mean
SD
Median
Min.
Max.
173
77.81
17.677
77.10
36.4
129.1
169
79.45
17.944
78.20
40.6
129.1
342
78.62
17.802
78.05
36.4
129.1
Body Mass Index
n
Mean
SD
Median
173
27.0
5.07
26.0
169
27.6
5.37
27.0
342
27.3
5.22
27.0
(50%)
(50%)
169
96
73
(57%)
(43%)
04MAR2010 13:52
342
182
160
(53%)
(47%)
CONFIDENTIAL
173
86
87
RM2010/00132/00
ADC111114
n
Female
Male
103
Sex
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 2
Table 5.7
Summary of Demographic Characteristics
FSC250/50+Tio Tiotropium
Total
(N=173)
(N=169)
(N=342)
----------------------------------------------------------------------------------------------------------Body Mass Index
Min.
15
16
15
Max.
40
40
40
CONFIDENTIAL
104
RM2010/00132/00
ADC111114
04MAR2010 13:52
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 5.8
Summary of Race and Racial Combinations
FSC250/50+Tio Tiotropium
Total
Race
(N=173)
(N=169)
(N=342)
------------------------------------------------------------------------------------------n
173
169
342
African American/African Heritage
7
(4%)
7
(4%)
14
(4%)
American Indian or Alaska Native
1 (<1%)
0
1 (<1%)
Asian
0
0
0
Native Hawaiian or other Pacific Islander
0
0
0
White
165 (95%)
162 (96%)
327 (96%)
CONFIDENTIAL
105
RM2010/00132/00
ADC111114
04MAR2010 14:01
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 5.9
Summary of Race and Racial Combination Details
RM2010/00132/00
ADC111114
05MAR2010 10:03
CONFIDENTIAL
106
FSC250/50+Tio Tiotropium
Total
Race
(N=173)
(N=169)
(N=342)
------------------------------------------------------------------------------------------n
173
169
342
African American/African Heritage
7
(4%)
7
(4%)
14
(4%)
American Indian or Alaska Native
1 (<1%)
0
1 (<1%)
Asian - Central/South Asian Heritage
0
0
0
Asian - East Asian Heritage
0
0
0
Asian - Japanese Heritage
0
0
0
Asian - South East Asian Heritage
0
0
0
Asian - Mixed Race
0
0
0
Native Hawaiian or other Pacific Islander
0
0
0
White - Arabic/North African Heritage
0
1 (<1%)
1 (<1%)
White - White/Caucasian/European Heritage
165 (95%)
161 (95%)
326 (95%)
White - Mixed Race
0
0
0
Mixed Race
0
0
0
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 2
Table 5.10
Summary of Disease Characteristics
FSC250/50+Tio Tiotropium
Total
(N=173)
(N=169)
(N=342)
---------------------------------------------------------------------------------------------------Duration of COPD (yrs)
n
173
169
342
Mean
6.88
6.36
6.62
SD
5.983
5.060
5.544
Median
5.83
5.00
5.58
Min.
0.1
0.1
0.1
Max.
35.0
29.0
35.0
169
48 (28%)
88 (52%)
33 (20%)
340
97 (29%)
173 (51%)
70 (21%)
Exacerbations in past 12 months requiring
hospitalization
n
0
1
>=2
173
165 (95%)
8 (5%)
0
169
162 (96%)
6 (4%)
1 (<1%)
342
327 (96%)
14 (4%)
1 (<1%)
Exacerbations in past 12 months requiring
OCS/antibiotic
n
0
1
2
>=3
173
117 (68%)
45 (26%)
7 (4%)
4 (2%)
169
125 (74%)
35 (21%)
6 (4%)
3 (2%)
342
242 (71%)
80 (23%)
13 (4%)
7 (2%)
09MAR2010 16:30
RM2010/00132/00
ADC111114
171
49 (29%)
85 (50%)
37 (22%)
CONFIDENTIAL
107
COPD Type
n
Chronic bronchitis
Emphysema
Both
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 2
Table 5.10
Summary of Disease Characteristics
FSC250/50+Tio Tiotropium
Total
(N=173)
(N=169)
(N=342)
---------------------------------------------------------------------------------------------------Smoking status
n
173
169
342
Current smoker
102 (59%)
96 (57%)
198 (58%)
Former smoker
71 (41%)
73 (43%)
144 (42%)
169
54.7
27.40
46.0
10
175
342
55.1
29.31
46.5
10
192
Modified MRC dyspnea score
n
Slight
Moderate
Severe
Very severe
173
1 (<1%)
99 (57%)
68 (39%)
5 (3%)
169
0
94 (56%)
70 (41%)
5 (3%)
342
1 (<1%)
193 (56%)
138 (40%)
10 (3%)
Numeric modified MRC dyspnea score
n
Mean
SD
Median
Min.
Max.
173
2.4
0.56
2.0
1
4
169
2.5
0.56
2.0
2
4
342
2.5
0.56
2.0
1
4
09MAR2010 16:30
RM2010/00132/00
ADC111114
173
55.4
31.13
47.0
10
192
CONFIDENTIAL
108
Pack-years
n
Mean
SD
Median
Min.
Max.
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 2
Table 5.11
Summary of Screening Pulmonary Function Tests
FSC250/50+Tio Tiotropium
Total
(N=173)
(N=169)
(N=342)
----------------------------------------------------------------------------------------------------------Pre-bronchodilator FEV1 (L)
n
172
169
341
Mean
1.50
1.54
1.52
SD
0.528
0.509
0.518
Median
1.42
1.47
1.44
Min.
0.70
0.59
0.59
Max.
3.39
3.03
3.39
172
49.9
11.31
47.9
24
84
169
52.2
11.68
51.1
25
89
341
51.1
11.54
49.5
24
89
Pre-bronchodilator FVC (L)
n
Mean
SD
Median
Min.
Max.
172
2.89
0.863
2.75
1.38
5.67
169
2.89
0.852
2.80
1.40
5.25
341
2.89
0.856
2.76
1.38
5.67
Post-bronchodilator FEV1 (L)
n
Mean
SD
Median
Min.
Max.
173
1.67
0.527
1.59
0.78
3.56
169
1.70
0.528
1.68
0.62
3.16
342
1.69
0.527
1.62
0.62
3.56
Post-bronchodilator FEV1 % predicted
n
Mean
SD
Median
Min.
173
56.0
10.65
54.7
36
169
57.4
10.57
56.8
37
342
56.7
10.62
55.2
36
09MAR2010 16:16
RM2010/00132/00
ADC111114
n
Mean
SD
Median
Min.
Max.
CONFIDENTIAL
109
Pre-bronchodilator FEV1 % predicted
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 2
Table 5.11
Summary of Screening Pulmonary Function Tests
FSC250/50+Tio Tiotropium
Total
(N=173)
(N=169)
(N=342)
----------------------------------------------------------------------------------------------------------Post-bronchodilator FEV1 % predicted
Max.
79
79
79
169
3.12
0.910
2.98
1.52
5.64
342
3.14
0.889
3.03
1.52
5.88
Post-bronchodilator FEV1/FVC
n
Mean
SD
Median
Min.
Max.
173
0.53
0.093
0.54
0.25
0.70
169
0.55
0.089
0.56
0.31
0.70
342
0.54
0.091
0.55
0.25
0.70
FEV1 % reversibility
n
Mean
SD
Median
Min.
Max.
173
13.8
12.48
11.9
-20
59
169
11.6
12.52
9.6
-21
53
342
12.7
12.53
10.4
-21
59
Reversibility
n
Nonreversible
Reversible
173
109 (63%)
64 (37%)
169
108 (64%)
61 (36%)
342
217 (63%)
125 (37%)
09MAR2010 16:16
CONFIDENTIAL
173
3.16
0.870
3.03
1.54
5.88
RM2010/00132/00
ADC111114
n
Mean
SD
Median
Min.
Max.
110
Post-bronchodilator FVC (L)
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 5.12
Summary of Current Medical Conditions
FSC250/50+Tio Tiotropium
Total
Medical condition classification
(N=173)
(N=169)
(N=342)
--------------------------------------------------------------------------------------------------------Any condition
172 (>99%)
168 (>99%)
340 (>99%)
111
99
90
88
76
60
42
42
40
39
30
34
34
27
20
18
12
2
(64%)
(57%)
(52%)
(51%)
(44%)
(35%)
(24%)
(24%)
(23%)
(23%)
(17%)
(20%)
(20%)
(16%)
(12%)
(10%)
(7%)
(1%)
124
118
87
68
73
49
52
40
41
40
45
35
30
28
28
14
8
7
(73%)
(70%)
(51%)
(40%)
(43%)
(29%)
(31%)
(24%)
(24%)
(24%)
(27%)
(21%)
(18%)
(17%)
(17%)
(8%)
(5%)
(4%)
235
217
177
156
149
109
94
82
81
79
75
69
64
55
48
32
20
9
(69%)
(63%)
(52%)
(46%)
(44%)
(32%)
(27%)
(24%)
(24%)
(23%)
(22%)
(20%)
(19%)
(16%)
(14%)
(9%)
(6%)
(3%)
4
2
1
(2%)
(1%)
(<1%)
4
0
0
(2%)
8
2
1
(2%)
(<1%)
(<1%)
RM2010/00132/00
ADC111114
10MAR2010 14:08
CONFIDENTIAL
111
Musculoskeletal and connective tissue disorders
Cardiac disorders
Gastrointestinal disorders
Respiratory, thoracic and mediastinal disorders
Psychiatric disorders
Nervous system disorders
Reproductive system and breast disorders
Immune system disorders
Vascular disorders
Renal and urinary disorders
Endocrine disorders
Skin and subcutaneous tissue disorders
Eye disorders
Metabolism and nutrition disorders
Ear and labyrinth disorders
Blood and lymphatic system disorders
Hepatobiliary disorders
Neoplasms benign, malignant and unspecified (incl cysts and
polyps)
Infections and infestations
Injury, poisoning and procedural complications
Congenital, familial and genetic disorders
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 2
Table 5.13
Summary of Prior COPD Medication Use
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Any medication
143 (83%)
125 (74%)
Note: A medication may be reported in more than one ATC Level.
(83%)
(55%)
(44%)
(13%)
(9%)
(5%)
(2%)
(2%)
(2%)
(1%)
(1%)
(2%)
(<1%)
(1%)
(1%)
(<1%)
(<1%)
(<1%)
(<1%)
5
(3%)
(<1%)
(<1%)
125
83
53
12
16
9
5
3
2
3
3
2
3
2
1
2
2
2
1
1
1
1
0
1
0
1
(74%)
(49%)
(31%)
(7%)
(9%)
(5%)
(3%)
(2%)
(1%)
(2%)
(2%)
(1%)
(2%)
(1%)
(<1%)
(1%)
(1%)
(1%)
(<1%)
(<1%)
(<1%)
(<1%)
6
(4%)
10MAR2010 14:49
(<1%)
(<1%)
RM2010/00132/00
ADC111114
DERMATOLOGICALS
Any medication
143
95
76
22
15
8
4
4
4
2
2
3
1
2
2
1
1
1
1
0
0
0
1
0
1
0
CONFIDENTIAL
112
RESPIRATORY SYSTEM
Any medication
SALBUTAMOL
TIOTROPIUM BROMIDE
SALMETEROL XINAFOATE+FLUTICASONE PROPIONATE
SALBUTAMOL SULFATE+IPRATROPIUM BROMIDE
FORMOTEROL FUMARATE
SALBUTAMOL SULFATE
LEVOSALBUTAMOL HYDROCHLORIDE
PROAIR (NOS)
IPRATROPIUM BROMIDE
PROCATEROL
TIOTROPIUM
MOMETASONE FUROATE
SALMETEROL XINAFOATE
BECLOMETASONE DIPROPIONATE
BUDESONIDE+FORMOTEROL FUMARATE
FLUTICASONE PROPIONATE
IPRATROPIUM
SALMETEROL+FLUTICASONE PROPIONATE
FLUNISOLIDE
FORMOTEROL
LEVALBUTEROL TARTRATE
MOMETASONE
OXYGEN
SALBUTAMOL+IPRATROPIUM
THEOPHYLLINE
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 2
Table 5.13
Summary of Prior COPD Medication Use
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------MOMETASONE FUROATE
1 (<1%)
3 (2%)
BECLOMETASONE DIPROPIONATE
2 (1%)
1 (<1%)
FLUTICASONE PROPIONATE
1 (<1%)
2 (1%)
MOMETASONE
1 (<1%)
0
2
2
VARIOUS
Any medication
OXYGEN
0
0
(1%)
(1%)
1 (<1%)
1 (<1%)
1 (<1%)
1 (<1%)
113
10MAR2010 14:49
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level
CONFIDENTIAL
ALIMENTARY TRACT AND METABOLISM
Any medication
BECLOMETASONE DIPROPIONATE
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 4
Table 5.14
Summary of COPD Concomitant Medications
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Any medication
25 (14%)
32 (19%)
(9%)
(8%)
(<1%)
(<1%)
(<1%)
ALIMENTARY TRACT AND METABOLISM
Any medication
PREDNISONE
BETAMETHASONE
DEXAMETHASONE
ACETYLSALICYLIC ACID
TRIAMCINOLONE ACETONIDE
ANTIINFECTIVES FOR SYSTEMIC USE
Any medication
AZITHROMYCIN
CIPROFLOXACIN HYDROCHLORIDE
AMOXICILLIN
LEVOFLOXACIN
AMOXICILLIN TRIHYDRATE+CLAVULANATE POTASSIUM
MOXIFLOXACIN
BIAXIN (NOS)
CEFALEXIN
CEFUROXIME AXETIL
CIPROFLOXACIN
DOXYCYCLINE
Note: A medication may be reported in more than one ATC Level.
(<1%)
22
18
2
1
1
1
0
(13%)
(11%)
(1%)
(<1%)
(<1%)
(<1%)
15
14
1
1
1
1
(9%)
(8%)
(<1%)
(<1%)
(<1%)
(<1%)
20
18
1
1
0
0
(12%)
(11%)
(<1%)
(<1%)
20
7
2
3
3
1
1
1
1
0
0
1
(12%)
(4%)
(1%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
15
8
3
1
0
1
1
0
0
1
1
0
(9%)
(5%)
(2%)
(<1%)
(<1%)
10MAR2010 14:52
(<1%)
(<1%)
(<1%)
(<1%)
RM2010/00132/00
ADC111114
15
14
1
1
1
0
1
CONFIDENTIAL
114
SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS
Any medication
PREDNISONE
METHYLPREDNISOLONE
BETAMETHASONE
DEXAMETHASONE
METHYLPREDNISOLONE SODIUM SUCCINATE
TRIAMCINOLONE ACETONIDE
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 4
Table 5.14
Summary of COPD Concomitant Medications
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------GEMIFLOXACIN MESILATE
1 (<1%)
0
PHENOXYMETHYLPENICILLIN POTASSIUM
1 (<1%)
0
Note: A medication may be reported in more than one ATC Level.
(5%)
(2%)
(1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
17
8
2
3
1
1
1
2
1
1
0
0
1
1
(10%)
(5%)
(1%)
(2%)
(<1%)
(<1%)
(<1%)
(1%)
(<1%)
(<1%)
(<1%)
(<1%)
0
1 (<1%)
0
0
0
1 (<1%)
1 (<1%)
0
0
1 (<1%)
1
1
1
0
0
1
1
0
(<1%)
(<1%)
(<1%)
4
7
(4%)
(2%)
10MAR2010 14:52
(<1%)
(<1%)
RM2010/00132/00
ADC111114
SENSORY ORGANS
Any medication
8
4
2
0
1
1
1
0
1
0
1
1
0
0
CONFIDENTIAL
115
RESPIRATORY SYSTEM
Any medication
SALBUTAMOL
GUAIFENESIN
OXYGEN
BETAMETHASONE
DEXAMETHASONE
HYDROCODONE+PHENYLTOLOXAMINE
IPRATROPIUM BROMIDE
LEVOSALBUTAMOL HYDROCHLORIDE
BENZONATATE
FLUTICASONE PROPIONATE
GUAIFENESIN+DIPROPHYLLINE
GUAIFENESIN+PSEUDOEPHEDRINE HYDROCHLORIDE
PARACETAMOL+DEXTROMETHORPHAN HYDROBROMIDE+PHENYLEPHRINE
HYDROCHLORIDE
PARACETAMOL+DEXTROMETHORPHAN HYDROBROMIDE+PSEUDOEPHEDRINE
HYDROCHLORIDE+DOXYLAMINE SUCCINATE
PARACETAMOL+GUAIFENESIN
PROCATEROL
ROBITUSSIN (NOS)
SALBUTAMOL SULFATE
SALMETEROL XINAFOATE
SALMETEROL XINAFOATE+FLUTICASONE PROPIONATE
TIOTROPIUM BROMIDE
TRIAMCINOLONE ACETONIDE
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 4
Table 5.14
Summary of COPD Concomitant Medications
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------CIPROFLOXACIN HYDROCHLORIDE
2 (1%)
3 (2%)
METHYLPREDNISOLONE
1 (<1%)
2 (1%)
DEXAMETHASONE
1 (<1%)
1 (<1%)
CIPROFLOXACIN
0
1 (<1%)
KETOROLAC TROMETAMOL
0
1 (<1%)
METHYLPREDNISOLONE SODIUM SUCCINATE
0
1 (<1%)
TRIAMCINOLONE ACETONIDE
1 (<1%)
0
(<1%)
5 (3%)
2 (1%)
1 (<1%)
1 (<1%)
0
1 (<1%)
0
CARDIOVASCULAR SYSTEM
Any medication
BETAMETHASONE
DEXAMETHASONE
2 (1%)
1 (<1%)
1 (<1%)
2 (1%)
1 (<1%)
1 (<1%)
VARIOUS
Any medication
OXYGEN
0
0
3
3
MUSCULO-SKELETAL SYSTEM
Any medication
ACETYLSALICYLIC ACID
KETOROLAC TROMETAMOL
1 (<1%)
1 (<1%)
0
1 (<1%)
0
1 (<1%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
NERVOUS SYSTEM
Note: A medication may be reported in more than one ATC Level.
10MAR2010 14:52
(2%)
(2%)
RM2010/00132/00
ADC111114
3
1
1
1
1
0
1
CONFIDENTIAL
116
DERMATOLOGICALS
Any medication
METHYLPREDNISOLONE
BETAMETHASONE
DEXAMETHASONE
FLUTICASONE PROPIONATE
METHYLPREDNISOLONE SODIUM SUCCINATE
TRIAMCINOLONE ACETONIDE
Protocol: ADC111114
Population: Intent-to-Treat
Page 4 of 4
Table 5.14
Summary of COPD Concomitant Medications
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Any medication
1 (<1%)
1 (<1%)
ACETYLSALICYLIC ACID
1 (<1%)
0
KETOROLAC TROMETAMOL
0
1 (<1%)
BLOOD AND BLOOD FORMING ORGANS
Any medication
ACETYLSALICYLIC ACID
1 (<1%)
1 (<1%)
0
0
CONFIDENTIAL
117
10MAR2010 14:52
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Any medication
159 (92%)
156 (92%)
(75%)
(31%)
(18%)
(14%)
(10%)
(7%)
(6%)
(5%)
(5%)
(3%)
(3%)
(5%)
(5%)
(2%)
(<1%)
(2%)
(2%)
(1%)
(2%)
(3%)
(2%)
(2%)
(2%)
(1%)
(2%)
(3%)
(2%)
(1%)
(3%)
132
43
33
26
12
15
12
6
6
9
8
5
4
6
7
4
4
5
3
2
3
3
3
5
3
1
3
4
0
10MAR2010 14:56
(78%)
(25%)
(20%)
(15%)
(7%)
(9%)
(7%)
(4%)
(4%)
(5%)
(5%)
(3%)
(2%)
(4%)
(4%)
(2%)
(2%)
(3%)
(2%)
(1%)
(2%)
(2%)
(2%)
(3%)
(2%)
(<1%)
(2%)
(2%)
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
129
54
32
24
17
12
10
8
8
5
6
8
9
4
1
4
4
2
4
5
4
4
4
2
3
5
3
2
5
CONFIDENTIAL
118
NERVOUS SYSTEM
Any medication
ACETYLSALICYLIC ACID
PARACETAMOL
IBUPROFEN
PARACETAMOL+HYDROCODONE BITARTRATE
HYDROCODONE
ALPRAZOLAM
LORAZEPAM
PAROXETINE HYDROCHLORIDE
TRAMADOL
ZOLPIDEM TARTRATE
GABAPENTIN
TRAZODONE
PARACETAMOL+OXYCODONE HYDROCHLORIDE
CYCLOBENZAPRINE HYDROCHLORIDE
DIAZEPAM
KETOROLAC TROMETAMOL
CLONAZEPAM
ESCITALOPRAM OXALATE
FLUOXETINE HYDROCHLORIDE
LIDOCAINE
QUETIAPINE FUMARATE
TEMAZEPAM
VARENICLINE TARTRATE
BUPROPION HYDROCHLORIDE
DIPHENHYDRAMINE HYDROCHLORIDE+PARACETAMOL
HYDROXYZINE
MIDAZOLAM
ACETYLSALICYLIC ACID+CAFFEINE+SALICYLAMIDE
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
10MAR2010 14:56
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
CONFIDENTIAL
119
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------AMITRIPTYLINE HYDROCHLORIDE
2 (1%)
3 (2%)
BUPROPION
2 (1%)
3 (2%)
DEXTROPROPOXYPHENE NAPSILATE+PARACETAMOL
4 (2%)
1 (<1%)
PREGABALIN
2 (1%)
3 (2%)
PROMETHAZINE
1 (<1%)
4 (2%)
TRAMADOL HYDROCHLORIDE
0
5 (3%)
VENLAFAXINE HYDROCHLORIDE
3 (2%)
2 (1%)
BUPIVACAINE HYDROCHLORIDE
1 (<1%)
3 (2%)
BUSPIRONE HYDROCHLORIDE
0
4 (2%)
CITALOPRAM HYDROBROMIDE
1 (<1%)
3 (2%)
DULOXETINE HYDROCHLORIDE
3 (2%)
1 (<1%)
NICOTINE
1 (<1%)
3 (2%)
PRAMIPEXOLE DIHYDROCHLORIDE
3 (2%)
1 (<1%)
SERTRALINE HYDROCHLORIDE
1 (<1%)
3 (2%)
CYCLOBENZAPRINE
1 (<1%)
2 (1%)
FENTANYL
3 (2%)
0
FENTANYL CITRATE
1 (<1%)
2 (1%)
FLUOXETINE
0
3 (2%)
MIRTAZAPINE
0
3 (2%)
MORPHINE
1 (<1%)
2 (1%)
OXYCODONE
2 (1%)
1 (<1%)
OXYCODONE HYDROCHLORIDE
2 (1%)
1 (<1%)
PARACETAMOL+HYDROCODONE
1 (<1%)
2 (1%)
PAROXETINE
1 (<1%)
2 (1%)
VALPROIC ACID
2 (1%)
1 (<1%)
ACETYLSALICYLIC ACID+SODIUM BICARBONATE+CITRIC ACID
1 (<1%)
1 (<1%)
AMITRIPTYLINE
0
2 (1%)
DIPHENHYDRAMINE+PARACETAMOL
1 (<1%)
1 (<1%)
EPINEPHRINE+LIDOCAINE
2 (1%)
0
HYDROXYZINE HYDROCHLORIDE
2 (1%)
0
LIDOCAINE HYDROCHLORIDE
0
2 (1%)
MORPHINE SULFATE
0
2 (1%)
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
10MAR2010 14:56
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
CONFIDENTIAL
120
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------PARACETAMOL+CAFFEINE+BUTALBITAL
2 (1%)
0
PARACETAMOL+DICHLORALPHENAZONE+ISOMETHEPTENE MUCATE
0
2 (1%)
PETHIDINE
0
2 (1%)
PHENYTOIN
1 (<1%)
1 (<1%)
PROPOFOL
1 (<1%)
1 (<1%)
ROPINIROLE HYDROCHLORIDE
1 (<1%)
1 (<1%)
TOPIRAMATE
1 (<1%)
1 (<1%)
ACETYLSALICYLIC ACID+PARACETAMOL+CAFFEINE
1 (<1%)
0
ARIPIPRAZOLE
1 (<1%)
0
BETHANECHOL CHLORIDE
0
1 (<1%)
BROMFENAC SODIUM
1 (<1%)
0
CHLORDIAZEPOXIDE
1 (<1%)
0
CLONIDINE
0
1 (<1%)
CLOZAPINE
0
1 (<1%)
DIPHENHYDRAMINE CITRATE+IBUPROFEN
1 (<1%)
0
DOXEPIN
1 (<1%)
0
DOXEPIN HYDROCHLORIDE
0
1 (<1%)
FLURAZEPAM
0
1 (<1%)
HALOPERIDOL
1 (<1%)
0
HALOTHANE
1 (<1%)
0
LEVETIRACETAM
0
1 (<1%)
MODAFINIL
1 (<1%)
0
NALBUPHINE HYDROCHLORIDE
1 (<1%)
0
NEFAZODONE
0
1 (<1%)
NEOSTIGMINE
0
1 (<1%)
NORTRIPTYLINE
0
1 (<1%)
OLANZAPINE
1 (<1%)
0
PARACETAMOL+CHLORPHENAMINE MALEATE+PHENYLEPHRINE HYDROCHLORIDE
1 (<1%)
0
PETHIDINE HYDROCHLORIDE
0
1 (<1%)
PRIMIDONE
1 (<1%)
0
RIZATRIPTAN BENZOATE
0
1 (<1%)
ROPIVACAINE
1 (<1%)
0
Protocol: ADC111114
Population: Intent-to-Treat
Page 4 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------SECBUTABARBITAL
1 (<1%)
0
SERTRALINE
0
1 (<1%)
SEVOFLURANE
1 (<1%)
0
TOMEXETINE HYDROCHLORIDE
0
1 (<1%)
TRIAZOLAM
0
1 (<1%)
TYLENOL #3 (NOS)
0
1 (<1%)
ZIPRASIDONE HYDROCHLORIDE
0
1 (<1%)
ZOLPIDEM
0
1 (<1%)
(72%)
(31%)
(20%)
(10%)
(5%)
(5%)
(5%)
(5%)
(7%)
(3%)
(3%)
(5%)
(3%)
(3%)
(2%)
(2%)
(2%)
(3%)
(2%)
(2%)
(2%)
(2%)
116
43
28
17
11
10
10
9
3
7
6
4
6
5
7
7
6
3
4
4
4
3
10MAR2010 14:56
(69%)
(25%)
(17%)
(10%)
(7%)
(6%)
(6%)
(5%)
(2%)
(4%)
(4%)
(2%)
(4%)
(3%)
(4%)
(4%)
(4%)
(2%)
(2%)
(2%)
(2%)
(2%)
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
125
54
35
18
9
8
8
8
12
6
6
8
5
5
3
3
3
6
4
3
3
3
CONFIDENTIAL
121
ALIMENTARY TRACT AND METABOLISM
Any medication
ACETYLSALICYLIC ACID
VITAMINS NOS
OMEPRAZOLE
ESOMEPRAZOLE MAGNESIUM
ASCORBIC ACID
CALCIUM
PANTOPRAZOLE
VITAMIN D NOS
PREDNISONE
POTASSIUM CHLORIDE
TOCOPHEROL
RANITIDINE HYDROCHLORIDE
CALCIUM CARBONATE
METFORMIN
RANITIDINE
LANSOPRAZOLE
METRONIDAZOLE
MINERALS NOS+VITAMINS NOS
ERGOCALCIFEROL+CALCIUM
POTASSIUM NOS
BISMUTH SUBSALICYLATE
Protocol: ADC111114
Population: Intent-to-Treat
Page 5 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
10MAR2010 14:56
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
CONFIDENTIAL
122
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------TRIAMCINOLONE ACETONIDE
5 (3%)
1 (<1%)
GLIMEPIRIDE
2 (1%)
3 (2%)
GLIPIZIDE
3 (2%)
2 (1%)
METFORMIN HYDROCHLORIDE
3 (2%)
2 (1%)
PROMETHAZINE
1 (<1%)
4 (2%)
DEXAMETHASONE
3 (2%)
1 (<1%)
MAALOX (NOS)
2 (1%)
2 (1%)
NYSTATIN
4 (2%)
0
SODIUM CHLORIDE
1 (<1%)
3 (2%)
CLOTRIMAZOLE
3 (2%)
0
FAMOTIDINE
1 (<1%)
2 (1%)
MECLOZINE
0
3 (2%)
ONDANSETRON
1 (<1%)
2 (1%)
SITAGLIPTIN
1 (<1%)
2 (1%)
VITAMIN B NOS
2 (1%)
1 (<1%)
ZINC
2 (1%)
1 (<1%)
ACETYLSALICYLIC ACID+SODIUM BICARBONATE+CITRIC ACID
1 (<1%)
1 (<1%)
ARGININE
2 (1%)
0
COD-LIVER OIL
1 (<1%)
1 (<1%)
DIHYDROXYALUMINUM SODIUM CARBONATE
1 (<1%)
1 (<1%)
DULCOLAX (NOS)
0
2 (1%)
FLEET ENEMA (NOS)
1 (<1%)
1 (<1%)
HYDROCORTISONE
0
2 (1%)
INSULIN GLARGINE
1 (<1%)
1 (<1%)
LOPERAMIDE HYDROCHLORIDE
1 (<1%)
1 (<1%)
MAGIC MOUTHWASH (NOS)
2 (1%)
0
METOCLOPRAMIDE HYDROCHLORIDE
0
2 (1%)
PLANTAGO OVATA
1 (<1%)
1 (<1%)
VITAMIN B SUBSTANCES NOS
1 (<1%)
1 (<1%)
ALUMINIUM HYDROXIDE GEL, DRIED+MAGNESIUM HYDROXIDE+DIMETICONE
1 (<1%)
0
ALUMINIUM HYDROXIDE GEL, DRIED+MAGNESIUM HYDROXIDE+DIMETICONE,
0
1 (<1%)
ACTIVATED
Protocol: ADC111114
Population: Intent-to-Treat
Page 6 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
10MAR2010 14:56
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
CONFIDENTIAL
123
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------ANTIBIOTICS NOS
1 (<1%)
0
ASCORBIC ACID+NICOTINIC ACID+THIAMINE
1 (<1%)
0
HYDROCHLORIDE+CYANOCOBALAMIN+PYRIDOXINE HYDROCHLORIDE+RIBOFLAV
ATROPINE SULFATE+DIPHENOXYLATE HYDROCHLORIDE
1 (<1%)
0
ATROPINE SULFATE+HYOSCINE HYDROBROMIDE+PHENOBARBITAL+HYOSCYAMINE
0
1 (<1%)
SULFATE
BISACODYL
1 (<1%)
0
CALCITRIOL
0
1 (<1%)
CALCIUM CARBONATE+MAGNESIUM HYDROXIDE+FAMOTIDINE
1 (<1%)
0
CALCIUM CITRATE
1 (<1%)
0
CALCIUM GLUCONATE+ERGOCALCIFEROL+CALCIUM CARBONATE+CALCIUM LACTATE
1 (<1%)
0
CALCIUM+MAGNESIUM
1 (<1%)
0
CALCIUM+VITAMIN D NOS
1 (<1%)
0
CALCIUM+VITAMINS NOS
1 (<1%)
0
CAROTENOIDS
1 (<1%)
0
CHLORDIAZEPOXIDE HYDROCHLORIDE+CLIDINIUM BROMIDE
1 (<1%)
0
CHLORHEXIDINE GLUCONATE
0
1 (<1%)
CYAMOPSIS TETRAGONOLOBUS
0
1 (<1%)
DICYCLOVERINE
1 (<1%)
0
DICYCLOVERINE HYDROCHLORIDE
0
1 (<1%)
DIMETICONE, ACTIVATED
1 (<1%)
0
DOCUSATE SODIUM
1 (<1%)
0
DOCUSATE SODIUM+CASANTHRANOL
0
1 (<1%)
DOLASETRON MESILATE
0
1 (<1%)
ERGOCALCIFEROL+CALCIUM CITRATE
1 (<1%)
0
ESOMEPRAZOLE
1 (<1%)
0
EX-LAX NOS
1 (<1%)
0
GELATIN+CURCUMA LONGA+PANICUM MILIACEUM EXTRACT+JAPANESE UBIQUINONE
1 (<1%)
0
GLIBENCLAMIDE
0
1 (<1%)
GLYCOPYRRONIUM BROMIDE
0
1 (<1%)
HYDROGEN PEROXIDE
0
1 (<1%)
HYOSCYAMINE
0
1 (<1%)
Protocol: ADC111114
Population: Intent-to-Treat
Page 7 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
10MAR2010 14:56
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
CONFIDENTIAL
124
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------INSULIN ASPART
0
1 (<1%)
INSULIN DETEMIR
0
1 (<1%)
INSULIN HUMAN
1 (<1%)
0
INSULIN LISPRO
1 (<1%)
0
INSULIN NOS
0
1 (<1%)
LACTULOSE
0
1 (<1%)
LUBIPROSTONE
1 (<1%)
0
MACROGOL
1 (<1%)
0
MACROGOL+ELECTROLYTES NOS
0
1 (<1%)
MAGNESIUM
1 (<1%)
0
MAGNESIUM CHLORIDE
0
1 (<1%)
MAGNESIUM HYDROXIDE
0
1 (<1%)
MAGNESIUM OXIDE
0
1 (<1%)
MESALAZINE
0
1 (<1%)
METFORMIN HYDROCHLORIDE+GLIBENCLAMIDE
1 (<1%)
0
METFORMIN HYDROCHLORIDE+PIOGLITAZONE HYDROCHLORIDE
0
1 (<1%)
METHYLCELLULOSE
1 (<1%)
0
METOCLOPRAMIDE
0
1 (<1%)
MINERALS NOS+VITAMINS NOS+HERBALS NOS
1 (<1%)
0
OTHER ANTIDIARRHOEALS
0
1 (<1%)
OXYBUTYNIN
0
1 (<1%)
PANCRELIPASE
1 (<1%)
0
PIOGLITAZONE HYDROCHLORIDE
0
1 (<1%)
POLYMYXIN B SULFATE
0
1 (<1%)
POTASSIUM GLUCONATE
1 (<1%)
0
PREDNISOLONE
1 (<1%)
0
RABEPRAZOLE SODIUM
1 (<1%)
0
SELENIUM
1 (<1%)
0
SENNOSIDES
1 (<1%)
0
STANNOUS FLUORIDE
1 (<1%)
0
SUCRALFATE
1 (<1%)
0
TETRACYCLINE
1 (<1%)
0
Protocol: ADC111114
Population: Intent-to-Treat
Page 8 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------TETRACYCLINE HYDROCHLORIDE
1 (<1%)
0
THIAMINE HYDROCHLORIDE
1 (<1%)
0
TRIAMCINOLONE
1 (<1%)
0
URSODEOXYCHOLIC ACID
1 (<1%)
0
112
18
25
15
14
10
8
5
6
6
7
6
6
3
6
1
5
5
3
4
4
4
3
3
3
2
10MAR2010 14:56
(66%)
(11%)
(15%)
(9%)
(8%)
(6%)
(5%)
(3%)
(4%)
(4%)
(4%)
(4%)
(4%)
(2%)
(4%)
(<1%)
(3%)
(3%)
(2%)
(2%)
(2%)
(2%)
(2%)
(2%)
(2%)
(1%)
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
99 (57%)
22 (13%)
13 (8%)
14 (8%)
13 (8%)
8 (5%)
10 (6%)
11 (6%)
9 (5%)
7 (4%)
6 (3%)
5 (3%)
4 (2%)
7 (4%)
3 (2%)
8 (5%)
4 (2%)
3 (2%)
5 (3%)
4 (2%)
3 (2%)
3 (2%)
4 (2%)
4 (2%)
3 (2%)
4 (2%)
CONFIDENTIAL
125
CARDIOVASCULAR SYSTEM
Any medication
SIMVASTATIN
LISINOPRIL
ATORVASTATIN CALCIUM
HYDROCHLOROTHIAZIDE
ATENOLOL
FUROSEMIDE
FISH OIL
ROSUVASTATIN CALCIUM
AMLODIPINE BESILATE
METOPROLOL
NICOTINIC ACID
FENOFIBRATE
METOPROLOL SUCCINATE
DILTIAZEM HYDROCHLORIDE
OMEGA-3 MARINE TRIGLYCERIDES
SIMVASTATIN+EZETIMIBE
HYDROCHLOROTHIAZIDE+LISINOPRIL
LOVASTATIN
VALSARTAN
CARVEDILOL
GLYCERYL TRINITRATE
LIDOCAINE
PRAVASTATIN
HYDROCHLOROTHIAZIDE+LOSARTAN POTASSIUM
NIFEDIPINE
Protocol: ADC111114
Population: Intent-to-Treat
Page 9 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
10MAR2010 14:56
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
CONFIDENTIAL
126
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------AMLODIPINE
3 (2%)
2 (1%)
BENAZEPRIL HYDROCHLORIDE+AMLODIPINE BESILATE
2 (1%)
3 (2%)
DILTIAZEM
1 (<1%)
4 (2%)
HYDROCHLOROTHIAZIDE+VALSARTAN
3 (2%)
2 (1%)
INDOMETACIN
3 (2%)
2 (1%)
DEXAMETHASONE
3 (2%)
1 (<1%)
DOXAZOSIN MESILATE
2 (1%)
2 (1%)
EZETIMIBE
2 (1%)
2 (1%)
GEMFIBROZIL
2 (1%)
2 (1%)
PRAVASTATIN SODIUM
1 (<1%)
3 (2%)
TERAZOSIN
0
4 (2%)
TERAZOSIN HYDROCHLORIDE
2 (1%)
2 (1%)
ATORVASTATIN
2 (1%)
1 (<1%)
DIGOXIN
2 (1%)
1 (<1%)
OLMESARTAN
0
3 (2%)
SPIRONOLACTONE
2 (1%)
1 (<1%)
TRIAMTERENE+HYDROCHLOROTHIAZIDE
1 (<1%)
2 (1%)
VERAPAMIL
0
3 (2%)
ALDACTONE (NOS)
0
2 (1%)
BENAZEPRIL
1 (<1%)
1 (<1%)
BENAZEPRIL HYDROCHLORIDE
1 (<1%)
1 (<1%)
BUMETANIDE
0
2 (1%)
ENALAPRIL
1 (<1%)
1 (<1%)
FLUVASTATIN SODIUM
1 (<1%)
1 (<1%)
HYDROCHLOROTHIAZIDE+IRBESARTAN
1 (<1%)
1 (<1%)
HYDROCORTISONE
0
2 (1%)
INDAPAMIDE
1 (<1%)
1 (<1%)
ISOSORBIDE
0
2 (1%)
LIDOCAINE HYDROCHLORIDE
0
2 (1%)
LOSARTAN POTASSIUM
0
2 (1%)
METOPROLOL TARTRATE
0
2 (1%)
RAMIPRIL
1 (<1%)
1 (<1%)
Protocol: ADC111114
Population: Intent-to-Treat
Page 10 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
10MAR2010 14:56
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
CONFIDENTIAL
127
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------TELMISARTAN
2 (1%)
0
UBIDECARENONE
1 (<1%)
1 (<1%)
AMLODIPINE BESILATE+OLMESARTAN
1 (<1%)
0
AMLODIPINE BESILATE+VALSARTAN
1 (<1%)
0
CAPTOPRIL
0
1 (<1%)
CHLORTALIDONE
1 (<1%)
0
CHLORTALIDONE+ATENOLOL
0
1 (<1%)
CLONIDINE
0
1 (<1%)
COLESTYRAMINE
0
1 (<1%)
DOXAZOSIN
0
1 (<1%)
FOSINOPRIL
0
1 (<1%)
FOSINOPRIL SODIUM
0
1 (<1%)
HEPARIN SODIUM
0
1 (<1%)
HYDRALAZINE
0
1 (<1%)
HYDRALAZINE HYDROCHLORIDE
1 (<1%)
0
HYDROCHLOROTHIAZIDE+BENAZEPRIL HYDROCHLORIDE
0
1 (<1%)
HYDROCHLOROTHIAZIDE+BISOPROLOL
0
1 (<1%)
HYDROCHLOROTHIAZIDE+MOEXIPRIL HYDROCHLORIDE
1 (<1%)
0
HYDROCHLOROTHIAZIDE+OLMESARTAN
0
1 (<1%)
IRBESARTAN
0
1 (<1%)
ISOSORBIDE MONONITRATE
0
1 (<1%)
MAGNESIUM CHLORIDE
0
1 (<1%)
METOLAZONE
0
1 (<1%)
MONASCUS PURPUREUS
1 (<1%)
0
PHENYLEPHRINE
0
1 (<1%)
PREDNISOLONE
1 (<1%)
0
QUINAPRIL
0
1 (<1%)
RANOLAZINE
0
1 (<1%)
TADALAFIL
0
1 (<1%)
TIMOLOL
1 (<1%)
0
TIMOLOL MALEATE
0
1 (<1%)
TOCOPHEROL+FISH OIL
0
1 (<1%)
Protocol: ADC111114
Population: Intent-to-Treat
Page 11 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------TRANDOLAPRIL
0
1 (<1%)
TRIAMTERENE
1 (<1%)
0
VERAPAMIL HYDROCHLORIDE
0
1 (<1%)
(54%)
(31%)
(14%)
(5%)
(2%)
(2%)
(1%)
(<1%)
(2%)
(2%)
(1%)
(2%)
(2%)
(2%)
(<1%)
(<1%)
(1%)
(<1%)
(<1%)
(<1%)
(<1%)
(1%)
(<1%)
(<1%)
10MAR2010 14:56
91
43
26
8
6
6
7
7
4
2
3
2
1
1
2
2
1
2
1
1
1
2
0
0
1
0
1
(54%)
(25%)
(15%)
(5%)
(4%)
(4%)
(4%)
(4%)
(2%)
(1%)
(2%)
(1%)
(<1%)
(<1%)
(1%)
(1%)
(<1%)
(1%)
(<1%)
(<1%)
(<1%)
(1%)
(<1%)
(<1%)
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
93
54
24
9
4
3
2
1
4
4
2
3
3
3
1
1
2
1
1
1
1
0
2
1
0
1
0
CONFIDENTIAL
128
MUSCULO-SKELETAL SYSTEM
Any medication
ACETYLSALICYLIC ACID
IBUPROFEN
NAPROXEN SODIUM
MELOXICAM
CARISOPRODOL
NAPROXEN
CYCLOBENZAPRINE HYDROCHLORIDE
KETOROLAC TROMETAMOL
RISEDRONATE SODIUM
CELECOXIB
INDOMETACIN
ALENDRONATE SODIUM
DICLOFENAC
BACLOFEN
CYCLOBENZAPRINE
GLUCOSAMINE
SODIUM IBANDRONATE
ALLOPURINOL
COLCHICINE
LEFLUNOMIDE
METAXALONE
ZOLEDRONIC ACID
BROMFENAC SODIUM
CHONDROITIN
CHONDROITIN+GLUCOSAMINE
CHONDROITIN+GLUCOSAMINE+COLLAGEN
Protocol: ADC111114
Population: Intent-to-Treat
Page 12 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
Note: A medication may be reported in more than one ATC Level.
77
54
7
6
9
4
3
1
4
1
2
(45%)
(31%)
(4%)
(3%)
(5%)
(2%)
(2%)
(<1%)
(2%)
(<1%)
(1%)
10MAR2010 14:56
62 (37%)
43 (25%)
11 (7%)
6 (4%)
2 (1%)
3 (2%)
4 (2%)
4 (2%)
0
3 (2%)
1 (<1%)
RM2010/00132/00
ADC111114
BLOOD AND BLOOD FORMING ORGANS
Any medication
ACETYLSALICYLIC ACID
CLOPIDOGREL BISULFATE
POTASSIUM CHLORIDE
CYANOCOBALAMIN
FOLIC ACID
POTASSIUM NOS
WARFARIN SODIUM
CILOSTAZOL
SODIUM CHLORIDE
FERROUS SULPHATE
CONFIDENTIAL
129
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------DICLOFENAC HYDROXYETHYLPYRROLIDINE
0
1 (<1%)
DICLOFENAC SODIUM
0
1 (<1%)
DIMETHYL SULFONE
0
1 (<1%)
ERGOCALCIFEROL+ALENDRONIC ACID
0
1 (<1%)
GLUCOSAMINE SULFATE
1 (<1%)
0
GLUCOSAMINE SULFATE+DIMETHYL SULFONE
0
1 (<1%)
HYDROXYCHLOROQUINE SULFATE
1 (<1%)
0
LEVOMENTHOL
0
1 (<1%)
METHOCARBAMOL
1 (<1%)
0
OXAPROZIN
1 (<1%)
0
PARACETAMOL+CHLORZOXAZONE
1 (<1%)
0
PIROXICAM
1 (<1%)
0
PROBENECID
1 (<1%)
0
QUININE
1 (<1%)
0
ROCURONIUM BROMIDE
0
1 (<1%)
SULINDAC
1 (<1%)
0
TERIPARATIDE
0
1 (<1%)
TIZANIDINE
0
1 (<1%)
TROLAMINE SALICYLATE
0
1 (<1%)
Protocol: ADC111114
Population: Intent-to-Treat
Page 13 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
130
Note: A medication may be reported in more than one ATC Level.
69 (40%)
12 (7%)
6 (3%)
7 (4%)
5 (3%)
4 (2%)
4 (2%)
5 (3%)
2 (1%)
5 (3%)
3 (2%)
2 (1%)
1 (<1%)
2 (1%)
3 (2%)
3 (2%)
2 (1%)
1 (<1%)
10MAR2010 14:56
62
15
6
5
4
4
3
1
4
1
2
3
4
3
1
1
2
3
(37%)
(9%)
(4%)
(3%)
(2%)
(2%)
(2%)
(<1%)
(2%)
(<1%)
(1%)
(2%)
(2%)
(2%)
(<1%)
(<1%)
(1%)
(2%)
RM2010/00132/00
ADC111114
RESPIRATORY SYSTEM
Any medication
HYDROCODONE
BENADRYL (NOS)
GUAIFENESIN
MONTELUKAST SODIUM
CETIRIZINE HYDROCHLORIDE
LIDOCAINE
DIPHENHYDRAMINE HYDROCHLORIDE+PARACETAMOL
MOMETASONE FUROATE
TRIAMCINOLONE ACETONIDE
FLUTICASONE PROPIONATE
GUAIFENESIN+DEXTROMETHORPHAN HYDROBROMIDE
PROMETHAZINE
PSEUDOEPHEDRINE HYDROCHLORIDE
AZELASTINE
DEXAMETHASONE
PSEUDOEPHEDRINE HYDROCHLORIDE+FEXOFENADINE HYDROCHLORIDE
SODIUM CHLORIDE
CONFIDENTIAL
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------ARGININE
2 (1%)
0
WARFARIN
0
2 (1%)
CHLORHEXIDINE GLUCONATE
0
1 (<1%)
CLOPIDOGREL
1 (<1%)
0
ENOXAPARIN SODIUM
1 (<1%)
0
FERROUS GLUCONATE
1 (<1%)
0
GELATIN
1 (<1%)
0
HEPARIN SODIUM
0
1 (<1%)
IRON
0
1 (<1%)
PHYTOMENADIONE
1 (<1%)
0
POTASSIUM CHLORIDE+SODIUM CHLORIDE+CALCIUM CHLORIDE+DL-LACTIC ACID
0
1 (<1%)
SODIUM SALT
Protocol: ADC111114
Population: Intent-to-Treat
Page 14 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
10MAR2010 14:56
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
CONFIDENTIAL
131
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------BENZONATATE
2 (1%)
1 (<1%)
COUGH COLD PREPARATIONS NOS
2 (1%)
1 (<1%)
DIPHENHYDRAMINE
1 (<1%)
2 (1%)
LORATADINE
2 (1%)
1 (<1%)
MECLOZINE
0
3 (2%)
OXYGEN
1 (<1%)
2 (1%)
PARACETAMOL+HYDROCODONE
1 (<1%)
2 (1%)
ROBITUSSIN (NOS)
2 (1%)
1 (<1%)
CETIRIZINE
2 (1%)
0
DIPHENHYDRAMINE HYDROCHLORIDE
2 (1%)
0
FEXOFENADINE
1 (<1%)
1 (<1%)
FEXOFENADINE HYDROCHLORIDE
2 (1%)
0
FLUNISOLIDE
0
2 (1%)
FLUTICASONE FUROATE
1 (<1%)
1 (<1%)
HYDROCODONE+PHENYLTOLOXAMINE
0
2 (1%)
LEVOCETIRIZINE HYDROCHLORIDE
1 (<1%)
1 (<1%)
LIDOCAINE HYDROCHLORIDE
0
2 (1%)
MECLOZINE HYDROCHLORIDE
1 (<1%)
1 (<1%)
PARACETAMOL+DEXTROMETHORPHAN HYDROBROMIDE+PSEUDOEPHEDRINE
2 (1%)
0
HYDROCHLORIDE+DOXYLAMINE SUCCINATE
TYLENOL SINUS (NOS)
1 (<1%)
1 (<1%)
ACETYLCYSTEINE
1 (<1%)
0
ANTIBIOTICS NOS
1 (<1%)
0
BACITRACIN
0
1 (<1%)
CHLORHEXIDINE GLUCONATE
0
1 (<1%)
CODEINE+PROMETHAZINE
0
1 (<1%)
CORICIDIN (NOS)
1 (<1%)
0
DESLORATADINE
1 (<1%)
0
DIPHENHYDRAMINE CITRATE+IBUPROFEN
1 (<1%)
0
EPHEDRINE
1 (<1%)
0
EPHEDRINE SULFATE
0
1 (<1%)
GUAIFENESIN+DEXTROMETHORPHAN
1 (<1%)
0
Protocol: ADC111114
Population: Intent-to-Treat
Page 15 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
Note: A medication may be reported in more than one ATC Level.
57 (33%)
24 (14%)
9 (5%)
6 (3%)
2 (1%)
4 (2%)
10MAR2010 14:56
62 (37%)
26 (15%)
8 (5%)
3 (2%)
7 (4%)
4 (2%)
RM2010/00132/00
ADC111114
GENITO URINARY SYSTEM AND SEX HORMONES
Any medication
IBUPROFEN
NAPROXEN SODIUM
METRONIDAZOLE
NAPROXEN
ESTROGENS CONJUGATED
CONFIDENTIAL
132
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------GUAIFENESIN+DEXTROMETHORPHAN HYDROBROMIDE+PHENYLPROPANOLAMINE
0
1 (<1%)
HYDROCHLORIDE
GUAIFENESIN+PSEUDOEPHEDRINE
0
1 (<1%)
GUAIFENESIN+PSEUDOEPHEDRINE HYDROCHLORIDE
1 (<1%)
0
HYDROCODONE POLISTIREX+CHLORPHENIRAMINE POLISTIREX
1 (<1%)
0
LEVOMENTHOL
0
1 (<1%)
METHYL SALICYLATE+THYMOL+LEVOMENTHOL+CINEOLE
1 (<1%)
0
OTHER RESPIRATORY SYSTEM PRODUCTS NOS
1 (<1%)
0
OXYMETAZOLINE HYDROCHLORIDE
1 (<1%)
0
PARACETAMOL+CHLORPHENAMINE MALEATE+PHENYLEPHRINE HYDROCHLORIDE
1 (<1%)
0
PARACETAMOL+CHLORPHENAMINE MALEATE+PSEUDOEPHEDRINE HYDROCHLORIDE
0
1 (<1%)
PARACETAMOL+DEXTROMETHORPHAN HYDROBROMIDE+PSEUDOEPHEDRINE
1 (<1%)
0
HYDROCHLORIDE
PHENYLEPHRINE
0
1 (<1%)
POVIDONE-IODINE
0
1 (<1%)
PREDNISOLONE
1 (<1%)
0
PSEUDOEPHEDRINE SULFATE+LORATADINE
0
1 (<1%)
PSEUDOEPHEDRINE+TRIPROLIDINE
0
1 (<1%)
ROBITUSSIN AC (NOS)
1 (<1%)
0
SALBUTAMOL
0
1 (<1%)
THEOPHYLLINE
0
1 (<1%)
TIOTROPIUM BROMIDE
1 (<1%)
0
TRIAMCINOLONE
1 (<1%)
0
TYLENOL COLD NOS
1 (<1%)
0
Protocol: ADC111114
Population: Intent-to-Treat
Page 16 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
10MAR2010 14:56
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
CONFIDENTIAL
133
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------DUTASTERIDE
2 (1%)
2 (1%)
FINASTERIDE
1 (<1%)
3 (2%)
NYSTATIN
4 (2%)
0
OXYBUTYNIN HYDROCHLORIDE
2 (1%)
2 (1%)
TAMSULOSIN HYDROCHLORIDE
2 (1%)
2 (1%)
TERAZOSIN
0
4 (2%)
TERAZOSIN HYDROCHLORIDE
2 (1%)
2 (1%)
CLOTRIMAZOLE
3 (2%)
0
ESTRADIOL
1 (<1%)
2 (1%)
SOLIFENACIN SUCCINATE
2 (1%)
1 (<1%)
SERENOA REPENS
1 (<1%)
1 (<1%)
SILDENAFIL CITRATE
2 (1%)
0
TOLTERODINE TARTRATE
1 (<1%)
1 (<1%)
VACCINIUM MACROCARPON
0
2 (1%)
ANTIBIOTICS NOS
1 (<1%)
0
BACITRACIN
0
1 (<1%)
CLINDAMYCIN
1 (<1%)
0
DARIFENACIN HYDROBROMIDE
0
1 (<1%)
DIMETHYL SULFONE
0
1 (<1%)
ESTRADIOL+LEVONORGESTREL
1 (<1%)
0
ESTRADIOL+NORGESTIMATE
1 (<1%)
0
ESTROGENS CONJUGATED+MEDROXYPROGESTERONE ACETATE
0
1 (<1%)
ETHINYLOESTRADIOL+NORETHISTERONE ACETATE
0
1 (<1%)
FURADONINE
0
1 (<1%)
KETOCONAZOLE
0
1 (<1%)
MAGNESIUM HYDROXIDE
0
1 (<1%)
MEGESTROL ACETATE
1 (<1%)
0
METHYLROSANILINIUM CHLORIDE
1 (<1%)
0
NORETHISTERONE
1 (<1%)
0
OXYBUTYNIN
0
1 (<1%)
PHENAZOPYRIDINE
1 (<1%)
0
POVIDONE-IODINE
0
1 (<1%)
Protocol: ADC111114
Population: Intent-to-Treat
Page 17 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------RALOXIFENE HYDROCHLORIDE
1 (<1%)
0
SODIUM PHOSPHATE MONOBASIC
0
1 (<1%)
TADALAFIL
0
1 (<1%)
TAMSULOSIN
0
1 (<1%)
VARDENAFIL HYDROCHLORIDE
1 (<1%)
0
(33%)
(3%)
(5%)
(3%)
(2%)
(2%)
(2%)
(2%)
(1%)
(3%)
(2%)
(<1%)
(2%)
(<1%)
(1%)
(2%)
(1%)
(2%)
(<1%)
(<1%)
(1%)
(1%)
10MAR2010 14:56
43
6
4
3
4
4
3
3
4
1
2
4
1
3
2
0
1
0
2
2
1
0
2
2
0
(25%)
(4%)
(2%)
(2%)
(2%)
(2%)
(2%)
(2%)
(2%)
(<1%)
(1%)
(2%)
(<1%)
(2%)
(1%)
(<1%)
(1%)
(1%)
(<1%)
(1%)
(1%)
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
57
6
8
6
4
3
4
3
2
5
3
1
3
1
2
4
2
3
1
0
1
2
0
0
2
CONFIDENTIAL
134
DERMATOLOGICALS
Any medication
BENADRYL (NOS)
TOCOPHEROL
METRONIDAZOLE
METHYLPREDNISOLONE
GLYCERYL TRINITRATE
LIDOCAINE
FLUCONAZOLE
MOMETASONE FUROATE
TRIAMCINOLONE ACETONIDE
FLUTICASONE PROPIONATE
PROMETHAZINE
DEXAMETHASONE
FINASTERIDE
METHYLPREDNISOLONE ACETATE
NYSTATIN
CALCIPOTRIOL
CLOTRIMAZOLE
DIPHENHYDRAMINE
ACYCLOVIR
COD-LIVER OIL
DIPHENHYDRAMINE HYDROCHLORIDE
HYDROCORTISONE
LIDOCAINE HYDROCHLORIDE
TACROLIMUS
Protocol: ADC111114
Population: Intent-to-Treat
Page 18 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
10MAR2010 14:56
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
CONFIDENTIAL
135
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------ACITRETIN
1 (<1%)
0
ANTIBIOTICS NOS
1 (<1%)
0
BACITRACIN
0
1 (<1%)
CALCITRIOL
0
1 (<1%)
CHLORHEXIDINE GLUCONATE
0
1 (<1%)
CLINDAMYCIN
1 (<1%)
0
CLOBETASOL PROPIONATE
0
1 (<1%)
COAL TAR
1 (<1%)
0
DOXEPIN HYDROCHLORIDE
0
1 (<1%)
ERYTHROMYCIN ETHYLSUCCINATE
1 (<1%)
0
ETHANOL+IODINE
0
1 (<1%)
GELATIN
1 (<1%)
0
GENTAMICIN
0
1 (<1%)
GLYCEROL+BETAINE+CARBOMER+OLEA EUROPAEA
1 (<1%)
0
OIL+HYETELLOSE+SQUALANE+VEGETABLE OIL
HYDROGEN PEROXIDE
0
1 (<1%)
KETOCONAZOLE
0
1 (<1%)
LEVOMENTHOL
0
1 (<1%)
METHYL HYDROXYBENZOATE
1 (<1%)
0
METHYLPREDNISOLONE SODIUM SUCCINATE
0
1 (<1%)
METHYLROSANILINIUM CHLORIDE
1 (<1%)
0
NEOMYCIN SULFATE+POLYMYXIN B SULFATE+BACITRACIN ZINC
1 (<1%)
0
NEOSPORIN (NOS)
1 (<1%)
0
POVIDONE-IODINE
0
1 (<1%)
PREDNISOLONE
1 (<1%)
0
PROPYLPARABEN
1 (<1%)
0
SELENIUM
1 (<1%)
0
TERBINAFINE
1 (<1%)
0
TETRACYCLINE
1 (<1%)
0
TETRACYCLINE HYDROCHLORIDE
1 (<1%)
0
TOCOPHERYL ACETATE+ALLANTOIN+HYALURONATE SODIUM+TELMESTEINE+VITIS
1 (<1%)
0
VINIFERA+PIROCTONE OLAMINE+BISABOL
Protocol: ADC111114
Population: Intent-to-Treat
Page 19 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------TRIAMCINOLONE
1 (<1%)
0
TRIAMCINOLONE ACETONIDE+ECONAZOLE NITRATE
1 (<1%)
0
TRIAMCINOLONE ACETONIDE+NYSTATIN
1 (<1%)
0
(26%)
(3%)
(3%)
(3%)
(3%)
(3%)
(2%)
(1%)
(2%)
(2%)
(2%)
(1%)
(2%)
(<1%)
(<1%)
(1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
10MAR2010 14:56
33
7
5
3
3
2
2
4
3
1
2
1
0
2
1
1
0
2
1
1
0
1
1
0
0
1
0
(20%)
(4%)
(3%)
(2%)
(2%)
(1%)
(1%)
(2%)
(2%)
(<1%)
(1%)
(<1%)
(1%)
(<1%)
(<1%)
(1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
45
6
5
6
5
6
4
2
3
4
3
2
3
0
1
1
2
0
1
1
1
0
0
1
1
0
1
CONFIDENTIAL
136
ANTIINFECTIVES FOR SYSTEMIC USE
Any medication
CEFALEXIN
AMOXICILLIN
METRONIDAZOLE
AZITHROMYCIN
LEVOFLOXACIN
CIPROFLOXACIN HYDROCHLORIDE
DOXYCYCLINE
FLUCONAZOLE
CIPROFLOXACIN
SULFAMETHOXAZOLE+TRIMETHOPRIM
MOXIFLOXACIN
TETANUS TOXOID
ACYCLOVIR
AMOXICILLIN TRIHYDRATE+CLAVULANATE POTASSIUM
CEFAZOLIN SODIUM
CEFTRIAXONE
INFLUENZA VACCINE
OSELTAMIVIR PHOSPHATE
PNEUMOCOCCAL VACCINE
ANTIBIOTICS NOS
BENZYLPENICILLIN
BIAXIN (NOS)
CEFDINIR
CLINDAMYCIN
DICLOXACILLIN
ERYTHROMYCIN ETHYLSUCCINATE
Protocol: ADC111114
Population: Intent-to-Treat
Page 20 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
Note: A medication may be reported in more than one ATC Level.
42 (24%)
4 (2%)
4 (2%)
4 (2%)
4 (2%)
5 (3%)
4 (2%)
3 (2%)
3 (2%)
3 (2%)
3 (2%)
1 (<1%)
0
0
0
10MAR2010 14:56
31
4
4
3
2
1
1
2
1
1
1
3
2
2
2
(18%)
(2%)
(2%)
(2%)
(1%)
(<1%)
(<1%)
(1%)
(<1%)
(<1%)
(<1%)
(2%)
(1%)
(1%)
(1%)
RM2010/00132/00
ADC111114
SENSORY ORGANS
Any medication
KETOROLAC TROMETAMOL
METHYLPREDNISOLONE
LIDOCAINE
CIPROFLOXACIN HYDROCHLORIDE
TRIAMCINOLONE ACETONIDE
CIPROFLOXACIN
INDOMETACIN
AZELASTINE
DEXAMETHASONE
DICLOFENAC
SODIUM CHLORIDE
ACYCLOVIR
HYDROCORTISONE
ISOSORBIDE
CONFIDENTIAL
137
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------FAMCICLOVIR
0
1 (<1%)
FURADONINE
0
1 (<1%)
GATIFLOXACIN
1 (<1%)
0
GENTAMICIN
0
1 (<1%)
INFLUENZA VIRUS VACCINE INACTIVATED
1 (<1%)
0
KETOCONAZOLE
0
1 (<1%)
MOXIFLOXACIN HYDROCHLORIDE
1 (<1%)
0
POLYMYXIN B SULFATE
0
1 (<1%)
SULFAMETHOXAZOLE
1 (<1%)
0
TETRACYCLINE
1 (<1%)
0
TETRACYCLINE HYDROCHLORIDE
1 (<1%)
0
TOBRAMYCIN
1 (<1%)
0
TRIMETHOPRIM
1 (<1%)
0
VALACICLOVIR
0
1 (<1%)
VALACICLOVIR HYDROCHLORIDE
0
1 (<1%)
Protocol: ADC111114
Population: Intent-to-Treat
Page 21 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
10MAR2010 14:56
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
CONFIDENTIAL
138
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------LIDOCAINE HYDROCHLORIDE
0
2 (1%)
ACETYLCYSTEINE
1 (<1%)
0
ANTIBIOTICS NOS
1 (<1%)
0
BACITRACIN
0
1 (<1%)
BENZYLPENICILLIN
0
1 (<1%)
BIMATOPROST
1 (<1%)
0
BRIMONIDINE TARTRATE
1 (<1%)
0
BROMFENAC SODIUM
1 (<1%)
0
CHLORHEXIDINE GLUCONATE
0
1 (<1%)
CLEAR EYES (NOS)
0
1 (<1%)
CLONIDINE
0
1 (<1%)
CORTISONE
1 (<1%)
0
DICLOFENAC HYDROXYETHYLPYRROLIDINE
0
1 (<1%)
DICLOFENAC SODIUM
0
1 (<1%)
EPHEDRINE
1 (<1%)
0
EPHEDRINE SULFATE
0
1 (<1%)
ERYTHROMYCIN ETHYLSUCCINATE
1 (<1%)
0
FAMCICLOVIR
0
1 (<1%)
GENTAMICIN
0
1 (<1%)
HEPARIN SODIUM
0
1 (<1%)
HYDROGEN PEROXIDE
0
1 (<1%)
MACROGOL
1 (<1%)
0
METHYLCELLULOSE
1 (<1%)
0
METHYLPREDNISOLONE SODIUM SUCCINATE
0
1 (<1%)
NEOMYCIN SULFATE+POLYMYXIN B SULFATE+BACITRACIN ZINC
1 (<1%)
0
NEOSPORIN (NOS)
1 (<1%)
0
NEOSTIGMINE
0
1 (<1%)
OXYMETAZOLINE HYDROCHLORIDE
1 (<1%)
0
PEGAPTANIB
0
1 (<1%)
PHENIRAMINE MALEATE+NAPHAZOLINE HYDROCHLORIDE
1 (<1%)
0
PHENYLEPHRINE
0
1 (<1%)
PIROXICAM
1 (<1%)
0
Protocol: ADC111114
Population: Intent-to-Treat
Page 22 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
139
29
8
6
3
4
5
3
2
0
1
0
1
0
0
1
0
1
VARIOUS
Any medication
OXYGEN
Note: A medication may be reported in more than one ATC Level.
(17%)
(5%)
(3%)
(2%)
(2%)
(3%)
(2%)
(1%)
(18%)
(5%)
(4%)
(5%)
(2%)
(<1%)
(<1%)
(1%)
(1%)
(<1%)
(<1%)
(<1%)
31
9
7
8
4
1
1
2
2
1
1
0
1
1
0
1
0
14 (8%)
1 (<1%)
10
2
(6%)
(1%)
(<1%)
(<1%)
(<1%)
10MAR2010 14:56
(<1%)
(<1%)
(<1%)
RM2010/00132/00
ADC111114
SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS
Any medication
LEVOTHYROXINE SODIUM
PREDNISONE
LEVOTHYROXINE
METHYLPREDNISOLONE
TRIAMCINOLONE ACETONIDE
DEXAMETHASONE
METHYLPREDNISOLONE ACETATE
HYDROCORTISONE
MELATONIN
BETAMETHASONE+LIDOCAINE
CORTISONE
DESMOPRESSIN
METHYLPREDNISOLONE SODIUM SUCCINATE
PREDNISOLONE
THIAMAZOLE
TRIAMCINOLONE
CONFIDENTIAL
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------POLYMYXIN B SULFATE
0
1 (<1%)
PREDNISOLONE
1 (<1%)
0
TETRACYCLINE
1 (<1%)
0
TETRACYCLINE HYDROCHLORIDE
1 (<1%)
0
TIMOLOL
1 (<1%)
0
TIMOLOL MALEATE
0
1 (<1%)
TIMOLOL MALEATE+DORZOLAMIDE HYDROCHLORIDE
0
1 (<1%)
TOBRAMYCIN
1 (<1%)
0
TRIAMCINOLONE
1 (<1%)
0
Protocol: ADC111114
Population: Intent-to-Treat
Page 23 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
Note: A medication may be reported in more than one ATC Level.
13
(8%)
10MAR2010 14:56
9
(5%)
RM2010/00132/00
ADC111114
ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
Any medication
CONFIDENTIAL
140
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------AMBIGUOUS MEDICATION
1 (<1%)
1 (<1%)
IOPAMIDOL
1 (<1%)
1 (<1%)
PLANTAGO OVATA
1 (<1%)
1 (<1%)
VACCINIUM MACROCARPON
0
2 (1%)
ACETYLCYSTEINE
1 (<1%)
0
ACETYLCYSTEINE+THIOCTIC ACID+LEVOGLUTAMIDE+GLUCOSAMINE+CALCIUM
1 (<1%)
0
ASCORBATE+QUERCETIN+HERBALS NOS
ALLIUM SATIVUM
1 (<1%)
0
CHONDROITIN
0
1 (<1%)
CHONDROITIN+GLUCOSAMINE
1 (<1%)
0
CYAMOPSIS TETRAGONOLOBUS
0
1 (<1%)
DIMETHYL SULFONE
0
1 (<1%)
ETHANOL
0
1 (<1%)
FUNGICURE (NOS)
0
1 (<1%)
GELATIN+CURCUMA LONGA+PANICUM MILIACEUM EXTRACT+JAPANESE UBIQUINONE
1 (<1%)
0
IRON+CYANOCOBALAMIN+ZINC+CHLOROPHYLL+BETACAROTENE+RIBONUCLEIC
1 (<1%)
0
ACID+DEOXYRIBONUCLEIC ACID
LINUM USITATISSIMUM OIL
1 (<1%)
0
MEBROFENIN
1 (<1%)
0
MEDICATION UNKNOWN
1 (<1%)
0
METHYL HYDROXYBENZOATE
1 (<1%)
0
MINERALS NOS+VITAMINS NOS+HERBALS NOS
1 (<1%)
0
MONASCUS PURPUREUS
1 (<1%)
0
PROPYLPARABEN
1 (<1%)
0
PYRIDOXINE HYDROCHLORIDE+TOCOPHEROL+CALCIUM+SOY ISOFLAVONES+HERBALS
1 (<1%)
0
NOS
SINCALIDE
1 (<1%)
0
SODIUM AMIDOTRIZOATE+MEGLUMINE AMIDOTRIZOATE
0
1 (<1%)
TERIPARATIDE
0
1 (<1%)
Protocol: ADC111114
Population: Intent-to-Treat
Page 24 of 24
Table 5.15
Summary of Non-COPD Concomitant Medications
141
ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS
Any medication
METRONIDAZOLE
HYDROXYCHLOROQUINE SULFATE
QUININE
10MAR2010 14:56
3
3
0
0
(2%)
(2%)
RM2010/00132/00
ADC111114
Note: A medication may be reported in more than one ATC Level.
8 (5%)
6 (3%)
1 (<1%)
1 (<1%)
CONFIDENTIAL
ATC Level 1
FSC250/50+Tio Tiotropium
Ingredient
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------ESTROGENS CONJUGATED
4 (2%)
4 (2%)
ESTRADIOL
1 (<1%)
2 (1%)
LEFLUNOMIDE
1 (<1%)
1 (<1%)
TACROLIMUS
2 (1%)
0
ADALIMUMAB
0
1 (<1%)
ANASTROZOLE
0
1 (<1%)
CICLOSPORIN
1 (<1%)
0
MEGESTROL ACETATE
1 (<1%)
0
METHOTREXATE
1 (<1%)
0
RALOXIFENE HYDROCHLORIDE
1 (<1%)
0
SOY ISOFLAVONES
1 (<1%)
0
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 5.16
Summary of Exposure to Study Drug
FSC250/50+Tio
Tiotropium
(N=173)
(N=169)
------------------------------------------------------------------------------------------------------Open-label treatment
Exposure to study drug (days)
n
170
166
Mean
173.8
171.7
SD
49.43
49.22
Median
195.0
192.5
Min.
27
13
Max.
220
229
142
n
Mean
SD
Median
Min.
Max.
170
146.4
49.26
167.0
1
190
166
144.0
47.66
165.0
1
177
RM2010/00132/00
ADC111114
10MAR2010 14:16
CONFIDENTIAL
Double-blind DISKUS
Exposure to study drug (days)
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 5.17
Summary of Treatment Compliance
FSC250/50+Tio
Tiotropium
(N=173)
(N=169)
--------------------------------------------------------------------------------------------DISKUS compliance (%)
n
154
156
Mean
98.2
97.2
SD
4.56
7.12
Median
99.4
99.4
Min.
64
47
Max.
114
100
HandiHaler compliance (%)
154
98.6
3.17
99.4
78
100
156
98.0
3.84
99.4
79
101
RM2010/00132/00
ADC111114
Note: Treatment compliance is reported for subjects at least 75% compliant with daily diary recordings of
study drug use.
26MAR2010 10:20
CONFIDENTIAL
143
n
Mean
SD
Median
Min.
Max.
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 5
Table 5.18
Listing of End of Study Record
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
CONFIDENTIAL
144
RM2010/00132/00
ADC111114
05MAR2010 08:32
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 5.19
Listing of Subjects for Whom the Treatment Blind was Broken
No data to report
CONFIDENTIAL
149
RM2010/00132/00
ADC111114
05MAR2010 08:26
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 5.20
Listing of Protocol Deviations
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
CONFIDENTIAL
150
RM2010/00132/00
ADC111114
22MAR2010 15:23
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 5.21
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
CONFIDENTIAL
151
RM2010/00132/00
ADC111114
04MAR2010 12:52
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 32
Table 5.22
Listing of Demographic Characteristics
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
CONFIDENTIAL
152
RM2010/00132/00
ADC111114
20APR2010 07:42
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 21
Table 5.23
Listing of Race
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy.
Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see
the Patient Level Data section of the GSK Clincal Study Register.
CONFIDENTIAL
184
RM2010/00132/00
ADC111114
20APR2010 07:42
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
205
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM ACETYLSALICYLIC ACID
ASA
ASPIRIN
ASPIRIN - ENTERIC COASTED
ASPIRIN ENTERIC COATED
ASPRIN
Aspirin
Asprin
Baby Aspirin
Bayer Aspirin
Bufferin
EXTRA STRENGTH ASPIRIN
Ecotrin
Enteric coated Aspirin
apirin
aspiirn
aspirin
asprin
ACETYLSALICYLIC ACID+SODIUM
ALKA-SELTZER
BICARBONATE+CITRIC ACID
alkaseltzer
ALUMINIUM HYDROXIDE GEL, DRIED+MAGNESIUM
Maalox Plus
HYDROXIDE+DIMETICONE
ALUMINIUM HYDROXIDE GEL, DRIED+MAGNESIUM
Mylanta
HYDROXIDE+DIMETICONE, ACTIVATED
ANTIBIOTICS NOS
unk I.V. Antibiotic
ARGININE
L-arginine
L. Arginine
ASCORBIC ACID
VITAMIN C
Vitamin C
Vitamine C
vitamin C
vitamin c
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
206
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM ASCORBIC ACID+NICOTINIC ACID+THIAMINE
Super B Complex with Vitamin C
HYDROCHLORIDE+CYANOCOBALAMIN+PYRIDOXINE
HYDROCHLORIDE+RIBOFLAV
ATROPINE SULFATE+DIPHENOXYLATE
Lomotil
HYDROCHLORIDE
ATROPINE SULFATE+HYOSCINE
Donnatal
HYDROBROMIDE+PHENOBARBITAL+HYOSCYAMINE
SULFATE
BECLOMETASONE DIPROPIONATE
qvar
BETAMETHASONE
Celestone
BISACODYL
Bisacodyl
Dulcolax Tablets
BISMUTH SUBSALICYLATE
PEPTO BISMAL
Pepto-bismol
Peptobismol
pepto Bismoal
pepto bismol
CALCITRIOL
Calcitroil
CALCIUM
CALCIUM
Calcium
Calcium 1000mg
calcium
CALCIUM CARBONATE
Calcarb
Caltrate
Caltrate Tablet
Citrical
Fortical
TUMS
fortical
oscal
tums
CALCIUM CARBONATE+MAGNESIUM
pepsid complete
HYDROXIDE+FAMOTIDINE
CALCIUM CITRATE
citracal
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
207
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM CALCIUM GLUCONATE+ERGOCALCIFEROL+CALCIUM
CALCET
CARBONATE+CALCIUM LACTATE
CALCIUM+MAGNESIUM
calcium/magnesium
CALCIUM+VITAMIN D NOS
calcium and vitamin D
suppliment
CALCIUM+VITAMINS NOS
calcium with Vitamin
CAROTENOIDS
Lutien
CHLORDIAZEPOXIDE HYDROCHLORIDE+CLIDINIUM
LIBRAX
BROMIDE
CHLORHEXIDINE GLUCONATE
Hibiclens
CLOTRIMAZOLE
Mycelex Troches
clotrimazole
clotrimozole
COD-LIVER OIL
COD LIVER OIL
Codliver Oil
CYAMOPSIS TETRAGONOLOBUS
Benefiber
DEXAMETHASONE
DEXAMETHASONE
DEZAMETHAZONE
Dexamethasone
decadron
DICYCLOVERINE
Dicyclomine
DICYCLOVERINE HYDROCHLORIDE
Bentyl
DIHYDROXYALUMINUM SODIUM CARBONATE
Rolaids
DIMETICONE, ACTIVATED
Gas X
DOCUSATE SODIUM
Docusate Sodium ( Colace)
DOCUSATE SODIUM+CASANTHRANOL
PERICOLACE
DOLASETRON MESILATE
Dolasetron Mesylate
DULCOLAX (NOS)
DULCOLAX
DULCOLAX EC
ERGOCALCIFEROL+CALCIUM
Calcium + Vitamin D
Calcium D
Calcium plus D
Calcuim with vitamin D
calcium and vitamin D
Protocol: ADC111114
Population: Intent-to-Treat
Page 4 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
208
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM ERGOCALCIFEROL+CALCIUM
calcium with vitamin D
ERGOCALCIFEROL+CALCIUM CITRATE
Citracil +D
ESOMEPRAZOLE
Esomeprazole
ESOMEPRAZOLE MAGNESIUM
NEXIUM
Nexium
nexium
EX-LAX NOS
EX-LAX PILLS
FAMOTIDINE
PEPCID
famotidine
FLEET ENEMA (NOS)
FLEET ENEMA
GELATIN+CURCUMA LONGA+PANICUM MILIACEUM
C Q10
EXTRACT+JAPANESE UBIQUINONE
GLIBENCLAMIDE
GLYBURIDE
Glyburide
GLIMEPIRIDE
Amaryl
amaryl
glimepiride
glimepride
GLIPIZIDE
GLIPIZIDE
GLUCOTROL - XL
Glipizide
Glucotrol-ER
glucotrol
GLYCOPYRRONIUM BROMIDE
ROBINUL
HYDROCORTISONE
Hydrocortisone Cream 1%
Hydrocortisone ointment
HYDROGEN PEROXIDE
Hydrogen peroxide
HYOSCYAMINE
Hyoscyamine
INSULIN ASPART
Novolog
novolog insulin
INSULIN DETEMIR
Levemir
levemir
INSULIN GLARGINE
Lantus
INSULIN HUMAN
NOVOLIN R
Protocol: ADC111114
Population: Intent-to-Treat
Page 5 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
209
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM INSULIN LISPRO
Humalog
INSULIN NOS
Insuline
LACTULOSE
Lactulose
LANSOPRAZOLE
Lansoprazole
PREVACID
Prevacid
prevacid
LOPERAMIDE HYDROCHLORIDE
Immodium
LUBIPROSTONE
amitiza
MAALOX (NOS)
Maalox
maalox
MACROGOL
miralax
MACROGOL+ELECTROLYTES NOS
GOLYTELY
Golytely
MAGIC MOUTHWASH (NOS)
Magic Mouth Wash
magic mouthwash
MAGNESIUM
magnesium
MAGNESIUM CHLORIDE
Slow-Mag
MAGNESIUM HYDROXIDE
MILK OF MAGNESIA
MAGNESIUM OXIDE
Magnesium Oxide
MECLOZINE
MECLIZINE
Meclizine
MESALAZINE
ASACOL
METFORMIN
METFORMIN
Metformin
metformin
METFORMIN HYDROCHLORIDE
Glucophage
glucophage
metformin HCL
metformin hcl
metphormin hcl
METFORMIN HYDROCHLORIDE+GLIBENCLAMIDE
Glucovance
METFORMIN HYDROCHLORIDE+PIOGLITAZONE
Actoplus Met
HYDROCHLORIDE
Protocol: ADC111114
Population: Intent-to-Treat
Page 6 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
210
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM METHYLCELLULOSE
Citrucel
METOCLOPRAMIDE
Metoclopramide
METOCLOPRAMIDE HYDROCHLORIDE
REGLAN
Reglan
METRONIDAZOLE
FLAGYL
Flagyl
Metrogel
Metrogel cream
Metronidazole
Metronidazole (Flagyl )
metrogel
MINERALS NOS+VITAMINS NOS
Centrim Silver
Centrum Silver
Centrum Silver Multivitamin
Mulitple Vitamin
Occuvit
One a Day for Women
Multivitamin
Women's one-a-day
centrum multivitamin
centrum silver
MINERALS NOS+VITAMINS NOS+HERBALS NOS
Male Response
NYSTATIN
Mycostatin Suspension
Nystatin
nystatin suspension
OMEPRAZOLE
OMEPRAZOLE
Omeprazole
PRILOSEC
Prilosec
omeprazol
omeprazole
omeprizol
omerprazole
prilosec
Protocol: ADC111114
Population: Intent-to-Treat
Page 7 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
211
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM ONDANSETRON
Ondansetron
ZOFRAN
Zofran
OTHER ANTIDIARRHOEALS
anti-diarrheal
OXYBUTYNIN
ORYBUTYNIN
PANCRELIPASE
Pangestym EC Capsules
PANTOPRAZOLE
PROTONIX
Pantoprozole
Protonix
protonix
PIOGLITAZONE HYDROCHLORIDE
Actos
PLANTAGO OVATA
Metamucil
metamucil
POLYMYXIN B SULFATE
polymyxin Sulfate
POTASSIUM CHLORIDE
K-Dur
KDur
KLOR-CON
Klor-Con
POTASSIUM CHLORIDE
Potassium CL
Potassium Chloride
potassium chloride
POTASSIUM GLUCONATE
Potassium Gluconate
POTASSIUM NOS
POTASSIUM
Potassium
Potassium (OTC)
potassium
PREDNISOLONE
prednisolone opthalmic
PREDNISONE
PREDINISONE
PREDNISONE
Predisone
Prednisone
Prednisone 30 mg X 2 days; 20
mg x 2 and 10 mg x 2days
Protocol: ADC111114
Population: Intent-to-Treat
Page 8 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
212
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM PREDNISONE
Prednisone Taper
Prednisone Taper 30mg x 2
days, 20 mg x 2 days, 10mg x 2
days
Prednisone Taper 30mgx2days,
20mgx2days, 10mgx2days
Prednisone Taper 40mg x 4 dys,
30mg x 2 dys, 20mg x 2 dys, 10
mg x 2 dys
Prednisone [10mg taper x 7
days]
prednisone
prednisone taper
PROMETHAZINE
Phenergan
Phernergan
Promethazine
phenergan
promethazine
RABEPRAZOLE SODIUM
Aciphex
RANITIDINE
RAMITIDINE
RANITIDINE
Ranitidine
ranitadine
RANITIDINE HYDROCHLORIDE
Ranitidine HCL
ZANTAC
Zantac
rantidine
zantac
RETINOL
Vitamin A
SELENIUM
selenium
SENNOSIDES
Sennosides, USP ( Exlax)
Sennosides,USP ( Exlax )
SITAGLIPTIN
Januvia
SODIUM CHLORIDE
NORMAL SALINE
Protocol: ADC111114
Population: Intent-to-Treat
Page 9 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
213
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM SODIUM CHLORIDE
Normal Saline IV
Normal Saline Infusion over 24
hours
Sodium Chloride
STANNOUS FLUORIDE
STANNOUS FLUORIDE DIHYDRATE
STEROIDS NOS
steroid injection
SUCRALFATE
Sucrafate
TETRACYCLINE
Tetracycline
TETRACYCLINE HYDROCHLORIDE
tetracyclin
THIAMINE HYDROCHLORIDE
vitamin B1
TOCOPHEROL
VITAMIN E
Vitamin E
vitamin E
TRIAMCINOLONE
Triamcinolone
TRIAMCINOLONE ACETONIDE
Kenalog
Kenalog Injection
NASACORT AQ
Nasacort
Triamcinelone Cream
nasocort AQ
URSODEOXYCHOLIC ACID
Ursodiol
VITAMIN B NOS
vitamin B
VITAMIN B SUBSTANCES NOS
B Complex Vitamine
vitamin B complex
VITAMIN D NOS
VITAMIN D
Vitamin D
Vitamin D 800mg
vitamin D
vitamin d
VITAMINS NOS
MILTIVITAMIN
MULTI VITAMIN
MULTI-VITAMIN
MULTIVITAIN
MULTIVITAMIN
Protocol: ADC111114
Population: Intent-to-Treat
Page 10 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
ANTIINFECTIVES FOR SYSTEMIC USE
ACYCLOVIR
AMOXICILLIN TRIHYDRATE+CLAVULANATE
POTASSIUM
ANTIBIOTICS NOS
AZITHROMYCIN
augmentin
unk I.V. Antibiotic
Azithromycin
20APR2010 07:42
RM2010/00132/00
ADC111114
AMOXICILLIN
Acylcovir
acyclovir
AMOXICILLIN
Amoxicillin
amoxicillin
Augmentin
CONFIDENTIAL
214
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ALIMENTARY TRACT AND METABOLISM VITAMINS NOS
MULTIVITAMINS
MUTIVITAMIN
MVI
Multi Vatimine
Multi Vitamin
Multi vitamin
Multi vitamins
Multi-Vitamin
MultiVitamin
Multiple Vitamin
Multiple vitamin
Multivitamin
One a Day Multivitamin
One-A-Day Vitamin
Vitamin Supplement
multi vitamin
multi-vitamin
multiple vitamin
multivitamin
multlivitamin
occu vitamin/multiple vitamin
ZINC
Zinc
zinc
Protocol: ADC111114
Population: Intent-to-Treat
Page 11 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
215
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ANTIINFECTIVES FOR SYSTEMIC USE AZITHROMYCIN
Azithromycin Z-Pak
Azithromyocin
Azthromycin
Z MAX SUSPENSION
Z-Pack
Z-Pack (Azithromycin)
Z-pack
Z-pak
ZITHROMYCIN
Zithromax
azithromycin
zithromax
BENZYLPENICILLIN
Penicillin
BIAXIN (NOS)
BIAXIN
Biaxin
CEFALEXIN
Cephalexin
Cephelaxin
KEFLEX
Keflex
keflex
CEFAZOLIN SODIUM
Ancef
CEFAZOLIN SULFATE (ANCEF TRADE NAME)
CEFDINIR
OMNICEF
CEFTRIAXONE
Ceftriaxone
Rocephin
rocephen
CEFUROXIME AXETIL
ceftin
CIPROFLOXACIN
CIPROFLOXACIN
Ciprofloxacin
Ciprofloxin
ciprofloxacin
CIPROFLOXACIN HYDROCHLORIDE
CIPRO
CIRPO
Protocol: ADC111114
Population: Intent-to-Treat
Page 12 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
216
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ANTIINFECTIVES FOR SYSTEMIC USE CIPROFLOXACIN HYDROCHLORIDE
Cipro
Ciprofloxacin HCl
cipro
CLARITHROMYCIN
Clarithromycin
CLINDAMYCIN
Clindamycin
DICLOXACILLIN
Dicoloxacillin
DOXYCYCLINE
Doxycycline
Doxycyline
doxycycline
ERYTHROMYCIN ETHYLSUCCINATE
erythrometh
FAMCICLOVIR
Famvir
FLUCONAZOLE
DIFLUCAN
Diflucan
diflucan
fluconazole
FURADONINE
Nitrofurantoin
nitrofurantoin
GATIFLOXACIN
gatifloxacin
GEMIFLOXACIN MESILATE
FACTIVE
GENTAMICIN
Gentamicin
IMIPENEM+CILASTATIN SODIUM
primaxin
INFLUENZA VACCINE
2009-2010 INFLUENZA VACCINE
Flu vaccine
INFLUENZA VIRUS VACCINE INACTIVATED
Fluvarin Vaccination
KETOCONAZOLE
KETCONZOLE SHAMPOO
LEVOFLOXACIN
IV Levaquin
LEVAQUIN
Levaquin
Levaquinn
Levofloxacin
Levofloxacin ( Levaquinn )
levaquin
METRONIDAZOLE
FLAGYL
Flagyl
Protocol: ADC111114
Population: Intent-to-Treat
Page 13 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
ADALIMUMAB
humira
ANASTROZOLE
CICLOSPORIN
Anastrozole
Restasis
20APR2010 07:42
RM2010/00132/00
ADC111114
ANTINEOPLASTIC AND
IMMUNOMODULATING AGENTS
CONFIDENTIAL
217
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ANTIINFECTIVES FOR SYSTEMIC USE METRONIDAZOLE
Metrogel
Metrogel cream
Metronidazole
Metronidazole (Flagyl )
metrogel
MOXIFLOXACIN
AVELOX
Avelox
avelox
MOXIFLOXACIN HYDROCHLORIDE
Vigamox opthalamic solution
OSELTAMIVIR PHOSPHATE
Tamiflu
PHENOXYMETHYLPENICILLIN POTASSIUM
PENICILLIN VK
PNEUMOCOCCAL VACCINE
PNEUMOVAX
Pneumococcal Vaccine
POLYMYXIN B SULFATE
polymyxin Sulfate
SULFAMETHOXAZOLE
SULFAMETHOXAZOLE
SULFAMETHOXAZOLE+TRIMETHOPRIM
Bactrim DS
Bactrium
Septra DS
Sulfamethoxazole/Trimethoprim
bactrim
TETANUS TOXOID
Tetanus Toxiod
Tetanus immunization
Tetanus vaccine
TETRACYCLINE
Tetracycline
TETRACYCLINE HYDROCHLORIDE
tetracyclin
TOBRAMYCIN
Tobramycin Ophthalmic
TRIMETHOPRIM
TRIMETHOPRIN
VALACICLOVIR
Valacyclovir
VALACICLOVIR HYDROCHLORIDE
VALTREX
Protocol: ADC111114
Population: Intent-to-Treat
Page 14 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
ANTIPARASITIC PRODUCTS,
INSECTICIDES AND REPELLENTS
HYDROXYCHLOROQUINE
HYDROXYCHLOROQUINE SULFATE
METRONIDAZOLE
BLOOD AND BLOOD FORMING ORGANS
ABCIXIMAB
ACETYLSALICYLIC ACID
abiximab
ASA
ASPIRIN
ASPIRIN - ENTERIC COASTED
20APR2010 07:42
RM2010/00132/00
ADC111114
QUININE
hydroxychloroquine
(antibiotic)
Plaquenil
FLAGYL
Flagyl
Metrogel
Metrogel cream
Metronidazole
Metronidazole (Flagyl )
metrogel
Leg Cramps with Quinine (OTC)
CONFIDENTIAL
218
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------ANTINEOPLASTIC AND
ESTRADIOL
ESTRADIOL
IMMUNOMODULATING AGENTS
estrace
estradiol
ESTROGENS CONJUGATED
Cenestin Synthetic
PREMARIN CREAM
Premarin
premarin
INFLIXIMAB
Remicade
LEFLUNOMIDE
Leflunomide
arava
MEGESTROL ACETATE
MEGACE
METHOTREXATE
methotrexate
RALOXIFENE HYDROCHLORIDE
Evista
SOY ISOFLAVONES
Soy Supplement
TACROLIMUS
Protopic
Protopoc Ointmenmt
Protocol: ADC111114
Population: Intent-to-Treat
Page 15 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
219
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------BLOOD AND BLOOD FORMING ORGANS
ACETYLSALICYLIC ACID
ASPIRIN ENTERIC COATED
ASPRIN
Aspirin
Asprin
Baby Aspirin
Bayer Aspirin
Bufferin
EXTRA STRENGTH ASPIRIN
Ecotrin
Enteric coated Aspirin
apirin
aspiirn
aspirin
asprin
ARGININE
L-arginine
L. Arginine
CHLORHEXIDINE GLUCONATE
Hibiclens
CILOSTAZOL
CILOCTAZOL
PLETAL
cilostazol
pletal
CLOPIDOGREL
Clopidogrel
CLOPIDOGREL BISULFATE
Clopidogrel Asbisulfate
Plavix
plavix
CYANOCOBALAMIN
B-12
B12
B12 Complex
Vitamin B 12
Vitamin B-12
Vitamin B12
Vitamin B12 Injection
vitamin B 12
vitamin B-12
Protocol: ADC111114
Population: Intent-to-Treat
Page 16 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
220
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------BLOOD AND BLOOD FORMING ORGANS
ENOXAPARIN SODIUM
Lovenox
FERROUS GLUCONATE
iron gluconate
FERROUS SULPHATE
Ferrous Sulfate
FOLIC ACID
FOLIC ACID
Folic Acid
Folic acid
folic acid
GELATIN
GELATIN
HEPARIN (NOS)
heparin
HEPARIN SODIUM
HEPARIN SODIUM
IRON
Feosol
Iron
PHYTOMENADIONE
Vitamin K 80mcg
POTASSIUM CHLORIDE
K-Dur
KDur
KLOR-CON
Klor-Con
POTASSIUM CHLORIDE
Potassium CL
Potassium Chloride
potassium chloride
POTASSIUM CHLORIDE+SODIUM CHLORIDE+CALCIUM LACTATED RINGERS
CHLORIDE+DL-LACTIC ACID SODIUM SALT
POTASSIUM NOS
POTASSIUM
Potassium
Potassium (OTC)
potassium
SODIUM CHLORIDE
NORMAL SALINE
Normal Saline IV
Normal Saline Infusion over 24
hours
Sodium Chloride
WARFARIN
WARFARIN
Warfarin
Protocol: ADC111114
Population: Intent-to-Treat
Page 17 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------BLOOD AND BLOOD FORMING ORGANS
WARFARIN SODIUM
COUMADIN
Coumadin
coumadin
CARDIOVASCULAR SYSTEM
ALDACTONE (NOS)
AMLODIPINE
221
AMLODIPINE BESILATE+OLMESARTAN
AMLODIPINE BESILATE+VALSARTAN
ATENOLOL
ATORVASTATIN
ATORVASTATIN CALCIUM
BENAZEPRIL HYDROCHLORIDE
BENAZEPRIL HYDROCHLORIDE+AMLODIPINE
BESILATE
BETAMETHASONE
Lotrel
lotrel
Celestone
20APR2010 07:42
RM2010/00132/00
ADC111114
BENAZEPRIL
CONFIDENTIAL
AMLODIPINE BESILATE
ALDACTONE
Aldactone
Amlodipine
Amplodine
amlodipine
AMLODIRINE BESYLATE
NORVASC
Norvasc
amlodipine besylate
norvasc
Azor - amlodipine/olmesartan
medoxomil 10/40 mg
Exforge
ATENELOL
ATENOLOL
Atenolol
atenolol
Astrovastatin
Atorvastatin
LIPITOR
Lipitor
lipitor
BENAZEPRIL
benazepril
LOTENSIN
LOTREL
Protocol: ADC111114
Population: Intent-to-Treat
Page 18 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
222
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------CARDIOVASCULAR SYSTEM
BUMETANIDE
Bumetadine
Bumex
CAPTOPRIL
captopril
CARVEDILOL
CARVESILOL
Carvedilol
Carvediolol
Coreg
Corrreg
coreg
CHLORTALIDONE
Chlorthalidone
CHLORTALIDONE+ATENOLOL
ATENOLOL/CHLORTHALIDONE
CLONIDINE
Clonidine
clonidine
COLESTYRAMINE
cholestyramine
DEXAMETHASONE
DEXAMETHASONE
DEZAMETHAZONE
Dexamethasone
decadron
DIGOXIN
DIGOXIN
Lanoxin
digoxin
DILTIAZEM
Diltiazem
Diltiazem ER
DILTIAZEM HYDROCHLORIDE
Cardizem
Cardizem la
Cartia XL
Cartia XT
DILTIAZEM HCL CR
Tiazac
cartia xt
diltia XT
DOXAZOSIN
doxazosin
DOXAZOSIN MESILATE
CARDURA
Doxazosin Mesylate
Protocol: ADC111114
Population: Intent-to-Treat
Page 19 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
223
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------CARDIOVASCULAR SYSTEM
DOXAZOSIN MESILATE
cardura
ENALAPRIL
ENALAPRIL
Vasotec
vasotec
EZETIMIBE
EZETIMIBE
ZETIA
Zetia
zetia
FENOFIBRATE
TRICOR
Tri Cor
Tricor
anterafenofibrate
fenofibrate
tricor
FISH OIL
FISH OIL
Fish Oil
Fish Oil Tablet
Fish oil
FishOil
fish oil
FLUVASTATIN SODIUM
Fluvastatin Sodium
Lescol
FOSINOPRIL
Fosonapril
FOSINOPRIL SODIUM
Monopril
FUROSEMIDE
Furosemide
LASIX
Lasix
furosemide
lasix
GEMFIBROZIL
GEMFIBROZIL
gemfibrozil
lopid
GINKGO BILOBA
Ginko Biloba
GLYCERYL TRINITRATE
NITRO QUICK
Protocol: ADC111114
Population: Intent-to-Treat
Page 20 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
224
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------CARDIOVASCULAR SYSTEM
GLYCERYL TRINITRATE
NitroQuick
Nitroglycerin
Nitroquick
nitroglycerin
nitroglycerin patch
nitroglycerin cream
HEPARIN (NOS)
heparin
HEPARIN SODIUM
HEPARIN SODIUM
HYDRALAZINE
Hydralazine
HYDRALAZINE HYDROCHLORIDE
Hydralazine HCL
HYDROCHLOROTHIAZIDE
Esidrix
HCTZ
HYDROCHLOROTHIAZIDE
Hydrochlorothiazide
Hydrochlorothyazide
Hydrocholothiazide
Maxide
hydrochlorothiazide
hydrochlorthiazide
HYDROCHLOROTHIAZIDE+BENAZEPRIL
Lotensin HCT
HYDROCHLORIDE
HYDROCHLOROTHIAZIDE+BISOPROLOL
Bisoprolol/HCTZ
HYDROCHLOROTHIAZIDE+IRBESARTAN
Avalide
HYDROCHLOROTHIAZIDE+LISINOPRIL
LISINOPRIL - HCTZ
ZESTORETIC
hydrochorothiazide/lisinopril
lisinopril/HCTZ
lisinopril/hctz
lisinopril/hydrochlorothiazide
zestoretic
HYDROCHLOROTHIAZIDE+LOSARTAN POTASSIUM
Hyzaar
HYDROCHLOROTHIAZIDE+MOEXIPRIL HYDROCHLORIDE uniretic
HYDROCHLOROTHIAZIDE+OLMESARTAN
benicar HCT
HYDROCHLOROTHIAZIDE+VALSARTAN
Diovan HCT
Protocol: ADC111114
Population: Intent-to-Treat
Page 21 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
225
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------CARDIOVASCULAR SYSTEM
HYDROCHLOROTHIAZIDE+VALSARTAN
diovan-hct
HYDROCORTISONE
Hydrocortisone Cream 1%
Hydrocortisone ointment
INDAPAMIDE
INDAPAMIDE
Indapamide
INDOMETACIN
INDOCIN
Indamethacin
Indocin
Indomethacin
IRBESARTAN
avapro
ISOSORBIDE
Isosorbide
ISOSORBIDE MONONITRATE
Isosorbide Mononitrate
LIDOCAINE
1% lidocaine
1% xylocaine
LIDODERM 5%
LIDODERM PATCHES
Lidocaine
Lidocaine 1%
Lidocaine 1% Injection
XYLOCAINE 1.5%
LIDOCAINE HYDROCHLORIDE
Viscous xlyocaine
XYLOCAINE 2%
LISINOPRIL
LISINOPRIL
LISINOPROL
Lisinopril
Lisinpril
lisinopril
LOSARTAN POTASSIUM
Cozaar
LOVASTATIN
LOVASTATIN
Lovastatin
lovastatin
MAGNESIUM CHLORIDE
Slow-Mag
METOLAZONE
metolazone
METOPROLOL
METOPROLOL
Protocol: ADC111114
Population: Intent-to-Treat
Page 22 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
226
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------CARDIOVASCULAR SYSTEM
METOPROLOL
Metoprolol
Metoprolol ER
metoprolol
metroprolol
METOPROLOL SUCCINATE
Metoprolol Succinate
TOPROL
TOPROL XL
Toporol XL
Toprol
Toprol XL
Toprol xl
METOPROLOL TARTRATE
Metoprolol Tartrate
Metroprolol Tartrate
MONASCUS PURPUREUS
Red yeast rice
NICOTINIC ACID
NIACIN
NIASPAN
Niacin
Niaspan
Niaspan ER
niacin
niaspan
NIFEDIPINE
NIFEDICAL XL
NIFEDIPINE
Nifedipine
Nifedipine ER
Procardia
procardia
OLMESARTAN
benicar
OMEGA-3 MARINE TRIGLYCERIDES
Fish Oil omega 3
Omega 3 Vitamin
Omega 3 fish oil
Omega-3
omega 3
omega 3 fis oil
Protocol: ADC111114
Population: Intent-to-Treat
Page 23 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
227
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------CARDIOVASCULAR SYSTEM
PHENYLEPHRINE
Contac-D
PRAVASTATIN
PRAVASTATIN
PREVASTATIN
Pravastain
Pravastatin
Provastatin
provastatin
PRAVASTATIN SODIUM
PRAVACHOL
Pravachol
pravachol
PREDNISOLONE
prednisolone opthalmic
QUINAPRIL
Accupril
RAMIPRIL
Altace
Ramipril
RANOLAZINE
Ranolazine
ROSUVASTATIN CALCIUM
Crestor
crestor
SIMVASTATIN
SIMVASTATIN
Simvastatin
Simvastatin - 40mg
Simvistatin
Zocor
simvastatin
simvistatin
symvastatin
zocor
SIMVASTATIN+EZETIMIBE
Vytorin
vytorin
SPIRONOLACTONE
Spironolactone
spironolactone
TADALAFIL
CIALIS
TELMISARTAN
Micardis
micardis
TERAZOSIN
TERAZOSIN
Protocol: ADC111114
Population: Intent-to-Treat
Page 24 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
DERMATOLOGICALS
ACITRETIN
ACYCLOVIR
BETAMETHASONE
CALCIPOTRIOL
CALCITRIOL
20APR2010 07:42
RM2010/00132/00
ADC111114
ANTIBIOTICS NOS
BACITRACIN
BECLOMETASONE DIPROPIONATE
BENADRYL (NOS)
Soriatane
Acylcovir
acyclovir
unk I.V. Antibiotic
Bacitracin Ophthalmic ointment
qvar
BENADRYL
Benadryl
benadryl
Celestone
1% dovonex cream
Dovonex ointment
duvonex
Calcitroil
CONFIDENTIAL
228
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------CARDIOVASCULAR SYSTEM
TERAZOSIN
terasosin
terazosin
TERAZOSIN HYDROCHLORIDE
HYTRIN
Terazosin (Hytrin)
hytrin
terazosin hydrochloride
TIMOLOL
Timolol 0.5%
TIMOLOL MALEATE
TIMOPTIC-XE
TOCOPHEROL+FISH OIL
omega fish oil
TRANDOLAPRIL
Mavik
TRIAMTERENE
Triamterene
TRIAMTERENE+HYDROCHLOROTHIAZIDE
Dyazide
Triamterene/HCTZ
triamterene/HCTZ
UBIDECARENONE
CoQ10
VALSARTAN
Diovan
diovan
VERAPAMIL
verapamil
VERAPAMIL HYDROCHLORIDE
Varapamil
Protocol: ADC111114
Population: Intent-to-Treat
Page 25 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
229
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------DERMATOLOGICALS
CHLORHEXIDINE GLUCONATE
Hibiclens
CLINDAMYCIN
Clindamycin
CLOBETASOL PROPIONATE
Temovate
CLOTRIMAZOLE
Mycelex Troches
clotrimazole
clotrimozole
COAL TAR
PSORIGEL OINTMENT
COD-LIVER OIL
COD LIVER OIL
Codliver Oil
DEXAMETHASONE
DEXAMETHASONE
DEZAMETHAZONE
Dexamethasone
decadron
DIPHENHYDRAMINE
DIPHENHYDRAMINE
Diphenhydramine
DIPHENHYDRAMINE HYDROCHLORIDE
BENADRYL ALLERGY
Tylenol simply sleep
DOXEPIN HYDROCHLORIDE
Doxepin HLC
ERYTHROMYCIN ETHYLSUCCINATE
erythrometh
ETHANOL+IODINE
Dura Prep
FINASTERIDE
FINAZLERIDE
Finasteride
PROSCAR
Proscar
proscar
FLUCONAZOLE
DIFLUCAN
Diflucan
diflucan
fluconazole
FLUTICASONE
Fluticasone
FLUTICASONE PROPIONATE
Flonase
Flovent
Flovent [110mcg]
flonase
Protocol: ADC111114
Population: Intent-to-Treat
Page 26 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
230
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------DERMATOLOGICALS
FLUTICASONE PROPIONATE
flovent
fluticasone nasal spray
GELATIN
GELATIN
GENTAMICIN
Gentamicin
GLYCEROL+BETAINE+CARBOMER+OLEA EUROPAEA
Mimyx
OIL+HYETELLOSE+SQUALANE+VEGETABLE OIL
GLYCERYL TRINITRATE
NITRO QUICK
NitroQuick
Nitroglycerin
Nitroquick
nitroglycerin
nitroglycerin patch
nitroglycerin cream
HYDROCORTISONE
Hydrocortisone Cream 1%
Hydrocortisone ointment
HYDROGEN PEROXIDE
Hydrogen peroxide
KETOCONAZOLE
KETCONZOLE SHAMPOO
LEVOMENTHOL
Flex-All
LIDOCAINE
1% lidocaine
1% xylocaine
LIDODERM 5%
LIDODERM PATCHES
Lidocaine
Lidocaine 1%
Lidocaine 1% Injection
XYLOCAINE 1.5%
LIDOCAINE HYDROCHLORIDE
Viscous xlyocaine
XYLOCAINE 2%
METHYL HYDROXYBENZOATE
METHYL-PARABEN
METHYLPREDNISOLONE
Depo-Medrol
METHLPREDNISONOLNE
METHLPREDNISOOLONE
METHYLPREDNISOLONE
METHYLPRESNISONE
Protocol: ADC111114
Population: Intent-to-Treat
Page 27 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
231
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------DERMATOLOGICALS
METHYLPREDNISOLONE
Medrol
Medrol Dose pack
Medrol dose Pack,4 mg
Methylprednisolone
Methylprednisone
medrol dosepack
methylprednisone
methylprenisone
METHYLPREDNISOLONE ACETATE
DEPOMEDAL
Depo Medrol
depomedrol
METHYLPREDNISOLONE SODIUM SUCCINATE
Solu-Medrol
Solu-medrol
Solumedrol
solumedrol
METHYLROSANILINIUM CHLORIDE
Gentian violet
METRONIDAZOLE
FLAGYL
Flagyl
Metrogel
Metrogel cream
Metronidazole
Metronidazole (Flagyl )
metrogel
MOMETASONE
Mometasone
MOMETASONE FUROATE
Asmanex
ELOCON CREAM
Nasonex
asmanex
NEOMYCIN SULFATE+POLYMYXIN B
Neosporin Ointment SULFATE+BACITRACIN ZINC
Neosporin/Polymixin/Dexamethas
one ointment
NEOSPORIN (NOS)
Neosporin
NYSTATIN
Mycostatin Suspension
Nystatin
Protocol: ADC111114
Population: Intent-to-Treat
Page 28 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
ANTIBIOTICS NOS
unk I.V. Antibiotic
20APR2010 07:42
RM2010/00132/00
ADC111114
GENITO URINARY SYSTEM AND SEX
HORMONES
CONFIDENTIAL
232
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------DERMATOLOGICALS
NYSTATIN
nystatin suspension
POVIDONE-IODINE
Betadine
PREDNISOLONE
prednisolone opthalmic
PROMETHAZINE
Phenergan
Phernergan
Promethazine
phenergan
promethazine
PROPYLPARABEN
PROPYLPARABEN
RETINOL
Vitamin A
SELENIUM
selenium
TACROLIMUS
Protopic
Protopoc Ointmenmt
TERBINAFINE
terbinafine
TETRACYCLINE
Tetracycline
TETRACYCLINE HYDROCHLORIDE
tetracyclin
TOCOPHEROL
VITAMIN E
Vitamin E
vitamin E
TOCOPHERYL ACETATE+ALLANTOIN+HYALURONATE
Atopiclair
SODIUM+TELMESTEINE+VITIS VINIFERA+PIROCTONE
OLAMINE+BISABOL
TRIAMCINOLONE
Triamcinolone
TRIAMCINOLONE ACETONIDE
Kenalog
Kenalog Injection
NASACORT AQ
Nasacort
Triamcinelone Cream
nasocort AQ
TRIAMCINOLONE ACETONIDE+ECONAZOLE NITRATE
Ecotrim
TRIAMCINOLONE ACETONIDE+NYSTATIN
NYSTATIN/TRIAMCINOLONE
Protocol: ADC111114
Population: Intent-to-Treat
Page 29 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
233
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------GENITO URINARY SYSTEM AND SEX
BACITRACIN
Bacitracin Ophthalmic ointment
HORMONES
CLINDAMYCIN
Clindamycin
CLOTRIMAZOLE
Mycelex Troches
clotrimazole
clotrimozole
DARIFENACIN HYDROBROMIDE
Enablex
DIMETHYL SULFONE
MSM
DUTASTERIDE
Avodart
avadart
ESTRADIOL
ESTRADIOL
estrace
estradiol
ESTRADIOL+LEVONORGESTREL
Climara Pro
ESTRADIOL+NORGESTIMATE
Ortho-Prefest
ESTROGENS CONJUGATED
Cenestin Synthetic
PREMARIN CREAM
Premarin
premarin
ESTROGENS CONJUGATED+MEDROXYPROGESTERONE
prempro
ACETATE
ETHINYLOESTRADIOL+NORETHISTERONE ACETATE
femhrt
FINASTERIDE
FINAZLERIDE
Finasteride
PROSCAR
Proscar
proscar
FURADONINE
Nitrofurantoin
nitrofurantoin
IBUPROFEN
ADVIL
Advil
IBUPROFEN
Ibuprofen
Ibuprofen ( Advil )
Protocol: ADC111114
Population: Intent-to-Treat
Page 30 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
234
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------GENITO URINARY SYSTEM AND SEX
IBUPROFEN
MOTRIN
HORMONES
Motrin
Motrin IB
advil
ibuprofen
ibuprophen
motrin
KETOCONAZOLE
KETCONZOLE SHAMPOO
MAGNESIUM HYDROXIDE
MILK OF MAGNESIA
MEGESTROL ACETATE
MEGACE
METHYLROSANILINIUM CHLORIDE
Gentian violet
METRONIDAZOLE
FLAGYL
Flagyl
Metrogel
Metrogel cream
Metronidazole
Metronidazole (Flagyl )
metrogel
NAPROXEN
NAPROXIN
Naproxen
Naproxin
naproxen
NAPROXEN SODIUM
Aleve
aleve
anaprox DS
NORETHISTERONE
Micro Nor
NYSTATIN
Mycostatin Suspension
Nystatin
nystatin suspension
OXYBUTYNIN
ORYBUTYNIN
OXYBUTYNIN HYDROCHLORIDE
DITROPAN
Oxybutin
oxybutynin chloride
Protocol: ADC111114
Population: Intent-to-Treat
Page 31 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
ACETYLSALICYLIC ACID
ASA
ASPIRIN
ASPIRIN - ENTERIC COASTED
ASPIRIN ENTERIC COATED
20APR2010 07:42
RM2010/00132/00
ADC111114
MUSCULO-SKELETAL SYSTEM
CONFIDENTIAL
235
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------GENITO URINARY SYSTEM AND SEX
PHENAZOPYRIDINE
phenazopyridine
HORMONES
POVIDONE-IODINE
Betadine
RALOXIFENE HYDROCHLORIDE
Evista
SERENOA REPENS
SAW PALMETTO
Saw Palmetto
SILDENAFIL CITRATE
VIAGRA
viagra
SODIUM PHOSPHATE MONOBASIC
Sodium biphosphate
SOLIFENACIN SUCCINATE
Vesicare
vesicar
vesicare
TADALAFIL
CIALIS
TAMSULOSIN
tamsulosin
TAMSULOSIN HYDROCHLORIDE
Flomax / Tamsulosin HCI
flomax
tamsulosin(flomax)
TERAZOSIN
TERAZOSIN
terasosin
terazosin
TERAZOSIN HYDROCHLORIDE
HYTRIN
Terazosin (Hytrin)
hytrin
terazosin hydrochloride
TOLTERODINE TARTRATE
Detrol
Detrol LA
VACCINIUM MACROCARPON
Cranberry Fruit Tablet
Cranberry Pill
VARDENAFIL HYDROCHLORIDE
Levitra
Protocol: ADC111114
Population: Intent-to-Treat
Page 32 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
236
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------MUSCULO-SKELETAL SYSTEM
ACETYLSALICYLIC ACID
ASPRIN
Aspirin
Asprin
Baby Aspirin
Bayer Aspirin
Bufferin
EXTRA STRENGTH ASPIRIN
Ecotrin
Enteric coated Aspirin
apirin
aspiirn
aspirin
asprin
ALENDRONATE SODIUM
Fosamax
fosamax
ALLOPURINOL
Allopurinol
allopurinol
BACLOFEN
Baclofen
baclofen
BROMFENAC SODIUM
Xibrom opthalmic solution
CARISOPRODOL
SOMA
Soma
carisoprodol
soma
CELECOXIB
Celebrex
Celecoxib
celebrex
CHONDROITIN
Chondroitin
CHONDROITIN+GLUCOSAMINE
glucasamine chondritin
CHONDROITIN+GLUCOSAMINE+COLLAGEN
Joint Care GLUCOSAMINE,
CHONDRITIN, AND COLLAGEN
COLCHICINE
Colchicine
CYCLOBENZAPRINE
Cyclobenzaprine
cyclobenzaprine
Protocol: ADC111114
Population: Intent-to-Treat
Page 33 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
237
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------MUSCULO-SKELETAL SYSTEM
CYCLOBENZAPRINE HYDROCHLORIDE
FLEXERIL
FLEXEROL
Flexeril
Flexeril - 10mg
Flexoril
felexeril
flexeril
DICLOFENAC
DICLOFENAC
Diclofenac
diclofenac
DICLOFENAC HYDROXYETHYLPYRROLIDINE
FLECTOR PATCHES
DICLOFENAC SODIUM
voltaren
DIMETHYL SULFONE
MSM
ERGOCALCIFEROL+ALENDRONIC ACID
Fosamax/ Brisphosphonate and
Vit. D
GLUCOSAMINE
Glucosamine
glucosamine
GLUCOSAMINE SULFATE
Glucosamine Sulfate
GLUCOSAMINE SULFATE+DIMETHYL SULFONE
Glucosamine MSM
HYDROXYCHLOROQUINE
hydroxychloroquine
(antibiotic)
HYDROXYCHLOROQUINE SULFATE
Plaquenil
IBUPROFEN
ADVIL
Advil
IBUPROFEN
Ibuprofen
Ibuprofen ( Advil )
MOTRIN
Motrin
Motrin IB
advil
ibuprofen
ibuprophen
motrin
Protocol: ADC111114
Population: Intent-to-Treat
Page 34 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
238
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------MUSCULO-SKELETAL SYSTEM
INDOMETACIN
INDOCIN
Indamethacin
Indocin
Indomethacin
KETOROLAC TROMETAMOL
Ketorolac Tromethamine
TORADOL
Toradol
Torodol
ketorolac tromethamine
toradol
toridol
LEFLUNOMIDE
Leflunomide
arava
LEVOMENTHOL
Flex-All
MELOXICAM
MELOXICAM
MELOXICAN
MOBIC
Metoxican
Mobic
meloxicam
mobic
METAXALONE
SKELAXIN
skelaxin
METHOCARBAMOL
methocarbanol
NAPROXEN
NAPROXIN
Naproxen
Naproxin
naproxen
NAPROXEN SODIUM
Aleve
aleve
anaprox DS
OXAPROZIN
oxaprozin
PARACETAMOL+CHLORZOXAZONE
Parafon Forte
PIROXICAM
Piroxicam
Protocol: ADC111114
Population: Intent-to-Treat
Page 35 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
239
NERVOUS SYSTEM
ACETYLSALICYLIC ACID
ACETYLSALICYLIC ACID+PARACETAMOL+CAFFEINE
20APR2010 07:42
RM2010/00132/00
ADC111114
ACETYLSALICYLIC ACID+CAFFEINE+SALICYLAMIDE
ASA
ASPIRIN
ASPIRIN - ENTERIC COASTED
ASPIRIN ENTERIC COATED
ASPRIN
Aspirin
Asprin
Baby Aspirin
Bayer Aspirin
Bufferin
EXTRA STRENGTH ASPIRIN
Ecotrin
Enteric coated Aspirin
apirin
aspiirn
aspirin
asprin
BC POWDER
BC Powder
Excedrin Migraine
CONFIDENTIAL
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------MUSCULO-SKELETAL SYSTEM
PROBENECID
Probenecid
QUININE
Leg Cramps with Quinine (OTC)
RISEDRONATE SODIUM
Actonel
actonel
ROCURONIUM BROMIDE
ZEMURON
SODIUM IBANDRONATE
Boniva
boniva
SULINDAC
sulindac
TERIPARATIDE
forteo
TIZANIDINE
Tizanidine
TROLAMINE SALICYLATE
AsperCreme with Aloe
ZOLEDRONIC ACID
Reclast
reclast
Protocol: ADC111114
Population: Intent-to-Treat
Page 36 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
240
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------NERVOUS SYSTEM
ACETYLSALICYLIC ACID+SODIUM
ALKA-SELTZER
BICARBONATE+CITRIC ACID
alkaseltzer
ALPRAZOLAM
ALPRAZOLAM
Alprazolam
Alprozalam
XANAX
Xanax
alprazolam
xanax
AMITRIPTYLINE
Amitriptyline
amitriptlyine
AMITRIPTYLINE HYDROCHLORIDE
Elavil
amitriptylin
amitripylin
elavil
elavil(amitryptyline)
ARIPIPRAZOLE
Abilify
BETHANECHOL CHLORIDE
bethanechol chloride
BROMFENAC SODIUM
Xibrom opthalmic solution
BUPIVACAINE
Bupivacaine
BUPIVACAINE HYDROCHLORIDE
Marcaine
Marcaine 0.25%
marcaine
BUPROPION
BUPROPRION
Bupropion
Bupropion SR
bupropion
BUPROPION HYDROCHLORIDE
Aminoketone Bupropion HCL
WELLBUTRIN
Wellbutrin
wellbutrin
BUSPIRONE HYDROCHLORIDE
BUSPAR
Buspar
Protocol: ADC111114
Population: Intent-to-Treat
Page 37 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
241
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------NERVOUS SYSTEM
BUSPIRONE HYDROCHLORIDE
buspar
CHLORDIAZEPOXIDE
Librium
CITALOPRAM HYDROBROMIDE
CELEXA
Celexa
celexa
CLONAZEPAM
Clonazapam
Clonazepam
Klonopin
clonazepam
klonopin
klonpin
CLONIDINE
Clonidine
clonidine
CLOZAPINE
Clozapine
CYCLOBENZAPRINE
Cyclobenzaprine
cyclobenzaprine
CYCLOBENZAPRINE HYDROCHLORIDE
FLEXERIL
FLEXEROL
Flexeril
Flexeril - 10mg
Flexoril
felexeril
flexeril
DEXTROPROPOXYPHENE NAPSILATE+PARACETAMOL
Darvocet
Darvocet N-100
darvocet
darvocet n100
DIAZEPAM
VALIUM
Valium
diazepam
valium
DIPHENHYDRAMINE CITRATE+IBUPROFEN
Ibuprofen/diphenhydraimine (
Advil PM )
DIPHENHYDRAMINE HYDROCHLORIDE+PARACETAMOL
TYLENOL PM
Protocol: ADC111114
Population: Intent-to-Treat
Page 38 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
242
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------NERVOUS SYSTEM
DIPHENHYDRAMINE HYDROCHLORIDE+PARACETAMOL
Tylenol PM
tylenol PM
tylenol pm
DIPHENHYDRAMINE+PARACETAMOL
Acetaminophen Diphenhydramin
acetaminophen with
Diphenhydramine
DOXEPIN
Doxepin
DOXEPIN HYDROCHLORIDE
Doxepin HLC
DULOXETINE HYDROCHLORIDE
Cymbalta
cymbalta
EPINEPHRINE+LIDOCAINE
1% lidocaine with epinephrine
Lidocaine 1%/ Epinephrine
ESCITALOPRAM OXALATE
Escitalopram Oxalate
LEXAPRO
Lexapro
lexapro
FENTANYL
Fentanyl
Fentil patch
fentanyl
FENTANYL CITRATE
Actiq
SUBLIMAZE
FLUOXETINE
FLUOXETINE
Fluoxetine
FLUOXETINE HYDROCHLORIDE
PROZAC
Prozac
FLURAZEPAM
flurazepam
GABAPENTIN
GABAPENTIN
Gabapentin
NEUROTIN
Neurontin
Neurotin
gabapentin
neurontin
GINKGO BILOBA
Ginko Biloba
Protocol: ADC111114
Population: Intent-to-Treat
Page 39 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
243
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------NERVOUS SYSTEM
HALOPERIDOL
haloperidol
HALOTHANE
Halothane
HYDROCODONE
HYDROCODONE
Hydrocodone
Hydrocodone 7.5/500
Hyrdocodone
hydrocodone
HYDROXYZINE
ATARAX
Vistaril
Visteral
hydroxyzine
HYDROXYZINE HYDROCHLORIDE
Hydoxycine HCL
Hydroxyzine HCl
IBUPROFEN
ADVIL
Advil
IBUPROFEN
Ibuprofen
Ibuprofen ( Advil )
MOTRIN
Motrin
Motrin IB
advil
ibuprofen
ibuprophen
motrin
KETOROLAC TROMETAMOL
Ketorolac Tromethamine
TORADOL
Toradol
Torodol
ketorolac tromethamine
toradol
toridol
LEVETIRACETAM
Keppra
LIDOCAINE
1% lidocaine
Protocol: ADC111114
Population: Intent-to-Treat
Page 40 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
244
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------NERVOUS SYSTEM
LIDOCAINE
1% xylocaine
LIDODERM 5%
LIDODERM PATCHES
Lidocaine
Lidocaine 1%
Lidocaine 1% Injection
XYLOCAINE 1.5%
LIDOCAINE HYDROCHLORIDE
Viscous xlyocaine
XYLOCAINE 2%
LORAZEPAM
ATIVAN
Ativan
LORAZEPAM
Loraxepam
Lorazepam
ativan
lorazepam
MIDAZOLAM
VERSED
Versed
medazolam
veresd
versed
MIRTAZAPINE
Mirtazapine
Remron
remeron
MODAFINIL
provigil
MORPHINE
MORPHINE
Morphine
morphine
MORPHINE SULFATE
MORPHINE SULFATE
MS Contin
NALBUPHINE HYDROCHLORIDE
Nubain
NEFAZODONE
NEFAZODONE
NEOSTIGMINE
PROSTIGMIN
NICOTINE
Nicoderm CQ
Protocol: ADC111114
Population: Intent-to-Treat
Page 41 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
245
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------NERVOUS SYSTEM
NICOTINE
Nicotine Patch
nicorette patch
nicotine patch
NORTRIPTYLINE
NORTRIPYLIN
OLANZAPINE
ZYPREXA
OXYCODONE
Oxycodone
oxycodone
OXYCODONE HYDROCHLORIDE
Oxycontin
Roxicodone
PARACETAMOL
ACEMINOPHEN
ACETAMINOPHEN
ACTEAMINOPHEN
APAP
Acetaminophen
Extra Stength Tylenol
Extra Strength Tylenol
Extra strenght tylenol
Extra strength Tylenol
REGULAR STRENGTH TYLENOL
TYLENOL
TYLENOL TABLETS
Tyenol
Tylenol
Tylenol ES
Tylenol Extra Strength
Tylenol PRN
Tylenol extra strength
Xtra Strength tylenol
acetaminophen
extra strength tylenol
tylenol
tylenol ES
tylenol arthritis
tylenol extra strength
Protocol: ADC111114
Population: Intent-to-Treat
Page 42 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
246
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------NERVOUS SYSTEM
PARACETAMOL+CAFFEINE+BUTALBITAL
Fioicet
Fioricet
PARACETAMOL+CHLORPHENAMINE
Alka Seltzer Plus
MALEATE+PHENYLEPHRINE HYDROCHLORIDE
PARACETAMOL+DICHLORALPHENAZONE+ISOMETHEPTEN Duradrin
E MUCATE
Midrin
PARACETAMOL+HYDROCODONE
Hydrocodone/APAP
Hydrocodone/Acetaminophen
hydrocodone/APAP
PARACETAMOL+HYDROCODONE BITARTRATE
LORTAB
Lortab
Lortab 10/500 mg
Lortab [500/50 mg PRN]
Norco
VICODIN
Vicoden ES
Vicodin
lortab
norco
vicodin es
PARACETAMOL+OXYCODONE HYDROCHLORIDE
PERCOCET
Percocet
percocet
PAROXETINE
Paroxetine
paroxetine
PAROXETINE HYDROCHLORIDE
Paroxetine HCL
Paxil
Paxil CR
paroxetine HCL
paxil
PETHIDINE
Meperidine
Meperitab
PETHIDINE HYDROCHLORIDE
Demerol
Protocol: ADC111114
Population: Intent-to-Treat
Page 43 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
247
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------NERVOUS SYSTEM
PHENYTOIN
Dilantin
PHENYTOIN
PRAMIPEXOLE DIHYDROCHLORIDE
Mirapex
Mirpex
PREGABALIN
LYRICA
Lyrica
lyrica
PRIMIDONE
primidone
PROMETHAZINE
Phenergan
Phernergan
Promethazine
phenergan
promethazine
PROPOFOL
DIPRIVAN
Propofol
QUETIAPINE FUMARATE
SERAQUEL
SEROQUEL
Seroquel
seroquel
RIZATRIPTAN BENZOATE
maxalt-10
ROPINIROLE HYDROCHLORIDE
Requip
Ropinirole HCL
ROPIVACAINE
Ropivacaine 0.5%
SECBUTABARBITAL
BUTISOL
SERTRALINE
Sereraline
SERTRALINE HYDROCHLORIDE
ZOLOFT
Zoloft
zoloft
SEVOFLURANE
Sevoflurane
TEMAZEPAM
RESTORIL
TAMAZEPAN
Temazepam
Tempazepam
restoril
Protocol: ADC111114
Population: Intent-to-Treat
Page 44 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
248
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------NERVOUS SYSTEM
TEMAZEPAM
temazepam
TOMEXETINE HYDROCHLORIDE
Strattera
TOPIRAMATE
Topamax
topamax
TRAMADOL
TRAMADOL
TRAMODOL
Tramadol
tramadol
tramodol
TRAMADOL HYDROCHLORIDE
Ultram
tramadol hcl
ultram
TRAZODONE
TRAZADOME
TRAZADONE
Trazadone
Trazodone
trazadone
trazodone
TRIAZOLAM
Halcion
TYLENOL #3 (NOS)
Tylenol #3
VALPROIC ACID
DEPAKOTE
depakote
VARENICLINE TARTRATE
Chantix
chantex
chantix
VENLAFAXINE HYDROCHLORIDE
EFFEXOR
Effexor
ZIPRASIDONE HYDROCHLORIDE
GEODON
ZOLPIDEM
zolpidem
ZOLPIDEM TARTRATE
AMBIEN
AMBIEN CR
Ambien
Ambien Cr
ambien
Protocol: ADC111114
Population: Intent-to-Treat
Page 45 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
249
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------RESPIRATORY SYSTEM
ACETYLCYSTEINE
acetylcysteine
ANTIBIOTICS NOS
unk I.V. Antibiotic
AZELASTINE
Astepro
BACITRACIN
Bacitracin Ophthalmic ointment
BECLOMETASONE DIPROPIONATE
qvar
BENADRYL (NOS)
BENADRYL
Benadryl
benadryl
BENZONATATE
Benzonatate
Tesslon Perles
benzonatate
BETAMETHASONE
Celestone
BUDESONIDE+FORMOTEROL FUMARATE
Symbicort
symbicort
CETIRIZINE
certirizine
cetirizine
CETIRIZINE HYDROCHLORIDE
Cetirizine HCL
ZYRTEC
Zyrtec
zyrtec
CHLORHEXIDINE GLUCONATE
Hibiclens
CODEINE+PROMETHAZINE
promethazine with codeine
CORICIDIN (NOS)
Coricidine
COUGH COLD PREPARATIONS NOS
OTC COUGH DROPS
Tylenol Cold & Sinus
alka seltzer cold capsule
DESLORATADINE
Clarinex
DEXAMETHASONE
DEXAMETHASONE
DEZAMETHAZONE
Dexamethasone
decadron
DIPHENHYDRAMINE
DIPHENHYDRAMINE
Diphenhydramine
Protocol: ADC111114
Population: Intent-to-Treat
Page 46 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
250
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------RESPIRATORY SYSTEM
DIPHENHYDRAMINE CITRATE+IBUPROFEN
Ibuprofen/diphenhydraimine (
Advil PM )
DIPHENHYDRAMINE HYDROCHLORIDE
BENADRYL ALLERGY
Tylenol simply sleep
DIPHENHYDRAMINE HYDROCHLORIDE+PARACETAMOL
TYLENOL PM
Tylenol PM
tylenol PM
tylenol pm
EPHEDRINE
Ephedrine
EPHEDRINE SULFATE
EPHEDRINE SULFATE
FEXOFENADINE
Fexafenadine
fexofenadine
FEXOFENADINE HYDROCHLORIDE
ALLEGRA
Allegra
FLUNISOLIDE
Aerobid
flunisolide nasal spray
FLUTICASONE
Fluticasone
FLUTICASONE FUROATE
Veramyst
FLUTICASONE PROPIONATE
Flonase
Flovent
Flovent [110mcg]
flonase
flovent
fluticasone nasal spray
FORMOTEROL
fomoterol
formoterol
FORMOTEROL FUMARATE
FORADIL
Foradil
foradil
foradil inhaler
formoterol fumarate
GUAIFENESIN
GUAIFENESIN
MUCINEX
Muccinex
Protocol: ADC111114
Population: Intent-to-Treat
Page 47 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
251
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------RESPIRATORY SYSTEM
GUAIFENESIN
Mucinex
guafenesin
guaifenesin
guifenesin
mucinex
musinex
GUAIFENESIN+DEXTROMETHORPHAN
guaifenesin/dextromethorphan
tablets
GUAIFENESIN+DEXTROMETHORPHAN HYDROBROMIDE
Chest Congestion Relief DM
(brand name) Dextromethorphan
HBr/Guaifenesin
Mucinex DM
mucinex dm
GUAIFENESIN+DEXTROMETHORPHAN
Tussin CF
HYDROBROMIDE+PHENYLPROPANOLAMINE
HYDROCHLORIDE
GUAIFENESIN+DIPROPHYLLINE
Panfil G
GUAIFENESIN+PSEUDOEPHEDRINE
guafenesin/psuedoephedrine
GUAIFENESIN+PSEUDOEPHEDRINE HYDROCHLORIDE
Guaifensin/Pseudophedrine HCI
( Mucinex DM )
Mucinex D
HYDROCODONE
HYDROCODONE
Hydrocodone
Hydrocodone 7.5/500
Hyrdocodone
hydrocodone
HYDROCODONE POLISTIREX+CHLORPHENIRAMINE
Tusionex Pennkinetic ER
POLISTIREX
HYDROCODONE+PHENYLTOLOXAMINE
TUSSIONIX
Tussionex
IPRATROPIUM
ipratropium
IPRATROPIUM BROMIDE
ATROVENT
Atrovent
Ipratropium Bromide - NEB
Protocol: ADC111114
Population: Intent-to-Treat
Page 48 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
252
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------RESPIRATORY SYSTEM
IPRATROPIUM BROMIDE
atrovent
LEVALBUTEROL TARTRATE
Xopenex HFA
LEVOCETIRIZINE HYDROCHLORIDE
XYZAL
LEVOMENTHOL
Flex-All
LEVOSALBUTAMOL HYDROCHLORIDE
XOPENEX
Xopenex
xopenex
xopenex nebulizer
xoponex
xoponex nebules
LIDOCAINE
1% lidocaine
1% xylocaine
LIDODERM 5%
LIDODERM PATCHES
Lidocaine
Lidocaine 1%
Lidocaine 1% Injection
XYLOCAINE 1.5%
LIDOCAINE HYDROCHLORIDE
Viscous xlyocaine
XYLOCAINE 2%
LORATADINE
Claritin
claritin
loratadine
MECLOZINE
MECLIZINE
Meclizine
MECLOZINE HYDROCHLORIDE
Antivert
antivert
METHYL
Listerine mouth wash
SALICYLATE+THYMOL+LEVOMENTHOL+CINEOLE
MOMETASONE
Mometasone
MOMETASONE FUROATE
Asmanex
ELOCON CREAM
Nasonex
asmanex
Protocol: ADC111114
Population: Intent-to-Treat
Page 49 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
253
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------RESPIRATORY SYSTEM
MONTELUKAST SODIUM
SINGULAIR
SINGULAR
Singulair
Singular
singulair
OTHER RESPIRATORY SYSTEM PRODUCTS NOS
SINUS TABLET
OXYGEN
Oxygen
Oxygen - 2L PRN
Oxygen prn
oxygen
oxygen prn
OXYMETAZOLINE HYDROCHLORIDE
Afrin
PARACETAMOL+CHLORPHENAMINE
Alka Seltzer Plus
MALEATE+PHENYLEPHRINE HYDROCHLORIDE
PARACETAMOL+CHLORPHENAMINE
TheraFLU
MALEATE+PSEUDOEPHEDRINE HYDROCHLORIDE
PARACETAMOL+DEXTROMETHORPHAN
Acetominophan,
HYDROBROMIDE+PHENYLEPHRINE HYDROCHLORIDE
Dextromethorphan hydrobromide,
Phenylephrine hydrochloride
PARACETAMOL+DEXTROMETHORPHAN
Tylenol cough syrup
HYDROBROMIDE+PSEUDOEPHEDRINE HYDROCHLORIDE
PARACETAMOL+DEXTROMETHORPHAN
NYQUIL
HYDROBROMIDE+PSEUDOEPHEDRINE
HYDROCHLORIDE+DOXYLAMINE SUCCINATE
Nyquil
PARACETAMOL+GUAIFENESIN
Topcare Chest Congestion
PARACETAMOL+HYDROCODONE
Hydrocodone/APAP
Hydrocodone/Acetaminophen
hydrocodone/APAP
PHENYLEPHRINE
Contac-D
POVIDONE-IODINE
Betadine
PREDNISOLONE
prednisolone opthalmic
PROAIR (NOS)
PROAIR
ProAir
Protocol: ADC111114
Population: Intent-to-Treat
Page 50 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
254
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------RESPIRATORY SYSTEM
PROAIR (NOS)
Proair
proair
PROCATEROL
Pro Air
Pro-Air
pro air
PROMETHAZINE
Phenergan
Phernergan
Promethazine
phenergan
promethazine
PSEUDOEPHEDRINE HYDROCHLORIDE
PSEUDOEPHEDRINE HCL
SUDAFED
Sudafed
sudafed
PSEUDOEPHEDRINE HYDROCHLORIDE+FEXOFENADINE ALLEGRA D
HYDROCHLORIDE
Allegra D
Allegra-D
allegra d
PSEUDOEPHEDRINE HYDROCHLORIDE+IBUPROFEN
Advil Cold and Sinus
PSEUDOEPHEDRINE SULFATE+LORATADINE
Claritin D
PSEUDOEPHEDRINE+TRIPROLIDINE
psuesoephedrine/triprolidine
RETINOL
Vitamin A
ROBITUSSIN (NOS)
Robitussin
robitussin
ROBITUSSIN AC (NOS)
Robitussin AC
SALBUTAMOL
Albuterol
ALBUTEROL
ALBUTEROL HFA
ALBUTEROL MDI
ALBUTEROL SOLUTION
Albuterol
Albuterol HFA
Albuterol HHN
Protocol: ADC111114
Population: Intent-to-Treat
Page 51 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
255
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------RESPIRATORY SYSTEM
SALBUTAMOL
Albuterol MDI
Albuterol Nebs
Albuterol Nebules
Albuterol Nebulizer
Albuterol PMDI
Albuterol Solution
Albuterol solution
PROVENTIL
Proventil
VENTOLIN
Ventolin
abuteral
albuterol
albuterol MDI
albuterol inhaler
albuterol nebules
albuterol nebulizer
proventil
SALBUTAMOL SULFATE
Albuterol Sulfate
Albuterol Sulfate - NEB
Albuterol Sulfate HFA
Pro Air FHA
ProAir (Albuterol) HFA
Proair HFA
Proventil HFA
proair HFA
vospire er(Albuterol)
SALBUTAMOL SULFATE+IPRATROPIUM BROMIDE
COMBIVENT
Combivent
DUO-NEB
Duo-Neb
Duoneb
combivent
combivent MDI
Protocol: ADC111114
Population: Intent-to-Treat
Page 52 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
256
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------RESPIRATORY SYSTEM
SALBUTAMOL SULFATE+IPRATROPIUM BROMIDE
duoneb
SALBUTAMOL+IPRATROPIUM
albuterol/ipratropium
SALMETEROL
Salmeterol
SALMETEROL XINAFOATE
Serevent
Serovent
serevent
SALMETEROL XINAFOATE+FLUTICASONE PROPIONATE Advair
Advair 250/50
Advair Diskus
Advair HFA 45/21
advair
advair diskus
SALMETEROL+FLUTICASONE PROPIONATE
Fluticasone
propionate/Saleterol
Fluticasone
propionate/Salmeterol
SODIUM CHLORIDE
NORMAL SALINE
Normal Saline IV
Normal Saline Infusion over 24
hours
Sodium Chloride
THEOPHYLLINE
Theophylline
theophyline
TIOTROPIUM
Tiotropium
tiotropium
TIOTROPIUM BROMIDE
Spiriva
SPIRIVA
Spireva
Spiriva
Spiriva [18mcg]
Spiriva handihaler
Spririva
Spriva
Sprivia
Protocol: ADC111114
Population: Intent-to-Treat
Page 53 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
257
SENSORY ORGANS
ACETYLCYSTEINE
ACYCLOVIR
CIPROFLOXACIN HYDROCHLORIDE
20APR2010 07:42
RM2010/00132/00
ADC111114
ANTIBIOTICS NOS
AZELASTINE
BACITRACIN
BENZYLPENICILLIN
BIMATOPROST
BRIMONIDINE TARTRATE
BROMFENAC SODIUM
CHLORHEXIDINE GLUCONATE
CIPROFLOXACIN
acetylcysteine
Acylcovir
acyclovir
unk I.V. Antibiotic
Astepro
Bacitracin Ophthalmic ointment
Penicillin
lumigan drops
alphagan drops
Xibrom opthalmic solution
Hibiclens
CIPROFLOXACIN
Ciprofloxacin
Ciprofloxin
ciprofloxacin
CIPRO
CIRPO
Cipro
Ciprofloxacin HCl
cipro
CONFIDENTIAL
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------RESPIRATORY SYSTEM
TIOTROPIUM BROMIDE
spiriva
spriva
sprivia
TRIAMCINOLONE
Triamcinolone
TRIAMCINOLONE ACETONIDE
Kenalog
Kenalog Injection
NASACORT AQ
Nasacort
Triamcinelone Cream
nasocort AQ
TYLENOL COLD NOS
TYLENOL COLD
TYLENOL SINUS (NOS)
TYLENOL SINUS
Tylenol Sinus
Protocol: ADC111114
Population: Intent-to-Treat
Page 54 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
258
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------SENSORY ORGANS
CLEAR EYES (NOS)
Clear eyes
CLONIDINE
Clonidine
clonidine
CORTISONE
Cortisone Cream
DEXAMETHASONE
DEXAMETHASONE
DEZAMETHAZONE
Dexamethasone
decadron
DICLOFENAC
DICLOFENAC
Diclofenac
diclofenac
DICLOFENAC HYDROXYETHYLPYRROLIDINE
FLECTOR PATCHES
DICLOFENAC SODIUM
voltaren
EPHEDRINE
Ephedrine
EPHEDRINE SULFATE
EPHEDRINE SULFATE
ERYTHROMYCIN ETHYLSUCCINATE
erythrometh
FAMCICLOVIR
Famvir
GENTAMICIN
Gentamicin
HEPARIN (NOS)
heparin
HEPARIN SODIUM
HEPARIN SODIUM
HYDROCORTISONE
Hydrocortisone Cream 1%
Hydrocortisone ointment
HYDROGEN PEROXIDE
Hydrogen peroxide
INDOMETACIN
INDOCIN
Indamethacin
Indocin
Indomethacin
ISOSORBIDE
Isosorbide
KETOROLAC TROMETAMOL
Ketorolac Tromethamine
TORADOL
Toradol
Torodol
ketorolac tromethamine
toradol
Protocol: ADC111114
Population: Intent-to-Treat
Page 55 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
259
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------SENSORY ORGANS
KETOROLAC TROMETAMOL
toridol
LIDOCAINE
1% lidocaine
1% xylocaine
LIDODERM 5%
LIDODERM PATCHES
Lidocaine
Lidocaine 1%
Lidocaine 1% Injection
XYLOCAINE 1.5%
LIDOCAINE HYDROCHLORIDE
Viscous xlyocaine
XYLOCAINE 2%
MACROGOL
miralax
METHYLCELLULOSE
Citrucel
METHYLPREDNISOLONE
Depo-Medrol
METHLPREDNISONOLNE
METHLPREDNISOOLONE
METHYLPREDNISOLONE
METHYLPRESNISONE
Medrol
Medrol Dose pack
Medrol dose Pack,4 mg
Methylprednisolone
Methylprednisone
medrol dosepack
methylprednisone
methylprenisone
METHYLPREDNISOLONE SODIUM SUCCINATE
Solu-Medrol
Solu-medrol
Solumedrol
solumedrol
NEOMYCIN SULFATE+POLYMYXIN B
Neosporin Ointment SULFATE+BACITRACIN ZINC
Neosporin/Polymixin/Dexamethas
one ointment
NEOSPORIN (NOS)
Neosporin
Protocol: ADC111114
Population: Intent-to-Treat
Page 56 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
BETAMETHASONE
Celestone
BETAMETHASONE+LIDOCAINE
Betamethasone/Xylocaine
Epidural Injection
20APR2010 07:42
RM2010/00132/00
ADC111114
SYSTEMIC HORMONAL PREPARATIONS,
EXCL. SEX HORMONES AND INSULINS
CONFIDENTIAL
260
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------SENSORY ORGANS
NEOSTIGMINE
PROSTIGMIN
OXYMETAZOLINE HYDROCHLORIDE
Afrin
PEGAPTANIB
pegaptanib
PHENIRAMINE MALEATE+NAPHAZOLINE
naphcon-A eye drops
HYDROCHLORIDE
PHENYLEPHRINE
Contac-D
PIROXICAM
Piroxicam
POLYMYXIN B SULFATE
polymyxin Sulfate
PREDNISOLONE
prednisolone opthalmic
RETINOL
Vitamin A
SODIUM CHLORIDE
NORMAL SALINE
Normal Saline IV
Normal Saline Infusion over 24
hours
Sodium Chloride
TETRACYCLINE
Tetracycline
TETRACYCLINE HYDROCHLORIDE
tetracyclin
TIMOLOL
Timolol 0.5%
TIMOLOL MALEATE
TIMOPTIC-XE
TIMOLOL MALEATE+DORZOLAMIDE HYDROCHLORIDE
Cosopt
TOBRAMYCIN
Tobramycin Ophthalmic
TRIAMCINOLONE
Triamcinolone
TRIAMCINOLONE ACETONIDE
Kenalog
Kenalog Injection
NASACORT AQ
Nasacort
Triamcinelone Cream
nasocort AQ
Protocol: ADC111114
Population: Intent-to-Treat
Page 57 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
261
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------SYSTEMIC HORMONAL PREPARATIONS, BETAMETHASONE+LIDOCAINE
Betamethasone/Xylocaine
EXCL. SEX HORMONES AND INSULINS
Epidural injection
CORTISONE
Cortisone Cream
DESMOPRESSIN
desmopressin
DEXAMETHASONE
DEXAMETHASONE
DEZAMETHAZONE
Dexamethasone
decadron
HYDROCORTISONE
Hydrocortisone Cream 1%
Hydrocortisone ointment
LEVOTHYROXINE
LEVOTHYROXINE
Levothyroxin
Levothyroxine
levothyroxin
levothyroxine
LEVOTHYROXINE SODIUM
L-Thyroxine
LEVOTHYROID
LEVOXIL
Levothyroid
Levoxyl
SYNTHROID
Synthroid
levothroid
synthroid
MELATONIN
Melatonin
METHYLPREDNISOLONE
Depo-Medrol
METHLPREDNISONOLNE
METHLPREDNISOOLONE
METHYLPREDNISOLONE
METHYLPRESNISONE
Medrol
Medrol Dose pack
Medrol dose Pack,4 mg
Methylprednisolone
Protocol: ADC111114
Population: Intent-to-Treat
Page 58 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
262
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------SYSTEMIC HORMONAL PREPARATIONS, METHYLPREDNISOLONE
Methylprednisone
EXCL. SEX HORMONES AND INSULINS
medrol dosepack
methylprednisone
methylprenisone
METHYLPREDNISOLONE ACETATE
DEPOMEDAL
Depo Medrol
depomedrol
METHYLPREDNISOLONE SODIUM SUCCINATE
Solu-Medrol
Solu-medrol
Solumedrol
solumedrol
PREDNISOLONE
prednisolone opthalmic
PREDNISONE
PREDINISONE
PREDNISONE
Predisone
Prednisone
Prednisone 30 mg X 2 days; 20
mg x 2 and 10 mg x 2days
Prednisone Taper
Prednisone Taper 30mg x 2
days, 20 mg x 2 days, 10mg x 2
days
Prednisone Taper 30mgx2days,
20mgx2days, 10mgx2days
Prednisone Taper 40mg x 4 dys,
30mg x 2 dys, 20mg x 2 dys, 10
mg x 2 dys
Prednisone [10mg taper x 7
days]
prednisone
prednisone taper
THIAMAZOLE
Methimazole
TRIAMCINOLONE
Triamcinolone
Protocol: ADC111114
Population: Intent-to-Treat
Page 59 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------SYSTEMIC HORMONAL PREPARATIONS, TRIAMCINOLONE ACETONIDE
Kenalog
EXCL. SEX HORMONES AND INSULINS
Kenalog Injection
NASACORT AQ
Nasacort
Triamcinelone Cream
nasocort AQ
VARIOUS
CHONDROITIN
CHONDROITIN+GLUCOSAMINE
CONTRAST MEDIA NOS
garlic
Flomax - 0.4mg
flomax
zicam
Chondroitin
glucasamine chondritin
Contrast dye [unknown type]
Oral Contrast [unknown dye]
Benefiber
MSM
Alcohol
Fungicure
C Q10
ISOVUE 300
Optiray
cholrella
Flax Seed Oil
MEBROFENIN
alopt
20APR2010 07:42
RM2010/00132/00
ADC111114
CYAMOPSIS TETRAGONOLOBUS
DIMETHYL SULFONE
ETHANOL
FUNGICURE (NOS)
GELATIN+CURCUMA LONGA+PANICUM MILIACEUM
EXTRACT+JAPANESE UBIQUINONE
IOPAMIDOL
IOVERSOL
IRON+CYANOCOBALAMIN+ZINC+CHLOROPHYLL+BETACA
ROTENE+RIBONUCLEIC ACID+DEOXYRIBONUCLEIC
ACID
LINUM USITATISSIMUM OIL
MEBROFENIN
MEDICATION UNKNOWN
acetylcysteine
MAX GXL
CONFIDENTIAL
263
ACETYLCYSTEINE
ACETYLCYSTEINE+THIOCTIC
ACID+LEVOGLUTAMIDE+GLUCOSAMINE+CALCIUM
ASCORBATE+QUERCETIN+HERBALS NOS
ALLIUM SATIVUM
AMBIGUOUS MEDICATION
Protocol: ADC111114
Population: Intent-to-Treat
Page 60 of 60
Table 5.24
Relationship of Medication Class, Dictionary Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:42
CONFIDENTIAL
264
ATC Level 1
Ingredient(s)
Verbatim Text
----------------------------------------------------------------------------------------------------------VARIOUS
METHYL HYDROXYBENZOATE
METHYL-PARABEN
MINERALS NOS+VITAMINS NOS+HERBALS NOS
Male Response
MONASCUS PURPUREUS
Red yeast rice
OXYGEN
Oxygen
Oxygen - 2L PRN
Oxygen prn
oxygen
oxygen prn
PLANTAGO OVATA
Metamucil
metamucil
PROPYLPARABEN
PROPYLPARABEN
PYRIDOXINE
Estroblend
HYDROCHLORIDE+TOCOPHEROL+CALCIUM+SOY
ISOFLAVONES+HERBALS NOS
SINCALIDE
KINEVAC
SODIUM AMIDOTRIZOATE+MEGLUMINE
GASTROGRAFIN
AMIDOTRIZOATE
TERIPARATIDE
forteo
VACCINIUM MACROCARPON
Cranberry Fruit Tablet
Cranberry Pill
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 13
Table 5.25
Listing of Exposure to Double-Blilnd Study Drug
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy.
Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clincal Study Register.
CONFIDENTIAL
265
RM2010/00132/00
ADC111114
05MAR2010 09:26
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 1 of 2
Table 8.1
Summary of Demographic Characteristics - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
Total
(N=104)
(N=107)
(N=211)
----------------------------------------------------------------------------------------------------------Age (y)
n
104
107
211
Mean
59.9
60.6
60.3
SD
8.70
9.89
9.31
Median
60.0
61.0
60.0
Min.
41
40
40
Max.
79
82
82
Ethnicity
n
Hispanic/Latino
Not Hispanic/Latino
104
0
104 (100%)
107
1 (<1%)
106 (>99%)
211
1 (<1%)
210 (>99%)
Height (cm)
n
Mean
SD
Median
Min.
Max.
104
169.9
10.47
170.0
142
198
107
169.2
9.41
169.0
150
193
211
169.6
9.93
170.0
142
198
Weight (kg)
n
Mean
SD
Median
Min.
Max.
104
76.27
17.911
76.60
36.4
125.5
107
78.81
18.010
77.30
43.7
129.1
211
77.56
17.964
77.10
36.4
129.1
Body Mass Index
n
Mean
SD
Median
104
26.2
5.02
25.5
107
27.4
5.33
27.0
211
26.8
5.20
26.0
(47%)
(53%)
107
61
46
(57%)
(43%)
09MAR2010 15:38
211
110
101
(52%)
(48%)
CONFIDENTIAL
104
49
55
RM2010/00132/00
ADC111114
n
Female
Male
278
Sex
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 2 of 2
Table 8.1
Summary of Demographic Characteristics - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
Total
(N=104)
(N=107)
(N=211)
----------------------------------------------------------------------------------------------------------Body Mass Index
Min.
15
17
15
Max.
39
40
40
CONFIDENTIAL
279
RM2010/00132/00
ADC111114
09MAR2010 15:38
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 1 of 1
Table 8.2
Summary of Race and Racial Combinations - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
Total
Race
(N=104)
(N=107)
(N=211)
------------------------------------------------------------------------------------------n
104
107
211
African American/African Heritage
6
(6%)
4
(4%)
10
(5%)
American Indian or Alaska Native
1 (<1%)
0
1 (<1%)
Asian
0
0
0
Native Hawaiian or other Pacific Islander
0
0
0
White
97 (93%)
103 (96%)
200 (95%)
CONFIDENTIAL
280
RM2010/00132/00
ADC111114
09MAR2010 15:47
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 1 of 2
Table 8.3
Summary of Disease Characteristics - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
Total
(N=104)
(N=107)
(N=211)
---------------------------------------------------------------------------------------------------Duration of COPD (yrs)
n
104
107
211
Mean
6.94
6.40
6.66
SD
6.718
5.291
6.028
Median
5.00
5.00
5.00
Min.
0.1
0.2
0.1
Max.
35.0
29.0
35.0
107
31 (29%)
56 (52%)
20 (19%)
210
61 (29%)
113 (54%)
36 (17%)
Exacerbations in past 12 months requiring
hospitalization
n
0
1
>=2
104
99 (95%)
5 (5%)
0
107
104 (97%)
2 (2%)
1 (<1%)
211
203 (96%)
7 (3%)
1 (<1%)
Exacerbations in past 12 months requiring
OCS/antibiotic
n
0
1
2
>=3
104
70 (67%)
28 (27%)
4 (4%)
2 (2%)
107
85 (79%)
18 (17%)
2 (2%)
2 (2%)
211
155 (73%)
46 (22%)
6 (3%)
4 (2%)
09MAR2010 16:54
RM2010/00132/00
ADC111114
103
30 (29%)
57 (55%)
16 (16%)
CONFIDENTIAL
281
COPD Type
n
Chronic bronchitis
Emphysema
Both
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 2 of 2
Table 8.3
Summary of Disease Characteristics - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
Total
(N=104)
(N=107)
(N=211)
---------------------------------------------------------------------------------------------------Smoking status
n
104
107
211
Current smoker
69 (66%)
64 (60%)
133 (63%)
Former smoker
35 (34%)
43 (40%)
78 (37%)
107
53.0
25.96
46.0
10
175
211
53.5
28.88
45.0
10
192
Modified MRC dyspnea score
n
Slight
Moderate
Severe
Very severe
104
1 (<1%)
59 (57%)
41 (39%)
3 (3%)
107
0
59 (55%)
47 (44%)
1 (<1%)
211
1 (<1%)
118 (56%)
88 (42%)
4 (2%)
Numeric modified MRC dyspnea score
n
Mean
SD
Median
Min.
Max.
104
2.4
0.57
2.0
1
4
107
2.5
0.52
2.0
2
4
211
2.5
0.54
2.0
1
4
09MAR2010 16:54
RM2010/00132/00
ADC111114
104
53.9
31.73
44.0
11
192
CONFIDENTIAL
282
Pack-years
n
Mean
SD
Median
Min.
Max.
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 1 of 2
Table 8.4
Summary of Screening Pulmonary Function Tests - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
Total
(N=104)
(N=107)
(N=211)
----------------------------------------------------------------------------------------------------------Pre-bronchodilator FEV1 (L)
n
104
107
211
Mean
1.69
1.72
1.70
SD
0.537
0.497
0.516
Median
1.61
1.65
1.64
Min.
0.76
0.76
0.76
Max.
3.39
3.03
3.39
104
55.1
10.54
54.5
34
84
107
57.8
9.91
57.0
34
89
211
56.5
10.29
55.8
34
89
Pre-bronchodilator FVC (L)
n
Mean
SD
Median
Min.
Max.
104
3.08
0.876
2.99
1.38
5.67
107
3.07
0.831
2.97
1.40
5.25
211
3.08
0.851
2.98
1.38
5.67
Post-bronchodilator FEV1 (L)
n
Mean
SD
Median
Min.
Max.
104
1.87
0.537
1.81
0.82
3.56
107
1.86
0.528
1.81
0.87
3.16
211
1.86
0.531
1.81
0.82
3.56
Post-bronchodilator FEV1 % predicted
n
Mean
SD
Median
Min.
104
61.1
9.66
61.1
45
107
62.5
9.10
62.7
39
211
61.8
9.38
61.6
39
09MAR2010 16:09
RM2010/00132/00
ADC111114
n
Mean
SD
Median
Min.
Max.
CONFIDENTIAL
283
Pre-bronchodilator FEV1 % predicted
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 2 of 2
Table 8.4
Summary of Screening Pulmonary Function Tests - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
Total
(N=104)
(N=107)
(N=211)
----------------------------------------------------------------------------------------------------------Post-bronchodilator FEV1 % predicted
Max.
79
79
79
107
3.27
0.888
3.18
1.52
5.64
211
3.28
0.881
3.25
1.52
5.88
Post-bronchodilator FEV1/FVC
n
Mean
SD
Median
Min.
Max.
104
0.57
0.081
0.57
0.37
0.70
107
0.57
0.075
0.58
0.37
0.70
211
0.57
0.078
0.57
0.37
0.70
FEV1 % reversibility
n
Mean
SD
Median
Min.
Max.
104
12.0
11.17
10.6
-20
45
107
9.0
10.27
7.6
-21
43
211
10.5
10.80
9.2
-21
45
Reversibility
n
Nonreversible
Reversible
104
64 (62%)
40 (38%)
107
73 (68%)
34 (32%)
211
137 (65%)
74 (35%)
09MAR2010 16:09
CONFIDENTIAL
104
3.30
0.877
3.27
1.54
5.88
RM2010/00132/00
ADC111114
n
Mean
SD
Median
Min.
Max.
284
Post-bronchodilator FVC (L)
CONFIDENTIAL
RM2010/00132/00
ADC111114
EFFICACY DATA SOURCE FIGURES AND TABLES
Page
Figure 6.1 Mean Pre-dose FEV1 Change from Baseline (mL) (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 6.2 Mean 2-hour Post-dose FEV1 Change from Baseline (mL)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 6.3 Mean Pre-dose FVC Change from Baseline (mL) (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 6.4 Mean 2-hour Post-dose FVC Change from Baseline (mL)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 6.5 Mean Pre-dose IC Change from Baseline (mL) (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.1 Summary of Pre-dose FEV1 (mL) (Intent-to-Treat Population) . . . . . . . . .
Table 6.2 Summary of 2-hour Post-dose FEV1 (mL) (Intent-to-Treat Population) . . .
Table 6.3 Summary of Pre-dose FVC (mL) (Intent-to-Treat Population) . . . . . . . . . .
Table 6.4 Summary of 2-hour Post-dose FVC (mL) (Intent-to-Treat Population) . . .
Table 6.5 Summary of Pre-dose IC (mL) (Intent-to-Treat Population) . . . . . . . . . . . .
Table 6.6 Summary of CRQ-SAS (Intent-to-Treat Population) . . . . . . . . . . . . . . . . .
Table 6.7 Summary of Supplemental Albuterol Use (puffs/day) (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.8 Summary of COPD Exacerbations (Intent-to-Treat Population) . . . . . . . .
Table 6.9 Analysis of COPD Exacerbations (Intent-to-Treat Population) . . . . . . . . .
Table 6.10 Summary of Health Care Utilization for COPD Exacerbations
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.11 Listing of COPD Exacerbations (Intent-to-Treat Population) . . . . . . . . . .
Table 6.12 Summary of QIDS-SR (Intent-to-Treat Population) . . . . . . . . . . . . . . . . .
Table 6.13 Summary of QIDS-SR - Subjects with Scores >=6 at Baseline
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.14 Summary of HADS (Intent-to-Treat Population). . . . . . . . . . . . . . . . . . . .
Table 6.15 Summary of HADS Depression Scale - Subjects with Scores >=8 at
Baseline (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.16 Summary of HADS Anxiety Scale - Subjects with Scores >=8 at
Baseline (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.5 Summary of Pre-dose FEV1 (mL) - Subjects >50% Predicted at Baseline
(Baseline FEV1 % Predicted>50% Population) . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.6 Summary of 2-hour Post-dose FEV1 (mL) - Subjects >50% Predicted at
Baseline (Baseline FEV1 % Predicted>50% Population) . . . . . . . . . . . . . . . . . .
Table 8.7 Summary of Pre-dose FVC (mL) - Subjects >50% Predicted at Baseline
(Baseline FEV1 % Predicted>50% Population) . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.8 Summary of 2-hour Post-dose FVC (mL) - Subjects >50% Predicted at
Baseline (Baseline FEV1 % Predicted>50% Population) . . . . . . . . . . . . . . . . . .
285
287
288
289
290
291
292
295
298
301
304
307
316
321
324
325
326
335
338
341
346
349
352
355
358
361
CONFIDENTIAL
RM2010/00132/00
ADC111114
Table 8.9 Summary of Pre-dose IC (mL) - Subjects >50% Predicted at Baseline
(Baseline FEV1 % Predicted>50% Population) . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.10 Summary of CRQ-SAS - Subjects >50% Predicted at Baseline
(Baseline FEV1 % Predicted>50% Population) . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.11 Summary of Pre-dose FEV1 (% predicted) - Subjects >50% Predicted
at Baseline (Baseline FEV1 % Predicted>50% Population) . . . . . . . . . . . . . . . .
286
364
367
376
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Figure 6.1
Mean Pre-dose FEV1 Change from Baseline (mL)
140
●
●
120
●
●
●
80
CONFIDENTIAL
287
FEV1 Change from Baseline (mL)
100
60
40
20
0
● ▲
▲
▲
-20
▲
▲
-40
▲
Baseline
4
8
16
Week
●
FSC250/50+Tio
▲
Tiotropium
Note: Vertical bars represent standard errors
08APR2010 11:32
24
Endpoint
RM2010/00132/00
ADC111114
-60
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Figure 6.2
Mean 2-hour Post-dose FEV1 Change from Baseline (mL)
260
240
●
●
●
●
220
●
180
160
140
120
100
▲
▲
80
▲
▲
60
CONFIDENTIAL
288
FEV1 Change from Baseline (mL)
200
▲
40
20
● ▲
Baseline
4
8
16
Week
●
FSC250/50+Tio
▲
Tiotropium
Note: Vertical bars represent standard errors
08APR2010 11:36
24
Endpoint
RM2010/00132/00
ADC111114
0
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Figure 6.3
Mean Pre-dose FVC Change from Baseline (mL)
160
140
●
120
●
●
80
60
CONFIDENTIAL
289
FVC Change from Baseline (mL)
●
100
●
40
20
0
● ▲
-20
▲
▲
▲
-40
▲
▲
-60
Baseline
4
8
16
Week
●
FSC250/50+Tio
▲
Tiotropium
Note: Vertical bars represent standard errors
08APR2010 11:36
24
Endpoint
RM2010/00132/00
ADC111114
-80
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Figure 6.4
Mean 2-hour Post-dose FVC Change from Baseline (mL)
300
●
●
●
200
150
▲
▲
100
▲
CONFIDENTIAL
290
FVC Change from Baseline (mL)
250
●
●
▲
50
● ▲
Baseline
4
8
16
Week
●
FSC250/50+Tio
▲
Tiotropium
Note: Vertical bars represent standard errors
08APR2010 11:36
24
Endpoint
RM2010/00132/00
ADC111114
0
▲
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Figure 6.5
Mean Pre-dose IC Change from Baseline (mL)
140
120
●
100
●
●
80
●
CONFIDENTIAL
291
IC Change from Baseline (mL)
●
60
40
20
0
▲
● ▲
▲
▲
▲
▲
-20
Baseline
4
8
16
Week
●
FSC250/50+Tio
▲
Tiotropium
Note: Vertical bars represent standard errors
08APR2010 11:36
24
Endpoint
RM2010/00132/00
ADC111114
-40
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 3
Table 6.1
Summary of Pre-dose FEV1 (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
FEV1
n
170
168
Mean
1597
1640
SE
44.4
42.3
Median
1484
1580
Min.
670
594
Max.
3456
3443
Endpoint
154
1695
45.6
1588
597
3669
155
1598
44.7
1528
646
3419
Change from baseline
n
Mean
SE
Median
Min.
Max.
152
101
21.8
67
-676
1204
155
-16
20.4
-11
-931
834
FEV1
n
Mean
SE
Median
Min.
Max.
154
1718
48.8
1631
692
3643
154
1601
43.4
1564
702
2953
115
29.5
(57,173)
<0.001
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 13:39
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
292
Week 4
FEV1
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 3
Table 6.1
Summary of Pre-dose FEV1 (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 4
Change from baseline
n
152
154
Mean
121
-18
138
(88,189)
SE
19.8
16.1
25.5
<0.001
Median
96
-27
Min.
-526
-646
Max.
913
772
Week 8
151
1681
47.7
1601
607
3669
145
1587
45.8
1546
616
3094
Change from baseline
n
Mean
SE
Median
Min.
Max.
149
86
18.8
82
-562
1032
145
-40
15.3
-40
-669
500
FEV1
n
Mean
SE
Median
Min.
Max.
141
1712
47.9
1626
634
3647
135
1582
47.9
1570
623
3260
128
24.5
(80,176)
<0.001
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 13:39
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
293
Week 16
FEV1
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 3
Table 6.1
Summary of Pre-dose FEV1 (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 16
Change from baseline
n
139
135
Mean
125
-29
156
(101,211)
SE
20.7
18.7
28.1
<0.001
Median
102
-41
Min.
-440
-931
Max.
1204
573
Week 24
n
Mean
SE
Median
Min.
Max.
137
1694
46.4
1604
597
3490
128
1596
50.5
1525
646
3419
Change from baseline
n
Mean
SE
Median
Min.
Max.
135
93
21.8
65
-676
751
128
-15
22.2
-16
-884
834
108
31.0
(46,169)
<0.001
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 13:39
CONFIDENTIAL
294
FEV1
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 3
Table 6.2
Summary of 2-hour Post-dose FEV1 (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
FEV1
n
170
168
Mean
1597
1640
SE
44.4
42.3
Median
1484
1580
Min.
670
594
Max.
3456
3443
Endpoint
154
1829
44.8
1727
866
3819
154
1690
45.5
1633
630
3233
Change from baseline
n
Mean
SE
Median
Min.
Max.
152
233
23.1
204
-779
1288
154
77
20.6
54
-858
850
FEV1
n
Mean
SE
Median
Min.
Max.
153
1827
48.7
1710
816
3899
154
1687
43.7
1673
635
2916
154
30.1
(95,214)
<0.001
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparison at Endpoint is 0.013.
05MAR2010 13:45
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
295
Week 4
FEV1
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 3
Table 6.2
Summary of 2-hour Post-dose FEV1 (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 4
Change from baseline
n
151
154
Mean
231
73
158
(106,210)
SE
20.1
17.7
26.4
<0.001
Median
211
51
Min.
-450
-682
Max.
996
915
Week 8
150
1801
47.2
1701
840
3828
146
1705
46.0
1674
670
3188
Change from baseline
n
Mean
SE
Median
Min.
Max.
148
211
19.4
194
-476
1123
146
82
18.5
74
-561
1013
FEV1
n
Mean
SE
Median
Min.
Max.
142
1816
47.6
1697
843
3856
134
1670
48.8
1632
686
3534
131
26.6
(79,184)
<0.001
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparison at Endpoint is 0.013.
05MAR2010 13:45
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
296
Week 16
FEV1
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 3
Table 6.2
Summary of 2-hour Post-dose FEV1 (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 16
Change from baseline
n
140
134
Mean
228
57
178
(122,234)
SE
20.7
20.0
28.4
<0.001
Median
189
46
Min.
-375
-732
Max.
1288
859
Week 24
n
Mean
SE
Median
Min.
Max.
136
1827
46.8
1730
866
3819
128
1701
50.7
1633
630
3233
Change from baseline
n
Mean
SE
Median
Min.
Max.
134
225
24.2
204
-779
1002
128
90
22.8
56
-858
850
140
32.7
(75,204)
<0.001
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparison at Endpoint is 0.013.
05MAR2010 13:45
CONFIDENTIAL
297
FEV1
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 3
Table 6.3
Summary of Pre-dose FVC (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
FVC
n
170
168
Mean
3024
3019
SE
66.8
69.4
Median
2953
2913
Min.
1251
1423
Max.
5553
5334
Endpoint
154
3101
70.8
3060
1276
5400
155
2959
69.7
2862
1454
5199
Change from baseline
n
Mean
SE
Median
Min.
Max.
152
95
32.7
67
-939
1763
155
-28
30.6
-26
-1145
891
FVC
n
Mean
SE
Median
Min.
Max.
154
3115
72.1
3040
1350
5653
154
2960
72.1
2835
1511
5536
122
44.0
(35,209)
0.006
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparison at Endpoint is 0.025.
05MAR2010 13:48
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
298
Week 4
FVC
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 3
Table 6.3
Summary of Pre-dose FVC (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 4
Change from baseline
n
152
154
Mean
107
-32
141
(65,216)
SE
27.6
26.7
38.2
<0.001
Median
78
-68
Min.
-712
-1012
Max.
1426
1187
Week 8
151
3059
70.9
3010
1518
5766
145
2957
73.0
2902
1479
5100
Change from baseline
n
Mean
SE
Median
Min.
Max.
149
57
27.3
55
-1019
1497
145
-53
24.6
-55
-863
1085
FVC
n
Mean
SE
Median
Min.
Max.
141
3125
75.2
3062
1417
5594
135
2961
77.2
2800
1385
5288
113
36.7
(41,185)
0.002
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparison at Endpoint is 0.025.
05MAR2010 13:48
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
299
Week 16
FVC
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 3
Table 6.3
Summary of Pre-dose FVC (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 16
Change from baseline
n
139
135
Mean
126
-47
181
(96,266)
SE
31.6
29.6
43.2
<0.001
Median
56
-59
Min.
-802
-1108
Max.
1763
1422
Week 24
n
Mean
SE
Median
Min.
Max.
137
3088
74.7
3059
1276
5400
128
2986
79.5
2855
1454
5199
Change from baseline
n
Mean
SE
Median
Min.
Max.
135
86
33.5
67
-939
1413
128
-24
34.0
-18
-1145
891
108
47.5
(14,201)
0.024
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparison at Endpoint is 0.025.
05MAR2010 13:48
CONFIDENTIAL
300
FVC
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 3
Table 6.4
Summary of 2-hour Post-dose FVC (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
FVC
n
170
168
Mean
3024
3019
SE
66.8
69.4
Median
2953
2913
Min.
1251
1423
Max.
5553
5334
Endpoint
154
3273
71.8
3167
1535
5831
154
3072
72.4
2972
1410
5136
Change from baseline
n
Mean
SE
Median
Min.
Max.
152
265
35.9
194
-902
2320
154
87
31.2
63
-1191
1975
FVC
n
Mean
SE
Median
Min.
Max.
153
3260
71.7
3206
1621
5950
154
3058
72.6
2970
1499
5040
175
46.4
(84,267)
<0.001
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparison at Endpoint is 0.01.
05MAR2010 14:38
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
301
Week 4
FVC
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 3
Table 6.4
Summary of 2-hour Post-dose FVC (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 4
Change from baseline
n
151
154
Mean
251
74
178
(98,257)
SE
30.8
27.0
40.2
<0.001
Median
203
50
Min.
-582
-687
Max.
1936
1457
Week 8
150
3209
71.8
3121
1596
5976
146
3110
75.5
2975
1542
5315
Change from baseline
n
Mean
SE
Median
Min.
Max.
148
216
28.8
162
-759
1730
146
103
28.1
104
-845
1291
FVC
n
Mean
SE
Median
Min.
Max.
142
3275
78.5
3179
1646
6113
134
3056
80.2
2879
1518
5431
117
39.7
(38,195)
0.004
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparison at Endpoint is 0.01.
05MAR2010 14:38
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
302
Week 16
FVC
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 3
Table 6.4
Summary of 2-hour Post-dose FVC (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 16
Change from baseline
n
140
134
Mean
279
48
237
(146,328)
SE
35.2
30.6
46.2
<0.001
Median
152
33
Min.
-420
-990
Max.
2610
1205
Week 24
n
Mean
SE
Median
Min.
Max.
136
3258
77.4
3188
1535
5831
128
3118
82.3
2981
1410
5136
Change from baseline
n
Mean
SE
Median
Min.
Max.
134
255
38.1
196
-902
2320
128
108
34.6
65
-1191
1975
151
50.9
(51,251)
0.003
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparison at Endpoint is 0.01.
05MAR2010 14:38
CONFIDENTIAL
303
FVC
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 3
Table 6.5
Summary of Pre-dose IC (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
IC
n
169
167
Mean
2233
2240
SE
52.2
52.4
Median
2118
2147
Min.
934
1022
Max.
4375
4798
Endpoint
154
2327
59.5
2226
877
4960
156
2180
53.5
2083
860
4448
Change from baseline
n
Mean
SE
Median
Min.
Max.
151
107
28.4
81
-1125
1210
154
-8
28.1
-39
-1306
1030
IC
n
Mean
SE
Median
Min.
Max.
154
2310
59.3
2232
892
4561
156
2172
51.9
2111
895
4133
141
41.0
(60,221)
<0.001
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum, treatment by reversibility interaction, and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparison at Endpoint is 0.017.
05MAR2010 14:01
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
304
Week 4
IC
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 3
Table 6.5
Summary of Pre-dose IC (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 4
Change from baseline
n
151
154
Mean
94
-18
151
(77,225)
SE
28.3
24.9
37.7
<0.001
Median
38
-42
Min.
-892
-1126
Max.
1485
968
Week 8
150
2282
58.1
2162
883
4818
146
2208
56.4
2148
795
4146
Change from baseline
n
Mean
SE
Median
Min.
Max.
148
70
30.6
35
-1095
1630
144
-5
27.0
-14
-983
1045
IC
n
Mean
SE
Median
Min.
Max.
141
2332
60.4
2205
989
4235
134
2203
58.6
2143
866
4454
96
41.8
(14,179)
0.022
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum, treatment by reversibility interaction, and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparison at Endpoint is 0.017.
05MAR2010 14:01
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
305
Week 16
IC
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 3
Table 6.5
Summary of Pre-dose IC (mL)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 16
Change from baseline
n
139
132
Mean
96
1
128
(43,213)
SE
28.8
30.7
43.3
0.003
Median
45
-32
Min.
-879
-1265
Max.
1210
1370
Week 24
n
Mean
SE
Median
Min.
Max.
136
2327
64.7
2226
877
4960
128
2192
59.6
2104
924
4448
Change from baseline
n
Mean
SE
Median
Min.
Max.
133
86
29.7
69
-1125
1068
126
-13
32.2
-34
-1306
1030
132
44.9
(43,220)
0.004
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum, treatment by reversibility interaction, and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparison at Endpoint is 0.017.
05MAR2010 14:01
CONFIDENTIAL
306
IC
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 9
Table 6.6
Summary of CRQ-SAS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Mastery
Baseline
Domain score
n
171
167
Mean
4.98
5.05
SE
0.107
0.107
Median
5.00
5.50
Min.
1.5
1.5
Max.
7.0
7.0
Endpoint
165
5.09
0.107
5.25
1.3
7.0
Chg from baseline
n
162
Mean
0.28
SE
0.078
Median
0.00
Min.
-2.0
Max.
4.8
164
0.04
0.090
0.00
-3.0
4.3
Domain score
n
148
Mean
5.24
SE
0.116
Median
5.50
Min.
1.5
Max.
7.0
147
5.12
0.115
5.50
1.8
7.0
0.20
0.112
(-0.02,0.42)
0.069
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparisons at Endpoint is 0.05.
05MAR2010 11:07
RM2010/00132/00
ADC111114
n
163
Mean
5.23
SE
0.115
Median
5.50
Min.
1.5
Max.
7.0
CONFIDENTIAL
307
Week 8
Domain score
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 9
Table 6.6
Summary of CRQ-SAS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Mastery
Week 8
Chg from baseline
n
148
146
Mean
0.23
0.07
0.15
(-0.07,0.37)
SE
0.080
0.090
0.112
0.181
Median
0.25
0.00
Min.
-3.3
-4.5
Max.
3.3
3.5
Week 24
n
135
Mean
5.34
SE
0.127
Median
5.75
Min.
1.5
Max.
7.0
130
5.16
0.119
5.50
1.3
7.0
Chg from baseline
n
134
Mean
0.29
SE
0.091
Median
0.00
Min.
-2.0
Max.
4.8
129
0.07
0.103
0.00
-3.0
4.3
Domain score
n
4.60
0.327
4.63
2.3
7.0
(-0.06,0.44)
0.144
24
4.81
0.293
4.75
2.3
7.0
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparisons at Endpoint is 0.05.
05MAR2010 11:07
RM2010/00132/00
ADC111114
Mean
SE
Median
Min.
Max.
20
0.19
0.127
CONFIDENTIAL
308
Early
withdrawal
Domain score
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 9
Table 6.6
Summary of CRQ-SAS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Mastery
Early
Chg from baseline
n
20
24
withdrawal
Mean
0.18
-0.20
0.27
(-0.42,0.96)
SE
0.147
0.236
0.339
0.436
Median
0.00
-0.25
Min.
-1.0
-2.3
Max.
1.8
2.3
n
171
Mean
3.91
SE
0.095
Median
4.00
Min.
1.0
Max.
6.8
167
3.82
0.103
4.00
1.0
6.5
Endpoint
Domain score
n
163
Mean
4.10
SE
0.114
Median
4.25
Min.
1.0
Max.
7.0
165
3.97
0.108
4.25
1.0
6.8
Chg from baseline
n
162
Mean
0.23
SE
0.094
Median
0.25
Min.
-2.8
Max.
4.5
164
0.17
0.091
0.25
-2.8
4.0
0.09
0.123
(-0.15,0.33)
0.470
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparisons at Endpoint is 0.05.
05MAR2010 11:07
RM2010/00132/00
ADC111114
Domain score
309
Baseline
CONFIDENTIAL
Fatigue
Protocol: ADC111114
Population: Intent-to-Treat
Page 4 of 9
Table 6.6
Summary of CRQ-SAS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Fatigue
Week 8
Domain score
n
148
147
Mean
3.95
3.87
SE
0.109
0.106
Median
4.00
4.00
Min.
1.0
1.0
Max.
7.0
7.0
146
-0.00
0.082
0.00
-3.3
2.5
Domain score
n
135
Mean
4.16
SE
0.124
Median
4.25
Min.
1.0
Max.
7.0
130
4.09
0.123
4.25
1.0
6.8
Chg from baseline
n
134
Mean
0.26
SE
0.105
Median
0.25
Min.
-2.8
Max.
4.5
129
0.13
0.100
0.25
-2.5
4.0
0.05
0.105
(-0.15,0.26)
0.611
0.10
0.135
(-0.17,0.36)
0.468
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparisons at Endpoint is 0.05.
05MAR2010 11:07
RM2010/00132/00
ADC111114
n
148
Mean
0.05
SE
0.079
Median
0.00
Min.
-2.8
Max.
3.8
CONFIDENTIAL
310
Week 24
Chg from baseline
Protocol: ADC111114
Population: Intent-to-Treat
Page 5 of 9
Table 6.6
Summary of CRQ-SAS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Fatigue
Early
Domain score
n
20
24
withdrawal
Mean
3.63
3.59
SE
0.353
0.251
Median
3.75
3.25
Min.
1.0
1.3
Max.
6.8
5.8
24
0.25
0.305
0.25
-2.8
4.0
Emotional
Baseline
Domain score
n
171
Mean
4.59
SE
0.100
Median
4.57
Min.
1.6
Max.
7.0
167
4.56
0.101
4.86
1.7
7.0
Endpoint
Domain score
n
163
Mean
4.81
SE
0.103
Median
4.86
Min.
1.3
Max.
7.0
165
4.71
0.102
4.86
1.1
7.0
-0.24
0.401
(-1.05,0.58)
0.559
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparisons at Endpoint is 0.05.
05MAR2010 11:07
CONFIDENTIAL
20
-0.06
0.231
0.13
-1.8
2.0
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
311
Chg from baseline
Protocol: ADC111114
Population: Intent-to-Treat
Page 6 of 9
Table 6.6
Summary of CRQ-SAS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Emotional Endpoint
Chg from baseline
n
162
164
Mean
0.24
0.16
0.08
(-0.11,0.27)
SE
0.072
0.073
0.096
0.394
Median
0.14
0.14
Min.
-3.3
-2.3
Max.
3.6
3.4
Week 8
147
4.64
0.107
4.71
1.7
6.9
Chg from baseline
n
148
Mean
0.17
SE
0.064
Median
0.14
Min.
-2.1
Max.
2.9
146
0.06
0.076
0.14
-3.0
2.6
Domain score
n
135
Mean
4.88
SE
0.113
Median
5.14
Min.
1.4
Max.
7.0
130
4.81
0.118
5.00
1.1
7.0
0.11
0.093
(-0.07,0.29)
0.240
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparisons at Endpoint is 0.05.
05MAR2010 11:07
RM2010/00132/00
ADC111114
n
148
Mean
4.78
SE
0.110
Median
4.86
Min.
1.4
Max.
7.0
CONFIDENTIAL
312
Week 24
Domain score
Protocol: ADC111114
Population: Intent-to-Treat
Page 7 of 9
Table 6.6
Summary of CRQ-SAS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Emotional Week 24
Chg from baseline
n
134
129
Mean
0.25
0.16
0.06
(-0.15,0.27)
SE
0.081
0.082
0.107
0.585
Median
0.21
0.14
Min.
-3.3
-2.0
Max.
3.6
3.4
Domain score
Baseline
20
24
4.38
0.302
4.57
1.3
6.9
4.36
0.227
4.29
2.7
6.3
Chg from baseline
n
Mean
SE
Median
Min.
Max.
20
0.13
0.176
-0.07
-0.9
2.0
24
0.08
0.224
0.07
-2.3
2.6
Domain score
n
171
Mean
4.72
SE
0.109
Median
4.80
Min.
1.4
Max.
7.0
167
4.66
0.111
4.80
1.0
7.0
0.13
0.301
(-0.48,0.74)
0.678
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparisons at Endpoint is 0.05.
05MAR2010 11:07
RM2010/00132/00
ADC111114
Mean
SE
Median
Min.
Max.
313
Dyspnea
n
CONFIDENTIAL
Early
withdrawal
Protocol: ADC111114
Population: Intent-to-Treat
Page 8 of 9
Table 6.6
Summary of CRQ-SAS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Dyspnea
Endpoint
Domain score
n
162
165
Mean
4.88
4.85
SE
0.115
0.115
Median
5.00
5.20
Min.
1.6
1.4
Max.
7.0
7.0
164
0.19
0.091
0.20
-3.6
5.0
Domain score
n
148
Mean
4.85
SE
0.124
Median
5.00
Min.
1.2
Max.
7.0
147
4.79
0.116
5.00
1.6
7.0
Chg from baseline
n
148
Mean
0.12
SE
0.090
Median
0.15
Min.
-4.1
Max.
4.0
146
0.11
0.086
0.20
-3.4
3.8
0.02
0.119
(-0.22,0.25)
0.879
0.02
0.116
(-0.21,0.25)
0.881
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparisons at Endpoint is 0.05.
05MAR2010 11:07
RM2010/00132/00
ADC111114
n
161
Mean
0.21
SE
0.091
Median
0.20
Min.
-3.8
Max.
4.0
CONFIDENTIAL
314
Week 8
Chg from baseline
Protocol: ADC111114
Population: Intent-to-Treat
Page 9 of 9
Table 6.6
Summary of CRQ-SAS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Dyspnea
Week 24
Domain score
n
134
130
Mean
4.94
4.92
SE
0.126
0.124
Median
5.00
5.20
Min.
1.8
1.4
Max.
7.0
7.0
n
133
Mean
0.15
SE
0.106
Median
0.10
Min.
-3.8
Max.
4.0
Domain score
n
Chg from baseline
20
129
0.17
0.105
0.20
-3.6
5.0
(-0.29,0.25)
0.860
0.02
0.316
(-0.62,0.66)
0.958
24
Mean
SE
Median
Min.
Max.
4.46
0.370
4.80
1.6
7.0
4.87
0.308
5.27
1.5
7.0
n
Mean
SE
Median
Min.
Max.
20
0.44
0.201
0.58
-1.0
2.8
24
0.35
0.209
0.10
-1.1
3.3
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
The Hochberg adjusted significance level for the treatment comparisons at Endpoint is 0.05.
05MAR2010 11:07
RM2010/00132/00
ADC111114
-0.02
0.137
CONFIDENTIAL
315
Early
withdrawal
Chg from baseline
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 5
Table 6.7
Summary of Supplemental Albuterol Use (puffs/day)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
Albuterol use
n
165
158
Mean
2.3
2.3
SE
0.20
0.23
Median
1.4
1.4
Min.
0
0
Max.
12
15
Weeks 1-24
n
Mean
SE
Median
Min.
Max.
167
1.7
0.17
0.9
0
11
163
2.2
0.22
1.1
0
14
Chg from baseline
n
Mean
SE
Median
Min.
Max.
160
-0.7
0.15
-0.0
-10
5
154
-0.2
0.14
0.0
-6
5
-0.5
0.18
(-0.9,-0.2)
0.004
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 14:17
CONFIDENTIAL
316
Albuterol use
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 5
Table 6.7
Summary of Supplemental Albuterol Use (puffs/day)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Weeks 1-4
Albuterol use
n
162
158
Mean
1.7
2.2
SE
0.16
0.22
Median
1.0
1.1
Min.
0
0
Max.
10
13
157
-0.6
0.13
0.0
-10
4
152
-0.2
0.14
0.0
-8
5
Albuterol use
n
Mean
SE
Median
Min.
Max.
149
1.6
0.18
0.8
0
12
143
2.3
0.25
1.1
0
14
Chg from baseline
n
Mean
SE
Median
Min.
Max.
146
-0.6
0.16
-0.0
-11
6
137
-0.2
0.15
0.0
-6
5
-0.4
0.17
(-0.8,-0.1)
0.009
-0.5
0.19
(-0.9,-0.1)
0.010
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 14:17
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
317
Weeks 5-8
Chg from baseline
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 5
Table 6.7
Summary of Supplemental Albuterol Use (puffs/day)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Weeks 9-12
Albuterol use
n
142
137
Mean
1.6
2.0
SE
0.18
0.23
Median
0.5
0.8
Min.
0
0
Max.
11
13
139
-0.7
0.16
-0.1
-8
6
130
-0.2
0.17
0.0
-6
5
Albuterol use
n
Mean
SE
Median
Min.
Max.
140
1.6
0.18
0.7
0
10
137
2.1
0.24
1.1
0
13
Chg from baseline
n
Mean
SE
Median
Min.
Max.
137
-0.7
0.16
-0.1
-8
5
128
-0.2
0.18
0.0
-7
6
-0.5
0.21
(-0.9,-0.1)
0.015
-0.5
0.22
(-0.9,-0.1)
0.018
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 14:17
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
318
Weeks 13-16
Chg from baseline
Protocol: ADC111114
Population: Intent-to-Treat
Page 4 of 5
Table 6.7
Summary of Supplemental Albuterol Use (puffs/day)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Weeks 17-20 Albuterol use
n
132
129
Mean
1.8
2.2
SE
0.22
0.26
Median
1.0
0.9
Min.
0
0
Max.
16
14
128
-0.6
0.19
-0.1
-8
9
122
-0.3
0.18
0.0
-6
9
Albuterol use
n
Mean
SE
Median
Min.
Max.
131
1.7
0.22
1.0
0
16
122
2.2
0.27
0.7
0
14
Chg from baseline
n
Mean
SE
Median
Min.
Max.
127
-0.7
0.19
-0.1
-8
9
115
-0.2
0.17
0.0
-6
6
-0.4
0.25
(-0.8,0.1)
0.153
-0.5
0.24
(-1.0,-0.0)
0.037
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 14:17
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
319
Weeks 21-24
Chg from baseline
Protocol: ADC111114
Population: Intent-to-Treat
Page 5 of 5
Table 6.7
Summary of Supplemental Albuterol Use (puffs/day)
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Endpoint
Albuterol use
n
165
162
Mean
1.8
2.4
SE
0.20
0.25
Median
0.8
1.1
Min.
0
0
Max.
16
15
Chg from baseline
160
-0.6
0.18
0.0
-11
9
154
-0.0
0.18
0.0
-6
9
-0.6
0.24
(-1.1,-0.1)
0.010
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 14:17
CONFIDENTIAL
320
n
Mean
SE
Median
Min.
Max.
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 3
Table 6.8
Summary of COPD Exacerbations
FSC250/50+Tio Tiotropium
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------------Number of Subjects with an
25 (14%)
26 (15%)
Exacerbation
Number of Exacerbations
26
0
1
2
148 (86%)
24 (14%)
1 (<1%)
143 (85%)
22 (13%)
4 (2%)
Severity
Mild
Moderate
Severe
9 (35%)
16 (62%)
1 (4%)
11 (37%)
13 (43%)
6 (20%)
Outcome
Resolved
Fatal
Not resolved
24 (92%)
0
2 (8%)
28 (93%)
0
2 (7%)
RM2010/00132/00
ADC111114
10MAR2010 14:32
CONFIDENTIAL
321
Number of Subjects by Number of Events
30
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 3
Table 6.8
Summary of COPD Exacerbations
Yes
No
3 (12%)
23 (88%)
2 (7%)
27 (93%)
Hospitalization
Yes
No
1 (4%)
25 (96%)
3 (10%)
27 (90%)
Oral corticosteroid taken
Yes
No
17 (65%)
9 (35%)
26 (87%)
4 (13%)
Antibiotic taken
Yes
No
23 (88%)
3 (12%)
17 (57%)
13 (43%)
Dyspnea
Yes
No
21 (81%)
5 (19%)
26 (87%)
4 (13%)
10MAR2010 14:32
RM2010/00132/00
ADC111114
Leading to withdrawal
CONFIDENTIAL
322
FSC250/50+Tio Tiotropium
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------------Primary cause
Cold air/Cold weather
1 (4%)
2 (7%)
Tobacco smoke
12 (46%)
7 (23%)
Upper respiratory infection
3 (12%)
3 (10%)
Air pollution
0
0
Allergy
0
2 (7%)
Exercise
0
0
Stress/Emotions
0
0
Beta-blockers
0
0
Aspirin
0
0
Other NSAIDS
0
0
Withholding or reducing COPD meds.
0
0
Unknown etiology
4 (15%)
7 (23%)
Lack of efficacy
0
0
Lower respiratory infection
2 (8%)
1 (3%)
Common cold
0
2 (7%)
Upper respiratory infection other
2 (8%)
1 (3%)
than common cold
Other
2 (8%)
5 (17%)
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 3
Table 6.8
Summary of COPD Exacerbations
FSC250/50+Tio Tiotropium
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------------Increased cough or wheeze
Yes
23 (88%)
25 (83%)
No
3 (12%)
5 (17%)
Increased sputum volume
Yes
No
20 (77%)
6 (23%)
22 (73%)
8 (27%)
CONFIDENTIAL
323
RM2010/00132/00
ADC111114
10MAR2010 14:32
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 6.9
Analysis of COPD Exacerbations
FSC250/50+Tio
Tiotropium
Overall
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------n
Mean exacerbation rate
173
0.14
Treatment Comparison (FSC+Tio/Tio)
Ratio
95% CI
p-value
0.845
(0.502, 1.422)
0.531
169
0.17
CONFIDENTIAL
324
RM2010/00132/00
ADC111114
Note: Rate estimates, ratio, CI and p-value are from a Poisson regression model with GEE adjusting for
treatment, pooled investigator, reversibility stratum, baseline severity and time on treatment.
20APR2010 07:42
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 6.10
Summary of Health Care Utilization for COPD Exacerbations
FSC250/50+Tio Tiotropium
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------------Number of Subjects with an
25 (14%)
26 (15%)
Exacerbation
Number of Exacerbations
26
30
0
1
2
>=3
3
20
3
0
(12%)
(77%)
(12%)
7
18
4
1
(23%)
(60%)
(13%)
(3%)
Urgent care visits
0
1
>=2
25
1
0
(96%)
(4%)
27
3
0
(90%)
(10%)
ER visits
0
1
>=2
26 (100%)
0
0
26
4
0
(87%)
(13%)
Days in general ward
0
1
2
3
4
5
6
>=7
24
0
0
0
1
0
0
0
26
0
0
1
1
0
0
1
(90%)
0
>=1
26 (100%)
0
(4%)
(3%)
(3%)
(3%)
29 (100%)
0
20APR2010 07:42
RM2010/00132/00
ADC111114
Days in ICU
(96%)
CONFIDENTIAL
325
Office visits
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 9
Table 6.11
Listing of COPD Exacerbations
Timing: During Treatment
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
CONFIDENTIAL
326
RM2010/00132/00
ADC111114
10MAR2010 14:21
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 3
Table 6.12
Summary of QIDS-SR
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
QIDS-SR score
n
163
155
Mean
5.9
6.6
SE
0.31
0.38
Median
5.0
5.0
Min.
1
0
Max.
19
22
Endpoint
152
6.2
0.35
5.0
0
22
157
6.8
0.37
5.0
0
21
Change from baseline
n
Mean
SE
Median
Min.
Max.
144
0.3
0.28
0.0
-10
11
145
0.1
0.28
0.0
-9
11
QIDS-SR score
n
Mean
SE
Median
Min.
Max.
136
6.1
0.35
5.0
0
19
140
6.4
0.37
5.0
0
21
0.0
0.37
(-0.7,0.8)
0.947
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 12:02
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
335
Week 8
QIDS-SR score
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 3
Table 6.12
Summary of QIDS-SR
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 8
Change from baseline
n
129
130
Mean
0.2
-0.2
0.3
(-0.4,1.0)
SE
0.26
0.29
0.36
0.390
Median
0.0
0.0
Min.
-9
-12
Max.
8
14
Week 24
124
6.2
0.39
5.0
0
21
126
6.5
0.40
5.0
0
20
Change from baseline
n
Mean
SE
Median
Min.
Max.
116
0.3
0.31
0.0
-10
11
117
0.5
0.30
0.0
-8
11
QIDS-SR score
n
20
20
Mean
SE
Median
Min.
Max.
6.6
1.18
5.0
2
22
7.3
0.94
6.0
2
17
-0.1
0.40
(-0.9,0.7)
0.736
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 12:02
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
336
Early
withdrawal
QIDS-SR score
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 3
Table 6.12
Summary of QIDS-SR
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Early
Change from baseline
n
20
18
withdrawal
Mean
0.6
-1.8
0.8
(-2.2,3.9)
SE
0.86
0.92
1.50
0.578
Median
0.0
-0.5
Min.
-4
-9
Max.
11
3
CONFIDENTIAL
337
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 12:02
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 3
Table 6.13
Summary of QIDS-SR - Subjects with Scores >=6 at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
QIDS-SR score
n
70
71
Mean
9.5
10.6
SE
0.41
0.46
Median
8.0
9.0
Min.
6
6
Max.
19
22
Endpoint
62
8.9
0.59
9.0
2
22
67
9.6
0.56
9.0
0
21
Change from baseline
n
Mean
SE
Median
Min.
Max.
62
-0.6
0.52
0.0
-10
11
67
-1.0
0.47
-1.0
-9
11
QIDS-SR score
n
Mean
SE
Median
Min.
Max.
55
9.0
0.58
8.0
2
19
60
9.0
0.56
8.0
1
21
-0.3
0.70
(-1.7,1.1)
0.681
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 12:08
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
338
Week 8
QIDS-SR score
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 3
Table 6.13
Summary of QIDS-SR - Subjects with Scores >=6 at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 8
Change from baseline
n
55
60
Mean
-0.6
-1.5
0.5
(-0.9,1.8)
SE
0.48
0.46
0.67
0.499
Median
-1.0
-2.0
Min.
-9
-12
Max.
8
9
Week 24
n
Mean
SE
Median
Min.
Max.
49
9.1
0.63
9.0
2
21
49
9.7
0.65
10.0
0
20
Change from baseline
n
Mean
SE
Median
Min.
Max.
49
-0.4
0.56
0.0
-10
5
49
-0.4
0.53
-1.0
-8
11
QIDS-SR score
n
8.9
2.16
8.0
2
22
(-1.9,1.0)
0.542
12
8.8
1.07
8.5
4
17
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 12:08
RM2010/00132/00
ADC111114
Mean
SE
Median
Min.
Max.
9
-0.5
0.75
CONFIDENTIAL
339
Early
withdrawal
QIDS-SR score
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 3
Table 6.13
Summary of QIDS-SR - Subjects with Scores >=6 at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Early
Change from baseline
n
9
12
withdrawal
Mean
-0.3
-2.8
1.2
(-4.3,6.7)
SE
1.63
1.25
2.57
0.642
Median
-2.0
-1.0
Min.
-4
-9
Max.
11
3
CONFIDENTIAL
340
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 12:08
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 5
Table 6.14
Summary of HADS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Scale
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Depression Baseline
Scale score
n
168
163
Mean
4.6
4.8
SE
0.29
0.30
Median
4.0
4.0
Min.
0
0
Max.
15
17
Endpoint
163
4.8
0.31
4.0
0
16
Chg from baseline
n
154
Mean
-0.1
SE
0.22
Median
0.0
Min.
-11
Max.
8
158
-0.1
0.19
0.0
-13
7
Scale score
n
146
Mean
4.6
SE
0.31
Median
4.0
Min.
0
Max.
17
143
4.7
0.32
4.0
0
16
-0.1
0.28
(-0.6,0.5)
0.789
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 11:35
RM2010/00132/00
ADC111114
n
157
Mean
4.6
SE
0.31
Median
4.0
Min.
0
Max.
19
CONFIDENTIAL
341
Week 8
Scale score
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 5
Table 6.14
Summary of HADS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Scale
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Depression Week 8
Chg from baseline
n
143
139
Mean
-0.0
-0.1
0.0
(-0.6,0.6)
SE
0.22
0.24
0.30
0.906
Median
0.0
0.0
Min.
-8
-12
Max.
8
12
Week 24
129
4.7
0.35
3.0
0
16
Chg from baseline
n
127
Mean
-0.2
SE
0.25
Median
0.0
Min.
-11
Max.
8
125
0.1
0.20
0.0
-13
6
Scale score
n
19
24
Mean
SE
Median
Min.
Max.
5.6
1.06
5.0
0
16
5.3
0.67
5.0
0
13
-0.2
0.30
(-0.8,0.4)
0.480
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 11:35
RM2010/00132/00
ADC111114
n
130
Mean
4.4
SE
0.34
Median
3.0
Min.
0
Max.
19
CONFIDENTIAL
342
Early
withdrawal
Scale score
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 5
Table 6.14
Summary of HADS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Scale
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Depression Early
Chg from baseline
n
19
23
withdrawal
Mean
0.4
-0.8
1.1
(-0.9,3.1)
SE
0.61
0.67
0.99
0.263
Median
0.0
-1.0
Min.
-4
-7
Max.
7
7
n
169
Mean
4.9
SE
0.31
Median
4.0
Min.
0
Max.
18
164
5.5
0.33
5.0
0
17
Endpoint
Scale score
n
155
Mean
5.1
SE
0.34
Median
4.0
Min.
0
Max.
18
161
5.1
0.35
4.0
0
17
Chg from baseline
n
153
Mean
-0.0
SE
0.26
Median
0.0
Min.
-12
Max.
10
158
-0.4
0.23
-1.0
-10
9
0.3
0.32
(-0.4,0.9)
0.438
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 11:35
RM2010/00132/00
ADC111114
Scale score
343
Baseline
CONFIDENTIAL
Anxiety
Protocol: ADC111114
Population: Intent-to-Treat
Page 4 of 5
Table 6.14
Summary of HADS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Scale
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Anxiety
Week 8
Scale score
n
145
143
Mean
5.2
5.2
SE
0.36
0.35
Median
4.0
4.0
Min.
0
0
Max.
17
16
140
-0.2
0.24
0.0
-14
13
Scale score
n
129
Mean
4.9
SE
0.38
Median
4.0
Min.
0
Max.
18
128
4.9
0.39
4.0
0
16
Chg from baseline
n
127
Mean
-0.1
SE
0.30
Median
0.0
Min.
-12
Max.
10
126
-0.2
0.25
0.0
-10
9
0.2
0.31
(-0.4,0.8)
0.456
0.2
0.36
(-0.5,0.9)
0.646
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 11:35
RM2010/00132/00
ADC111114
n
144
Mean
0.0
SE
0.22
Median
0.0
Min.
-10
Max.
8
CONFIDENTIAL
344
Week 24
Chg from baseline
Protocol: ADC111114
Population: Intent-to-Treat
Page 5 of 5
Table 6.14
Summary of HADS
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Scale
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Anxiety
Early
Scale score
n
18
23
withdrawal
Mean
5.7
5.9
SE
1.09
0.90
Median
4.5
5.0
Min.
1
0
Max.
18
17
345
n
Mean
SE
Median
Min.
Max.
18
0.4
0.57
0.0
-3
6
22
-0.8
0.79
-1.0
-8
7
0.8
1.08
(-1.4,3.0)
0.489
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 11:35
CONFIDENTIAL
Chg from baseline
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 3
Table 6.15
Summary of HADS Depression Scale - Subjects with Scores >=8 at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
Depression score
n
35
40
Mean
10.5
10.5
SE
0.35
0.37
Median
10.0
10.0
Min.
8
8
Max.
15
17
Endpoint
33
9.0
0.69
9.0
1
19
40
9.2
0.65
10.0
0
16
Change from baseline
n
Mean
SE
Median
Min.
Max.
33
-1.7
0.63
-1.0
-11
4
40
-1.3
0.54
-0.5
-13
5
Depression score
n
Mean
SE
Median
Min.
Max.
31
9.1
0.63
8.0
3
17
35
8.6
0.68
8.0
1
16
-0.0
0.83
(-1.7,1.7)
1.000
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 11:40
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
346
Week 8
Depression score
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 3
Table 6.15
Summary of HADS Depression Scale - Subjects with Scores >=8 at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 8
Change from baseline
n
31
35
Mean
-1.5
-1.7
0.6
(-1.1,2.3)
SE
0.56
0.59
0.85
0.490
Median
-1.0
-1.0
Min.
-8
-12
Max.
4
5
Week 24
n
Mean
SE
Median
Min.
Max.
26
8.8
0.80
8.5
1
19
28
9.8
0.77
11.0
0
16
Change from baseline
n
Mean
SE
Median
Min.
Max.
26
-1.7
0.72
-1.0
-11
4
28
-0.5
0.67
0.0
-13
5
Depression score
n
11.0
2.08
11.0
6
16
(-2.6,1.5)
0.605
8
7.4
1.36
6.5
3
13
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 11:40
RM2010/00132/00
ADC111114
Mean
SE
Median
Min.
Max.
4
-0.5
1.01
CONFIDENTIAL
347
Early
withdrawal
Depression score
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 3
Table 6.15
Summary of HADS Depression Scale - Subjects with Scores >=8 at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Early
Change from baseline
n
4
8
withdrawal
Mean
-0.3
-3.4
4.4
(-0.0,8.8)
SE
1.75
0.86
1.81
0.051
Median
-0.5
-3.0
Min.
-4
-7
Max.
4
0
CONFIDENTIAL
348
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 11:40
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 3
Table 6.16
Summary of HADS Anxiety Scale - Subjects with Scores >=8 at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
Anxiety score
n
42
49
Mean
10.9
10.9
SE
0.40
0.38
Median
10.0
10.0
Min.
8
8
Max.
18
17
Endpoint
40
9.0
0.73
8.0
0
18
46
9.5
0.62
9.5
0
17
Change from baseline
n
Mean
SE
Median
Min.
Max.
40
-1.9
0.61
-1.5
-12
5
46
-1.4
0.52
-1.0
-10
6
Anxiety score
n
Mean
SE
Median
Min.
Max.
39
9.9
0.61
10.0
3
17
40
9.6
0.55
9.0
1
16
-0.5
0.79
(-2.0,1.1)
0.564
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 11:47
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
349
Week 8
Anxiety score
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 3
Table 6.16
Summary of HADS Anxiety Scale - Subjects with Scores >=8 at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 8
Change from baseline
n
39
40
Mean
-1.0
-1.2
0.2
(-1.3,1.8)
SE
0.53
0.55
0.77
0.778
Median
-1.0
-1.0
Min.
-10
-14
Max.
3
5
Week 24
n
Mean
SE
Median
Min.
Max.
33
8.8
0.83
8.0
0
18
35
9.6
0.71
10.0
0
16
Change from baseline
n
Mean
SE
Median
Min.
Max.
33
-2.2
0.69
-2.0
-12
5
35
-0.9
0.61
-1.0
-10
6
Anxiety score
n
11.0
2.61
9.5
7
18
(-3.0,0.6)
0.188
8
8.6
1.72
7.5
3
17
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 11:47
RM2010/00132/00
ADC111114
Mean
SE
Median
Min.
Max.
4
-1.2
0.89
CONFIDENTIAL
350
Early
withdrawal
Anxiety score
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 3
Table 6.16
Summary of HADS Anxiety Scale - Subjects with Scores >=8 at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=173)
(N=169)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Early
Change from baseline
n
4
8
withdrawal
Mean
0.5
-3.4
2.4
(-2.7,7.5)
SE
1.85
1.15
2.08
0.296
Median
0.0
-3.5
Min.
-3
-8
Max.
5
1
CONFIDENTIAL
351
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 11:47
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 1 of 3
Table 8.5
Summary of Pre-dose FEV1 (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
FEV1
n
104
107
Mean
1873
1865
SE
54.1
48.8
Median
1773
1823
Min.
965
764
Max.
3456
3443
Endpoint
93
1885
61.2
1794
824
3669
98
1803
55.4
1786
783
3419
Change from baseline
n
Mean
SE
Median
Min.
Max.
93
25
25.9
-9
-676
685
98
-31
26.3
-46
-931
834
FEV1
n
Mean
SE
Median
Min.
Max.
93
1937
64.3
1872
930
3643
98
1806
52.5
1762
904
2953
50
36.8
(-23,123)
0.178
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:09
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
352
Week 4
FEV1
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 2 of 3
Table 8.5
Summary of Pre-dose FEV1 (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 4
Change from baseline
n
93
98
Mean
77
-28
99
(33,166)
SE
24.7
22.0
33.6
0.003
Median
73
-44
Min.
-526
-646
Max.
913
772
Week 8
92
1892
63.1
1822
702
3669
93
1797
54.7
1778
616
3094
Change from baseline
n
Mean
SE
Median
Min.
Max.
92
44
23.3
57
-562
1032
93
-39
19.3
-50
-532
500
FEV1
n
Mean
SE
Median
Min.
Max.
85
1907
62.1
1840
990
3647
85
1789
57.7
1724
723
3260
82
30.7
(22,143)
0.008
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:09
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
353
Week 16
FEV1
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 3 of 3
Table 8.5
Summary of Pre-dose FEV1 (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 16
Change from baseline
n
85
85
Mean
67
-44
106
(40,172)
SE
23.4
23.2
33.4
0.002
Median
54
-66
Min.
-440
-931
Max.
937
573
Week 24
n
Mean
SE
Median
Min.
Max.
85
1868
60.7
1797
824
3490
80
1816
63.7
1762
783
3419
Change from baseline
n
Mean
SE
Median
Min.
Max.
85
24
27.3
-11
-676
685
80
-18
28.4
-40
-656
834
35
39.1
(-42,112)
0.368
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:09
CONFIDENTIAL
354
FEV1
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 1 of 3
Table 8.6
Summary of 2-hour Post-dose FEV1 (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
FEV1
n
104
107
Mean
1873
1865
SE
54.1
48.8
Median
1773
1823
Min.
965
764
Max.
3456
3443
Endpoint
93
2005
59.3
1986
991
3819
97
1887
55.7
1803
732
3233
Change from baseline
n
Mean
SE
Median
Min.
Max.
93
145
27.1
127
-779
848
97
54
25.3
19
-732
805
FEV1
n
Mean
SE
Median
Min.
Max.
93
2037
64.7
1955
1043
3899
97
1883
52.1
1814
851
2916
82
36.6
(10,154)
0.026
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:12
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
355
Week 4
FEV1
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 2 of 3
Table 8.6
Summary of 2-hour Post-dose FEV1 (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 4
Change from baseline
n
93
97
Mean
177
49
119
(54,184)
SE
24.3
22.1
32.9
<0.001
Median
171
12
Min.
-450
-594
Max.
909
801
Week 8
91
2001
61.9
1957
1022
3828
93
1898
55.2
1843
869
3188
Change from baseline
n
Mean
SE
Median
Min.
Max.
91
158
24.0
137
-476
1040
93
62
23.5
57
-561
1013
FEV1
n
Mean
SE
Median
Min.
Max.
86
2003
61.8
1990
1090
3856
85
1863
59.8
1774
836
3534
89
33.7
(23,156)
0.009
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:12
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
356
Week 16
FEV1
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 3 of 3
Table 8.6
Summary of 2-hour Post-dose FEV1 (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 16
Change from baseline
n
86
85
Mean
165
29
129
(62,196)
SE
23.0
25.9
33.9
<0.001
Median
154
2
Min.
-375
-732
Max.
843
859
Week 24
n
Mean
SE
Median
Min.
Max.
84
1989
60.6
1993
991
3819
80
1901
62.9
1824
732
3233
Change from baseline
n
Mean
SE
Median
Min.
Max.
84
145
29.6
131
-779
848
80
67
27.3
22
-438
805
68
39.8
(-11,146)
0.092
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:12
CONFIDENTIAL
357
FEV1
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 1 of 3
Table 8.7
Summary of Pre-dose FVC (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
FVC
n
104
107
Mean
3291
3285
SE
83.1
81.3
Median
3239
3190
Min.
1824
1823
Max.
5553
5334
Endpoint
93
3251
88.0
3185
1606
5400
98
3171
86.7
3077
1479
5199
Change from baseline
n
Mean
SE
Median
Min.
Max.
93
-12
35.5
-26
-939
782
98
-60
36.3
-68
-1145
783
FVC
n
Mean
SE
Median
Min.
Max.
93
3288
90.6
3249
1833
5653
98
3167
85.4
3045
1511
4921
40
50.8
(-60,140)
0.431
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:15
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
358
Week 4
FVC
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 2 of 3
Table 8.7
Summary of Pre-dose FVC (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 4
Change from baseline
n
93
98
Mean
24
-65
87
(-1,174)
SE
29.2
32.8
44.4
0.052
Median
45
-78
Min.
-712
-1012
Max.
588
892
Week 8
92
3237
90.7
3196
1663
5766
93
3169
86.5
3075
1479
5100
Change from baseline
n
Mean
SE
Median
Min.
Max.
92
-12
33.5
-1
-1019
992
93
-72
29.0
-60
-697
668
FVC
n
Mean
SE
Median
Min.
Max.
85
3281
90.2
3310
1633
5594
85
3163
90.3
2966
1721
5288
59
45.1
(-30,148)
0.190
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:15
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
359
Week 16
FVC
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 3 of 3
Table 8.7
Summary of Pre-dose FVC (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 16
Change from baseline
n
85
85
Mean
35
-91
123
(30,216)
SE
31.7
34.7
47.1
0.010
Median
33
-128
Min.
-802
-1108
Max.
694
490
Week 24
n
Mean
SE
Median
Min.
Max.
85
3234
89.3
3213
1606
5400
80
3213
99.5
3114
1657
5199
Change from baseline
n
Mean
SE
Median
Min.
Max.
85
-15
37.5
-29
-939
782
80
-42
39.9
-26
-1145
783
15
54.5
(-93,122)
0.789
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:15
CONFIDENTIAL
360
FVC
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 1 of 3
Table 8.8
Summary of 2-hour Post-dose FVC (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
FVC
n
104
107
Mean
3291
3285
SE
83.1
81.3
Median
3239
3190
Min.
1824
1823
Max.
5553
5334
Endpoint
93
3384
86.3
3385
1593
5831
97
3254
87.0
3090
1568
5136
Change from baseline
n
Mean
SE
Median
Min.
Max.
93
121
34.3
87
-902
1059
97
25
34.0
7
-990
866
FVC
n
Mean
SE
Median
Min.
Max.
93
3405
91.9
3459
1836
5950
97
3243
85.1
3090
1792
5019
84
47.8
(-10,178)
0.081
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:19
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
361
Week 4
FVC
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 2 of 3
Table 8.8
Summary of 2-hour Post-dose FVC (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 4
Change from baseline
n
93
97
Mean
142
14
121
(35,206)
SE
30.9
29.7
43.2
0.006
Median
123
30
Min.
-582
-687
Max.
862
601
Week 8
91
3357
90.4
3308
1596
5976
93
3288
87.7
3229
1568
5315
Change from baseline
n
Mean
SE
Median
Min.
Max.
91
117
31.1
80
-759
716
93
46
34.3
61
-845
1291
FVC
n
Mean
SE
Median
Min.
Max.
86
3406
93.0
3362
1692
5947
85
3255
94.5
3003
1638
5431
63
46.6
(-29,155)
0.179
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:19
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
362
Week 16
FVC
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 3 of 3
Table 8.8
Summary of 2-hour Post-dose FVC (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 16
Change from baseline
n
86
85
Mean
167
1
160
(61,259)
SE
32.0
39.2
50.3
0.002
Median
111
-13
Min.
-420
-990
Max.
976
1205
Week 24
n
Mean
SE
Median
Min.
Max.
84
3375
89.6
3387
1593
5831
80
3298
99.0
3174
1592
5136
Change from baseline
n
Mean
SE
Median
Min.
Max.
84
124
37.5
82
-902
1059
80
43
35.6
-5
-656
866
66
51.5
(-35,168)
0.199
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:19
CONFIDENTIAL
363
FVC
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 1 of 3
Table 8.9
Summary of Pre-dose IC (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
IC
n
104
106
Mean
2378
2386
SE
67.9
67.0
Median
2233
2319
Min.
1182
1221
Max.
4375
4798
Endpoint
93
2413
82.5
2259
1058
4960
98
2327
68.5
2254
860
4448
Change from baseline
n
Mean
SE
Median
Min.
Max.
93
53
35.3
27
-1125
1068
97
4
35.0
-46
-803
1030
IC
n
Mean
SE
Median
Min.
Max.
93
2415
82.9
2259
964
4561
98
2309
65.6
2287
895
4133
53
49.4
(-45,150)
0.286
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:22
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
364
Week 4
IC
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 2 of 3
Table 8.9
Summary of Pre-dose IC (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 4
Change from baseline
n
93
97
Mean
55
-16
65
(-27,157)
SE
33.0
32.6
46.6
0.163
Median
10
-51
Min.
-892
-1126
Max.
1034
968
Week 8
92
2368
77.3
2250
1022
4818
93
2345
70.1
2275
860
4146
Change from baseline
n
Mean
SE
Median
Min.
Max.
92
25
36.6
-3
-1095
1027
92
1
36.8
-5
-983
1045
IC
n
Mean
SE
Median
Min.
Max.
86
2408
81.1
2272
1072
4235
84
2352
70.8
2270
1249
4155
28
51.3
(-74,129)
0.592
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:22
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
365
Week 16
IC
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 3 of 3
Table 8.9
Summary of Pre-dose IC (mL) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 16
Change from baseline
n
86
83
Mean
43
22
25
(-81,131)
SE
35.6
39.8
53.8
0.639
Median
1
-6
Min.
-879
-1265
Max.
1055
1370
Week 24
n
Mean
SE
Median
Min.
Max.
85
2407
87.3
2271
1058
4960
80
2340
76.0
2254
1072
4448
Change from baseline
n
Mean
SE
Median
Min.
Max.
85
38
37.6
9
-1125
1068
79
13
40.8
-30
-803
1030
31
55.2
(-78,140)
0.573
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:22
CONFIDENTIAL
366
IC
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 1 of 9
Table 8.10
Summary of CRQ-SAS - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Mastery
Baseline
Domain score
n
103
106
Mean
4.96
5.06
SE
0.140
0.134
Median
5.25
5.50
Min.
1.8
2.0
Max.
7.0
7.0
Endpoint
98
5.17
0.153
5.50
1.5
7.0
105
5.21
0.135
5.50
1.3
7.0
Chg from baseline
n
Mean
SE
Median
Min.
Max.
97
0.24
0.111
0.00
-2.0
4.8
104
0.14
0.104
0.00
-2.5
4.3
Domain score
n
Mean
SE
Median
Min.
Max.
89
5.17
0.153
5.25
1.5
7.0
94
5.21
0.147
5.50
1.8
7.0
0.07
0.144
(-0.21,0.36)
0.623
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:26
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
367
Week 8
Domain score
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 2 of 9
Table 8.10
Summary of CRQ-SAS - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Mastery
Week 8
Chg from baseline
n
89
93
Mean
0.13
0.13
0.00
(-0.29,0.29)
SE
0.107
0.114
0.147
0.980
Median
0.00
0.25
Min.
-3.3
-4.5
Max.
2.8
3.5
Week 24
n
Mean
SE
Median
Min.
Max.
83
5.31
0.164
5.75
1.5
7.0
81
5.33
0.153
5.75
1.3
7.0
Chg from baseline
n
Mean
SE
Median
Min.
Max.
82
0.25
0.128
0.00
-2.0
4.8
80
0.23
0.123
0.25
-2.5
4.3
Domain score
n
11
15
4.32
0.474
4.25
2.3
7.0
(-0.32,0.33)
0.963
4.61
0.332
4.75
2.3
6.5
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:26
RM2010/00132/00
ADC111114
Mean
SE
Median
Min.
Max.
0.01
0.164
CONFIDENTIAL
368
Early
withdrawal
Domain score
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 3 of 9
Table 8.10
Summary of CRQ-SAS - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Mastery
Early
Chg from baseline
n
11
15
withdrawal
Mean
0.23
-0.29
0.77
(-0.09,1.62)
SE
0.239
0.232
0.407
0.076
Median
0.25
-0.25
Min.
-1.0
-2.3
Max.
1.8
1.8
n
103
Mean
3.87
SE
0.123
Median
4.00
Min.
1.0
Max.
6.3
106
3.71
0.130
3.75
1.0
6.5
Endpoint
Domain score
n
Mean
SE
Median
Min.
Max.
98
3.96
0.143
4.00
1.0
6.8
105
4.04
0.142
4.25
1.3
6.8
Chg from baseline
n
Mean
SE
Median
Min.
Max.
97
0.14
0.129
0.25
-2.8
4.5
104
0.34
0.108
0.25
-2.5
4.0
-0.18
0.159
(-0.49,0.13)
0.257
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:26
RM2010/00132/00
ADC111114
Domain score
369
Baseline
CONFIDENTIAL
Fatigue
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 4 of 9
Table 8.10
Summary of CRQ-SAS - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Fatigue
Week 8
Domain score
n
89
94
Mean
3.83
3.89
SE
0.141
0.137
Median
3.75
4.00
Min.
1.0
1.0
Max.
6.8
7.0
89
-0.05
0.094
0.00
-2.8
2.5
93
0.14
0.102
0.25
-3.0
2.5
Domain score
n
Mean
SE
Median
Min.
Max.
83
4.07
0.156
4.25
1.0
6.8
81
4.27
0.161
4.25
1.3
6.8
Chg from baseline
n
Mean
SE
Median
Min.
Max.
82
0.19
0.144
0.25
-2.8
4.5
80
0.39
0.126
0.38
-2.5
4.0
-0.16
0.131
(-0.42,0.10)
0.224
-0.21
0.178
(-0.56,0.14)
0.238
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:26
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
370
Week 24
Chg from baseline
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 5 of 9
Table 8.10
Summary of CRQ-SAS - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Fatigue
Early
Domain score
n
11
15
withdrawal
Mean
3.32
3.18
SE
0.433
0.258
Median
3.50
3.00
Min.
1.8
1.3
Max.
6.8
5.0
15
-0.02
0.284
0.25
-2.0
1.8
Emotional
Baseline
Domain score
n
103
Mean
4.51
SE
0.129
Median
4.57
Min.
1.6
Max.
7.0
106
4.48
0.130
4.50
1.7
7.0
Endpoint
Domain score
n
Mean
SE
Median
Min.
Max.
105
4.73
0.134
5.00
1.1
7.0
98
4.71
0.132
4.71
1.4
7.0
-0.05
0.506
(-1.11,1.01)
0.924
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:26
CONFIDENTIAL
11
-0.20
0.353
-0.25
-1.5
2.0
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
371
Chg from baseline
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 6 of 9
Table 8.10
Summary of CRQ-SAS - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Emotional Endpoint
Chg from baseline
n
97
104
Mean
0.24
0.25
-0.01
(-0.24,0.23)
SE
0.090
0.089
0.120
0.942
Median
0.14
0.21
Min.
-1.9
-1.7
Max.
3.6
3.4
Week 8
89
4.64
0.140
4.71
1.4
7.0
94
4.63
0.135
4.71
2.1
6.9
Chg from baseline
n
Mean
SE
Median
Min.
Max.
89
0.09
0.084
0.14
-2.1
2.9
93
0.16
0.094
0.29
-3.0
2.1
Domain score
n
Mean
SE
Median
Min.
Max.
83
4.80
0.144
4.86
1.4
7.0
81
4.87
0.156
5.29
1.1
7.0
-0.05
0.117
(-0.28,0.18)
0.650
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:26
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
372
Week 24
Domain score
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 7 of 9
Table 8.10
Summary of CRQ-SAS - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Emotional Week 24
Chg from baseline
n
82
80
Mean
0.24
0.31
-0.07
(-0.34,0.20)
SE
0.103
0.105
0.136
0.600
Median
0.14
0.29
Min.
-1.9
-1.7
Max.
3.6
3.4
Domain score
Baseline
11
15
4.21
0.380
4.14
2.0
6.9
4.22
0.277
4.14
2.7
6.3
Chg from baseline
n
Mean
SE
Median
Min.
Max.
11
0.19
0.213
0.00
-0.7
1.6
15
-0.10
0.215
-0.14
-1.4
1.7
Domain score
n
103
Mean
4.73
SE
0.137
Median
4.80
Min.
1.8
Max.
7.0
106
4.69
0.140
5.00
1.0
7.0
0.53
0.299
(-0.10,1.16)
0.094
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:26
RM2010/00132/00
ADC111114
Mean
SE
Median
Min.
Max.
373
Dyspnea
n
CONFIDENTIAL
Early
withdrawal
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 8 of 9
Table 8.10
Summary of CRQ-SAS - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Dyspnea
Endpoint
Domain score
n
97
105
Mean
4.88
5.00
SE
0.152
0.145
Median
5.00
5.20
Min.
1.6
1.4
Max.
7.0
7.0
96
0.20
0.127
0.20
-3.8
4.0
104
0.30
0.109
0.40
-2.8
5.0
Domain score
n
Mean
SE
Median
Min.
Max.
89
4.88
0.161
5.00
1.2
7.0
94
4.90
0.147
5.20
1.8
7.0
Chg from baseline
n
Mean
SE
Median
Min.
Max.
89
0.13
0.124
0.15
-4.1
4.0
93
0.19
0.099
0.20
-2.8
3.8
-0.11
0.158
(-0.42,0.20)
0.501
-0.04
0.150
(-0.34,0.25)
0.776
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:26
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
374
Week 8
Chg from baseline
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 9 of 9
Table 8.10
Summary of CRQ-SAS - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff
95% CI
Domain
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Dyspnea
Week 24
Domain score
n
82
81
Mean
4.97
5.12
SE
0.157
0.157
Median
5.00
5.60
Min.
1.8
1.4
Max.
7.0
7.0
n
Mean
SE
Median
Min.
Max.
81
0.18
0.146
0.20
-3.8
4.0
80
0.36
0.128
0.40
-2.4
5.0
Domain score
n
11
15
Chg from baseline
4.15
0.616
3.80
1.6
7.0
4.82
0.396
5.20
2.0
7.0
n
Mean
SE
Median
Min.
Max.
11
0.19
0.218
0.20
-1.0
1.0
15
0.25
0.214
0.20
-1.0
2.0
(-0.53,0.18)
0.338
-0.02
0.375
(-0.81,0.76)
0.950
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:26
RM2010/00132/00
ADC111114
Mean
SE
Median
Min.
Max.
-0.17
0.181
CONFIDENTIAL
375
Early
withdrawal
Chg from baseline
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 1 of 3
Table 8.11
Summary of Pre-dose FEV1 (% predicted) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Baseline
FEV1 % predicted
n
104
107
Mean
61
63
SE
1.0
0.9
Median
59
62
Min.
50
50
Max.
92
89
Endpoint
93
62
1.2
61
39
89
98
61
1.2
60
36
103
Change from baseline
n
Mean
SE
Median
Min.
Max.
93
1
0.8
-0
-21
23
98
-1
0.9
-2
-29
24
FEV1 % predicted
n
Mean
SE
Median
Min.
Max.
93
63
1.2
63
36
94
98
62
1.2
59
41
107
2
1.2
(-1,4)
0.201
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:29
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
376
Week 4
FEV1 % predicted
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 2 of 3
Table 8.11
Summary of Pre-dose FEV1 (% predicted) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 4
Change from baseline
n
93
98
Mean
2
-1
3
(1,5)
SE
0.8
0.7
1.1
0.007
Median
2
-2
Min.
-20
-18
Max.
25
25
Week 8
92
62
1.2
60
35
89
93
61
1.2
60
37
107
Change from baseline
n
Mean
SE
Median
Min.
Max.
92
1
0.8
2
-17
34
93
-2
0.7
-1
-16
19
FEV1 % predicted
n
Mean
SE
Median
Min.
Max.
85
63
1.2
61
38
94
85
61
1.2
60
41
101
3
1.1
(1,5)
0.007
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:29
RM2010/00132/00
ADC111114
n
Mean
SE
Median
Min.
Max.
CONFIDENTIAL
377
Week 16
FEV1 % predicted
Protocol: ADC111114
Population: Baseline FEV1 % Predicted >50%
Page 3 of 3
Table 8.11
Summary of Pre-dose FEV1 (% predicted) - Subjects >50% Predicted at Baseline
FSC250/50+Tio Tiotropium
LS Mean Diff 95% CI
Week
(N=104)
(N=107)
Std Error
p-value
-----------------------------------------------------------------------------------------------------------Week 16
Change from baseline
n
85
85
Mean
2
-2
4
(1,6)
SE
0.8
0.8
1.1
0.002
Median
2
-3
Min.
-14
-29
Max.
31
17
Week 24
n
Mean
SE
Median
Min.
Max.
85
62
1.2
59
39
89
80
61
1.4
60
36
103
Change from baseline
n
Mean
SE
Median
Min.
Max.
85
1
0.9
-0
-21
23
80
-1
1.0
-1
-22
24
1
1.3
(-1,4)
0.346
RM2010/00132/00
ADC111114
Note: LS Mean Diff, Std Error, CI and p-values are from an ANCOVA model with terms for treatment,
pooled investigator, reversibility stratum and baseline value.
LS Mean Diffs are calculated as FSC250/50+Tio - Tiotropium.
05MAR2010 15:29
CONFIDENTIAL
378
FEV1 % predicted
CONFIDENTIAL
RM2010/00132/00
ADC111114
SAFETY DATA SOURCE TABLES
Page
Table 7.1 Summary of All Adverse Events (Run-In Failure Population) (Run-in
failure Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.2 Summary of All Adverse Events During Run-In (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.3 Summary of All Adverse Events During Treatment (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.4 Summary of Most Common (>2%) Adverse Events During Treatment
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.5 Summary of Drug-Related Adverse Events Post Randomization
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.6 Summary of Adverse Events Leading to Withdrawal from the Study
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.7 Summary of All Adverse Events Post-Treatment (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.8 Summary of Serious Adverse Events Post Randomization
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.9 Summary of Pneumonia Adverse Events Post Randomization
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.10 Listing of All Adverse Events (Intent-to-Treat Population) . . . . . . . . . . . .
Table 7.11 Listing of Subject Numbers for Individual Adverse Events
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.12 Relationship of Adverse Event System Organ Class, Preferred Term
and Verbatim Text (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.13 Listing of Adverse Events Leading to Withdrawal from the Study
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.14 Listing of Fatal Adverse Events (Safety Population) (Safety Population)
Table 7.15 Listing of Non-Fatal Serious Adverse Events (Safety Population)
(Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.16 Listing of Pneumonia Adverse Events (Intent-to-Treat Population) . . . . .
Table 7.17 Listing of Pneumonia Chest X-rays (Intent-to-Treat Population) . . . . . . .
Table 7.18 Listing of Pneumonia Chest X-rays - Cultures and Clinical Findings
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.19 Listing of Pneumonia Chest X-rays - Treatment and Outcome
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.20 Listing of Positive Pregnancy Tests (Intent-to-Treat Population) . . . . . . .
379
380
382
385
393
394
397
399
401
403
404
563
585
600
607
608
620
621
622
623
624
Protocol: ADC111114
Population: Run-in failure
Page 1 of 2
Table 7.1
Summary of All Adverse Events (Run-In Failure Population)
Not
System Organ Class
Randomized
Preferred Term
(N=63)
---------------------------------------------------------------------------------------------Any event
19 (30%)
Respiratory, thoracic and mediastinal disorders
Any event
Chronic obstructive pulmonary disease
Asthma
Cough
Dyspnoea
Wheezing
6 (10%)
3 (5%)
1 (2%)
1 (2%)
1 (2%)
1 (2%)
Gastrointestinal disorders
Any event
Abdominal pain
Dyspepsia
Swollen tongue
3
1
1
1
(5%)
(2%)
(2%)
(2%)
Cardiac disorders
Any event
Coronary artery disease
Myocardial infarction
2
1
1
(3%)
(2%)
(2%)
Musculoskeletal and connective tissue disorders
Any event
Arthritis
2
1
(3%)
(2%)
08MAR2010 13:28
RM2010/00132/00
ADC111114
6 (10%)
3 (5%)
1 (2%)
1 (2%)
1 (2%)
1 (2%)
CONFIDENTIAL
380
Infections and infestations
Any event
Bronchitis
Nasopharyngitis
Pneumonia
Respiratory tract infection
Upper respiratory tract infection
Protocol: ADC111114
Population: Run-in failure
Page 2 of 2
Table 7.1
Summary of All Adverse Events (Run-In Failure Population)
Not
System Organ Class
Randomized
Preferred Term
(N=63)
---------------------------------------------------------------------------------------------Back pain
1 (2%)
(3%)
(2%)
(2%)
Blood and lymphatic system disorders
Any event
Lymphadenopathy
1
1
(2%)
(2%)
Immune system disorders
Any event
Hypersensitivity
1
1
(2%)
(2%)
Injury, poisoning and procedural complications
Any event
Device lead damage
1
1
(2%)
(2%)
Reproductive system and breast disorders
Any event
Endometrial hypertrophy
1
1
(2%)
(2%)
Skin and subcutaneous tissue disorders
Any event
Pruritus
1
1
(2%)
(2%)
08MAR2010 13:28
RM2010/00132/00
ADC111114
2
1
1
CONFIDENTIAL
381
Vascular disorders
Any event
Deep vein thrombosis
Hypotension
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 3
Table 7.2
Summary of All Adverse Events During Run-In
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Any event
34 (20%)
28 (17%)
Nervous system disorders
Any event
Headache
Sinus headache
Dizziness
Neuropathy peripheral
(3%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
11
4
4
1
1
0
0
1
1
1
0
1
(7%)
(2%)
(2%)
(<1%)
(<1%)
10 (6%)
6 (3%)
2 (1%)
1 (<1%)
1 (<1%)
6
6
0
0
0
(4%)
(4%)
8 (5%)
3 (2%)
0
0
0
1 (<1%)
0
1 (<1%)
0
7
4
1
1
1
0
1
0
1
(4%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
08MAR2010 13:39
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
RM2010/00132/00
ADC111114
Infections and infestations
Any event
Nasopharyngitis
Body tinea
Conjunctivitis infective
Gastroenteritis viral
Gingival infection
Herpes simplex
Lobar pneumonia
Pharyngitis streptococcal
6
1
1
1
1
1
1
0
0
0
1
0
CONFIDENTIAL
382
Respiratory, thoracic and mediastinal disorders
Any event
Cough
Oropharyngeal pain
Epistaxis
Respiratory tract congestion
Dry throat
Dyspnoea
Dyspnoea exertional
Increased upper airway secretion
Nasal congestion
Postnasal drip
Sinus congestion
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 3
Table 7.2
Summary of All Adverse Events During Run-In
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Pneumonia
1 (<1%)
0
Rash pustular
1 (<1%)
0
Tooth abscess
1 (<1%)
0
8
1
2
1
1
2
0
0
0
0
1
Musculoskeletal and connective tissue disorders
Any event
Back pain
Pain in extremity
Arthralgia
Muscle spasms
Neck pain
5 (3%)
3 (2%)
3 (2%)
0
0
1 (<1%)
6 (4%)
4 (2%)
1 (<1%)
1 (<1%)
1 (<1%)
0
General disorders and administration site conditions
Any event
Chest pain
Oedema peripheral
Pain
Fatigue
Local swelling
5 (3%)
2 (1%)
1 (<1%)
2 (1%)
0
1 (<1%)
2 (1%)
0
1 (<1%)
0
1 (<1%)
0
(5%)
(<1%)
(1%)
(<1%)
(<1%)
(1%)
(<1%)
6
1
0
1
1
0
2
1
1
1
0
(<1%)
(<1%)
(1%)
(<1%)
(<1%)
(<1%)
RM2010/00132/00
ADC111114
08MAR2010 13:39
(4%)
(<1%)
CONFIDENTIAL
383
Gastrointestinal disorders
Any event
Abdominal pain upper
Constipation
Diarrhoea
Dry mouth
Toothache
Vomiting
Dyspepsia
Glossodynia
Irritable bowel syndrome
Nausea
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 3
Table 7.2
Summary of All Adverse Events During Run-In
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Skin and subcutaneous tissue disorders
Any event
3 (2%)
2 (1%)
Dermatitis
1 (<1%)
0
Dermatitis contact
0
1 (<1%)
Night sweats
0
1 (<1%)
Pruritus generalised
1 (<1%)
0
Rash
1 (<1%)
0
Psychiatric disorders
Any event
Anxiety
Insomnia
1 (<1%)
0
1 (<1%)
1 (<1%)
1 (<1%)
0
Blood and lymphatic system disorders
Any event
Lymphadenopathy
1 (<1%)
1 (<1%)
0
0
Ear and labyrinth disorders
Any event
Ear pain
0
0
1 (<1%)
1 (<1%)
Vascular disorders
Any event
Haematoma
1 (<1%)
1 (<1%)
0
0
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
0
0
0
0
0
08MAR2010 13:39
RM2010/00132/00
ADC111114
3
1
1
1
1
CONFIDENTIAL
384
Injury, poisoning and procedural complications
Any event
Contusion
Excoriation
Joint sprain
Skin laceration
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 8
Table 7.3
Summary of All Adverse Events During Treatment
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Any event
97 (56%)
85 (50%)
Infections and infestations
Any event
Nasopharyngitis
Bronchitis
Oral candidiasis
Upper respiratory tract infection
Urinary tract infection
Viral infection
Gastroenteritis viral
Pharyngitis
Sinusitis
Candidiasis
Fungal infection
46 (27%)
5 (3%)
6 (3%)
5 (3%)
3 (2%)
4 (2%)
4 (2%)
0
2 (1%)
3 (2%)
2 (1%)
2 (1%)
(23%)
(14%)
(3%)
(2%)
(2%)
(1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
08MAR2010 13:55
41
24
4
3
2
5
3
3
2
2
1
0
1
1
0
1
(24%)
(14%)
(2%)
(2%)
(1%)
(3%)
(2%)
(2%)
(1%)
(1%)
(<1%)
29
6
3
1
3
1
1
4
2
1
1
0
(17%)
(4%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)
(2%)
(1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
RM2010/00132/00
ADC111114
39
24
6
3
4
0
2
1
1
1
1
1
0
0
1
0
CONFIDENTIAL
385
Respiratory, thoracic and mediastinal disorders
Any event
Chronic obstructive pulmonary disease
Oropharyngeal pain
Cough
Dysphonia
Dyspnoea
Nasal congestion
Sinus congestion
Epistaxis
Respiratory tract congestion
Sputum increased
Haemoptysis
Oropharyngeal blistering
Pneumothorax
Rhinorrhoea
Sleep apnoea syndrome
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 8
Table 7.3
Summary of All Adverse Events During Treatment
15
2
3
(9%)
(1%)
(2%)
08MAR2010 13:55
19 (11%)
3 (2%)
2 (1%)
RM2010/00132/00
ADC111114
Gastrointestinal disorders
Any event
Nausea
Toothache
CONFIDENTIAL
386
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Gastroenteritis
1 (<1%)
1 (<1%)
Influenza
1 (<1%)
1 (<1%)
Tinea pedis
1 (<1%)
1 (<1%)
Vaginitis bacterial
2 (1%)
0
Vulvovaginal mycotic infection
2 (1%)
0
Abscess
1 (<1%)
0
Abscess limb
1 (<1%)
0
Acute sinusitis
1 (<1%)
0
Cellulitis
1 (<1%)
0
Cystitis
1 (<1%)
0
Diverticulitis
0
1 (<1%)
Ear infection
0
1 (<1%)
Furuncle
0
1 (<1%)
Gastric infection
0
1 (<1%)
Gastrointestinal bacterial infection
0
1 (<1%)
Gastrointestinal infection
0
1 (<1%)
Groin infection
1 (<1%)
0
Herpes zoster
0
1 (<1%)
Hordeolum
0
1 (<1%)
Laryngitis
1 (<1%)
0
Localised infection
1 (<1%)
0
Otitis media
0
1 (<1%)
Pharyngitis streptococcal
1 (<1%)
0
Pilonidal cyst
0
1 (<1%)
Pneumonia
1 (<1%)
0
Pneumonia bacterial
1 (<1%)
0
Staphylococcal infection
1 (<1%)
0
Tooth abscess
1 (<1%)
0
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 8
Table 7.3
Summary of All Adverse Events During Treatment
21
11
3
3
1
1
1
0
1
1
1
1
(12%)
(6%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
08MAR2010 13:55
13
9
1
1
1
0
0
1
0
0
0
0
(8%)
(5%)
(<1%)
(<1%)
(<1%)
(<1%)
RM2010/00132/00
ADC111114
Nervous system disorders
Any event
Headache
Dizziness
Sinus headache
Neuropathy peripheral
Carotid artery occlusion
Carpal tunnel syndrome
Cerebrovascular accident
Loss of consciousness
Migraine
Presyncope
Syncope
CONFIDENTIAL
387
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Constipation
1 (<1%)
3 (2%)
Dry mouth
1 (<1%)
3 (2%)
Abdominal discomfort
1 (<1%)
2 (1%)
Abdominal pain
1 (<1%)
2 (1%)
Abdominal pain upper
2 (1%)
1 (<1%)
Diarrhoea
3 (2%)
0
Gastrooesophageal reflux disease
1 (<1%)
1 (<1%)
Glossodynia
1 (<1%)
1 (<1%)
Vomiting
2 (1%)
0
Diverticulum intestinal
0
1 (<1%)
Dyspepsia
1 (<1%)
0
Gastritis
1 (<1%)
0
Glossitis
1 (<1%)
0
Hiatus hernia
1 (<1%)
0
Ileus
0
1 (<1%)
Inguinal hernia
0
1 (<1%)
Lower gastrointestinal haemorrhage
0
1 (<1%)
Oesophagitis
0
1 (<1%)
Protocol: ADC111114
Population: Intent-to-Treat
Page 4 of 8
Table 7.3
Summary of All Adverse Events During Treatment
7
3
2
0
1
1
1
1
1
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
Injury, poisoning and procedural complications
Any event
Procedural pain
6
2
(3%)
(1%)
(4%)
(2%)
(1%)
08MAR2010 13:55
9 (5%)
2 (1%)
2 (1%)
2 (1%)
1 (<1%)
1 (<1%)
1 (<1%)
0
0
5
0
(3%)
RM2010/00132/00
ADC111114
General disorders and administration site conditions
Any event
Oedema peripheral
Chest pain
Chest discomfort
Fatigue
Non-cardiac chest pain
Pyrexia
Asthenia
Pain
CONFIDENTIAL
388
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Musculoskeletal and connective tissue disorders
Any event
10 (6%)
22 (13%)
Back pain
5 (3%)
9 (5%)
Pain in extremity
2 (1%)
2 (1%)
Arthralgia
2 (1%)
1 (<1%)
Musculoskeletal pain
1 (<1%)
2 (1%)
Arthritis
0
2 (1%)
Muscle spasms
0
2 (1%)
Arthropathy
0
1 (<1%)
Bone pain
0
1 (<1%)
Bursitis
1 (<1%)
0
Costochondritis
1 (<1%)
0
Musculoskeletal chest pain
0
1 (<1%)
Neck pain
1 (<1%)
0
Osteoarthritis
0
1 (<1%)
Rheumatoid arthritis
0
1 (<1%)
Tendonitis
1 (<1%)
0
Tenosynovitis stenosans
0
1 (<1%)
Protocol: ADC111114
Population: Intent-to-Treat
Page 5 of 8
Table 7.3
Summary of All Adverse Events During Treatment
389
6
1
2
1
1
1
Skin and subcutaneous tissue disorders
Any event
Dermatitis contact
Rash
Hyperhidrosis
Ingrowing nail
Pruritus generalised
Rash generalised
5 (3%)
1 (<1%)
2 (1%)
0
0
1 (<1%)
1 (<1%)
4 (2%)
2 (1%)
0
1 (<1%)
1 (<1%)
0
0
Vascular disorders
Any event
Hypertension
Aortic aneurysm
Femoral artery occlusion
Haematoma
4 (2%)
0
2 (1%)
1 (<1%)
1 (<1%)
5
4
0
0
0
(3%)
(<1%)
(1%)
(<1%)
(<1%)
(<1%)
08MAR2010 13:55
5
4
2
0
0
0
(3%)
(2%)
(1%)
(3%)
(2%)
RM2010/00132/00
ADC111114
Psychiatric disorders
Any event
Depression
Insomnia
Anxiety
Confusional state
Tension
CONFIDENTIAL
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Skeletal injury
1 (<1%)
1 (<1%)
Spinal compression fracture
1 (<1%)
1 (<1%)
Arthropod bite
1 (<1%)
0
Contusion
0
1 (<1%)
Fall
0
1 (<1%)
Ligament sprain
0
1 (<1%)
Muscle strain
1 (<1%)
0
Post procedural swelling
0
1 (<1%)
Splenic rupture
0
1 (<1%)
Protocol: ADC111114
Population: Intent-to-Treat
Page 6 of 8
Table 7.3
Summary of All Adverse Events During Treatment
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Haemorrhage
0
1 (<1%)
Hypotension
0
1 (<1%)
Intermittent claudication
1 (<1%)
0
Peripheral arterial occlusive disease
0
1 (<1%)
7
2
1
1
1
1
1
1
Eye disorders
Any event
Vision blurred
Dry eye
Macular degeneration
Visual acuity reduced
Visual impairment
4
1
1
0
1
1
(<1%)
(<1%)
2 (1%)
1 (<1%)
0
1 (<1%)
0
0
Investigations
Any event
Blood pressure increased
Heart rate increased
Hepatic enzyme increased
Hepatobiliary scan abnormal
Weight increased
5 (3%)
2 (1%)
1 (<1%)
1 (<1%)
1 (<1%)
0
1 (<1%)
0
0
0
0
1 (<1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Any event
2
3
(2%)
(<1%)
(<1%)
(1%)
08MAR2010 13:55
(4%)
(1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
RM2010/00132/00
ADC111114
1 (<1%)
0
1 (<1%)
0
0
0
0
0
CONFIDENTIAL
390
Metabolism and nutrition disorders
Any event
Diabetes mellitus
Hypokalaemia
Dehydration
Gout
Hypercholesterolaemia
Hyperglycaemia
Hyperlipidaemia
Protocol: ADC111114
Population: Intent-to-Treat
Page 7 of 8
Table 7.3
Summary of All Adverse Events During Treatment
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Adrenal adenoma
0
1 (<1%)
Basal cell carcinoma
0
1 (<1%)
Bladder transitional cell carcinoma recurrent
1 (<1%)
0
Bone neoplasm malignant
0
1 (<1%)
Myelodysplastic syndrome
1 (<1%)
0
4 (2%)
2 (1%)
1 (<1%)
1 (<1%)
1 (<1%)
Cardiac disorders
Any event
Cardiac failure congestive
Cardiomyopathy
Coronary artery disease
Palpitations
Tachycardia
1 (<1%)
1 (<1%)
1 (<1%)
0
0
0
3 (2%)
0
0
1 (<1%)
1 (<1%)
1 (<1%)
Renal and urinary disorders
Any event
Calculus ureteric
Dysuria
Haematuria
Hypertonic bladder
2 (1%)
1 (<1%)
0
1 (<1%)
0
2 (1%)
0
1 (<1%)
0
1 (<1%)
Surgical and medical procedures
Any event
Tooth extraction
Finger amputation
Shoulder operation
2
2
0
0
2 (1%)
0
1 (<1%)
1 (<1%)
(1%)
(1%)
08MAR2010 13:55
RM2010/00132/00
ADC111114
0
0
0
0
0
CONFIDENTIAL
391
Blood and lymphatic system disorders
Any event
Anaemia
Anaemia macrocytic
Haemolytic anaemia
Thrombocytopenia
Protocol: ADC111114
Population: Intent-to-Treat
Page 8 of 8
Table 7.3
Summary of All Adverse Events During Treatment
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------2 (1%)
1 (<1%)
0
1 (<1%)
1 (<1%)
1 (<1%)
0
1 (<1%)
0
0
Ear and labyrinth disorders
Any event
Eustachian tube dysfunction
Hearing impaired
2 (1%)
1 (<1%)
1 (<1%)
0
0
0
Hepatobiliary disorders
Any event
Cholecystitis
0
0
1 (<1%)
1 (<1%)
Immune system disorders
Any event
Allergy to arthropod sting
1 (<1%)
1 (<1%)
0
0
RM2010/00132/00
ADC111114
08MAR2010 13:55
CONFIDENTIAL
392
Reproductive system and breast disorders
Any event
Endometriosis
Gynaecomastia
Ovarian cyst
Varicocele
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 7.4
Summary of Most Common (>2%) Adverse Events During Treatment
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Any event
97 (56%)
85 (50%)
24 (14%)
11 (6%)
5 (3%)
5 (3%)
6 (3%)
6 (3%)
5 (3%)
0
393
RM2010/00132/00
ADC111114
08MAR2010 15:15
24 (14%)
9 (5%)
9 (5%)
6 (4%)
4 (2%)
3 (2%)
1 (<1%)
5 (3%)
CONFIDENTIAL
Chronic obstructive pulmonary disease
Headache
Back pain
Nasopharyngitis
Oropharyngeal pain
Bronchitis
Oral candidiasis
Dyspnoea
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 3
Table 7.5
Summary of Drug-Related Adverse Events Post Randomization
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Any event
21 (12%)
12 (7%)
394
(7%)
(3%)
(1%)
(1%)
(<1%)
(<1%)
Respiratory, thoracic and mediastinal disorders
Any event
Dysphonia
Cough
Oropharyngeal pain
Chronic obstructive pulmonary disease
Dyspnoea
5
3
0
2
0
0
(3%)
(2%)
Eye disorders
Any event
Vision blurred
Dry eye
2 (1%)
1 (<1%)
1 (<1%)
1 (<1%)
1 (<1%)
0
Gastrointestinal disorders
Any event
Dry mouth
Constipation
Glossitis
2 (1%)
1 (<1%)
0
1 (<1%)
1 (<1%)
1 (<1%)
1 (<1%)
0
(<1%)
(<1%)
(1%)
20APR2010 07:44
2 (1%)
1 (<1%)
0
0
0
0
1 (<1%)
0
0
5 (3%)
1 (<1%)
2 (1%)
0
1 (<1%)
1 (<1%)
RM2010/00132/00
ADC111114
12
5
2
2
1
1
0
1
1
CONFIDENTIAL
Infections and infestations
Any event
Oral candidiasis
Candidiasis
Pharyngitis
Bronchitis
Fungal infection
Furuncle
Laryngitis
Urinary tract infection
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 3
Table 7.5
Summary of Drug-Related Adverse Events Post Randomization
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Nervous system disorders
Any event
1 (<1%)
2 (1%)
Dizziness
1 (<1%)
0
Headache
0
1 (<1%)
Sinus headache
0
1 (<1%)
1 (<1%)
0
1 (<1%)
Skin and subcutaneous tissue disorders
Any event
Hyperhidrosis
Rash
1 (<1%)
0
1 (<1%)
1 (<1%)
1 (<1%)
0
General disorders and administration site conditions
Any event
Fatigue
0
0
1 (<1%)
1 (<1%)
Musculoskeletal and connective tissue disorders
Any event
Arthralgia
1 (<1%)
1 (<1%)
0
0
Psychiatric disorders
Any event
Insomnia
0
0
1 (<1%)
1 (<1%)
Renal and urinary disorders
Any event
Urinary retention
1 (<1%)
1 (<1%)
0
0
20APR2010 07:44
RM2010/00132/00
ADC111114
1 (<1%)
1 (<1%)
0
CONFIDENTIAL
395
Investigations
Any event
Heart rate increased
Weight increased
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 3
Table 7.5
Summary of Drug-Related Adverse Events Post Randomization
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Vascular disorders
Any event
1 (<1%)
0
Aortic aneurysm
1 (<1%)
0
CONFIDENTIAL
396
RM2010/00132/00
ADC111114
20APR2010 07:44
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 2
Table 7.6
Summary of Adverse Events Leading to Withdrawal from the Study
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Any event
12 (7%)
10 (6%)
5 (3%)
3 (2%)
1 (<1%)
0
1 (<1%)
0
General disorders and administration site conditions
Any event
Chest pain
Fatigue
Non-cardiac chest pain
2 (1%)
1 (<1%)
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Any event
Bone neoplasm malignant
Myelodysplastic syndrome
Non-small cell lung cancer
1 (<1%)
0
1 (<1%)
0
2 (1%)
1 (<1%)
0
1 (<1%)
Eye disorders
Any event
Vision blurred
1 (<1%)
1 (<1%)
1 (<1%)
1 (<1%)
Infections and infestations
Any event
Oral candidiasis
Upper respiratory tract infection
2 (1%)
1 (<1%)
1 (<1%)
0
0
0
Investigations
Any event
1 (<1%)
1 (<1%)
20APR2010 07:44
RM2010/00132/00
ADC111114
5 (3%)
3 (2%)
0
1 (<1%)
0
1 (<1%)
CONFIDENTIAL
397
Respiratory, thoracic and mediastinal disorders
Any event
Chronic obstructive pulmonary disease
Cough
Dysphonia
Dyspnoea
Oropharyngeal pain
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 2
Table 7.6
Summary of Adverse Events Leading to Withdrawal from the Study
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Heart rate increased
1 (<1%)
0
Weight increased
0
1 (<1%)
1 (<1%)
0
1 (<1%)
1 (<1%)
1 (<1%)
0
Cardiac disorders
Any event
Cardiac failure congestive
1 (<1%)
1 (<1%)
0
0
Nervous system disorders
Any event
Cerebrovascular accident
0
0
1 (<1%)
1 (<1%)
Renal and urinary disorders
Any event
Urinary retention
1 (<1%)
1 (<1%)
0
0
RM2010/00132/00
ADC111114
20APR2010 07:44
CONFIDENTIAL
398
Musculoskeletal and connective tissue disorders
Any event
Arthritis
Back pain
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 2
Table 7.7
Summary of All Adverse Events Post-Treatment
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Any event
8 (5%)
8 (5%)
3 (2%)
0
1 (<1%)
0
1 (<1%)
1 (<1%)
Metabolism and nutrition disorders
Any event
Hyperglycaemia
Hypercholesterolaemia
Hypokalaemia
Type 2 diabetes mellitus
2 (1%)
0
1 (<1%)
0
1 (<1%)
2 (1%)
2 (1%)
0
1 (<1%)
0
Gastrointestinal disorders
Any event
Ileus
Constipation
Nausea
1 (<1%)
1 (<1%)
0
0
2 (1%)
1 (<1%)
1 (<1%)
1 (<1%)
Respiratory, thoracic and mediastinal disorders
Any event
Chronic obstructive pulmonary disease
0
0
3
3
Musculoskeletal and connective tissue disorders
Any event
Back pain
Torticollis
2 (1%)
1 (<1%)
1 (<1%)
0
0
0
20APR2010 07:44
(2%)
(2%)
RM2010/00132/00
ADC111114
3 (2%)
2 (1%)
0
1 (<1%)
0
0
CONFIDENTIAL
399
Infections and infestations
Any event
Nasopharyngitis
Bronchitis
Fungal skin infection
Oral candidiasis
Prostate infection
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 2
Table 7.7
Summary of All Adverse Events Post-Treatment
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Nervous system disorders
Any event
1 (<1%)
1 (<1%)
Dizziness
1 (<1%)
0
Transient ischaemic attack
0
1 (<1%)
2 (1%)
2 (1%)
1 (<1%)
Blood and lymphatic system disorders
Any event
Iron deficiency anaemia
0
0
1 (<1%)
1 (<1%)
Injury, poisoning and procedural complications
Any event
Patella fracture
1 (<1%)
1 (<1%)
0
0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Any event
Non-small cell lung cancer
0
0
1 (<1%)
1 (<1%)
Renal and urinary disorders
Any event
Urinary retention
1 (<1%)
1 (<1%)
0
0
Reproductive system and breast disorders
Any event
Benign prostatic hyperplasia
1 (<1%)
1 (<1%)
0
0
Vascular disorders
Any event
Hypertension
0
0
1 (<1%)
1 (<1%)
20APR2010 07:44
RM2010/00132/00
ADC111114
0
0
0
CONFIDENTIAL
400
Psychiatric disorders
Any event
Insomnia
Anxiety
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 2
Table 7.8
Summary of Serious Adverse Events Post Randomization
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Any event
7 (4%)
13 (8%)
1 (<1%)
1 (<1%)
5
5
Gastrointestinal disorders
Any event
Ileus
Lower gastrointestinal haemorrhage
Oesophagitis
0
0
0
0
3 (2%)
1 (<1%)
1 (<1%)
1 (<1%)
Infections and infestations
Any event
Gastric infection
Gastroenteritis
Gastroenteritis viral
1 (<1%)
0
1 (<1%)
0
2 (1%)
1 (<1%)
0
1 (<1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Any event
Bladder transitional cell carcinoma recurrent
Bone neoplasm malignant
Non-small cell lung cancer
1 (<1%)
1 (<1%)
0
0
2 (1%)
0
1 (<1%)
1 (<1%)
General disorders and administration site conditions
Any event
Non-cardiac chest pain
1 (<1%)
1 (<1%)
1 (<1%)
1 (<1%)
Injury, poisoning and procedural complications
Any event
Spinal compression fracture
Splenic rupture
1 (<1%)
1 (<1%)
0
1 (<1%)
0
1 (<1%)
RM2010/00132/00
ADC111114
20APR2010 07:44
(3%)
(3%)
CONFIDENTIAL
401
Respiratory, thoracic and mediastinal disorders
Any event
Chronic obstructive pulmonary disease
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 2
Table 7.8
Summary of Serious Adverse Events Post Randomization
System Organ Class
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Metabolism and nutrition disorders
Any event
1 (<1%)
1 (<1%)
Hypokalaemia
1 (<1%)
1 (<1%)
2 (1%)
1 (<1%)
1 (<1%)
Renal and urinary disorders
Any event
Calculus ureteric
Urinary retention
2 (1%)
1 (<1%)
1 (<1%)
0
0
0
Surgical and medical procedures
Any event
Finger amputation
Shoulder operation
0
0
0
2 (1%)
1 (<1%)
1 (<1%)
Vascular disorders
Any event
Aortic aneurysm
Haemorrhage
1 (<1%)
1 (<1%)
0
1 (<1%)
0
1 (<1%)
Blood and lymphatic system disorders
Any event
Haemolytic anaemia
Thrombocytopenia
0
0
0
1 (<1%)
1 (<1%)
1 (<1%)
Cardiac disorders
Any event
Coronary artery disease
0
0
1 (<1%)
1 (<1%)
20APR2010 07:44
RM2010/00132/00
ADC111114
0
0
0
CONFIDENTIAL
402
Nervous system disorders
Any event
Cerebrovascular accident
Transient ischaemic attack
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 7.9
Summary of Pneumonia Adverse Events Post Randomization
FSC250/50+Tio Tiotropium
Preferred Term
(N=173)
(N=169)
---------------------------------------------------------------------------------------------------Any event
2 (1%)
0
Pneumonia
Pneumonia bacterial
1 (<1%)
1 (<1%)
0
0
CONFIDENTIAL
403
RM2010/00132/00
ADC111114
08MAR2010 14:14
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 159
Table 7.10
Listing of All Adverse Events
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
CONFIDENTIAL
404
RM2010/00132/00
ADC111114
09MAR2010 10:21
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 22
Table 7.11
Listing of Subject Numbers for Individual Adverse Events
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
CONFIDENTIAL
563
RM2010/00132/00
ADC111114
09MAR2010 10:43
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Blood and lymphatic system
Anaemia
Anemia
disorders
Anaemia macrocytic
MACROCYTIC ANEMIA
Haemolytic anaemia
Hemolytic Anemia
Iron deficiency anaemia
Iron Deficiency Anemia
Lymphadenopathy
Foliculosis
Thrombocytopenia
Thrombocytopenia
Cardiac disorders
585
Palpitations
Tachycardia
Ear and labyrinth disorders
Ear pain
Eustachian tube dysfunction
Hearing impaired
Eye disorders
Dry eye
Macular degeneration
Vision blurred
Gastrointestinal disorders
Abdominal discomfort
Abdominal pain
Abdominal pain upper
earache
Dizziness due to Eustachian Tube
Dysfunction
Hearing Impairment
dry eyes
Macular Degeneration
Blurred Vision
Blurred vision
Worsening vision
Visual Disturbance
Gastric upset
gastro intestinal upset
upset tomach
Abdominal pain
abdominal pain
Right Upper Quadrant pain
STOMACH PAIN - INTERMITTENT
20APR2010 07:44
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ADC111114
Visual acuity reduced
Visual impairment
Acute CHF
cardiomyopathy
Worsening of Coronary Artery
Disease
Heart Palpatations
Tachycardia
CONFIDENTIAL
Cardiac failure congestive
Cardiomyopathy
Coronary artery disease
Protocol: ADC111114
Population: Intent-to-Treat
Page 2 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:44
CONFIDENTIAL
586
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Gastrointestinal disorders
Abdominal pain upper
Stomach Ache
Stomachache
right upper quadrant abdominal
pain
Constipation
CONSTIPATION
Constipation
INTERMITTENT CONSTIPATION
Worsening of constipation
constipation
worsening constipation
worsening contipation
Diarrhoea
Diarrhea
diarrhea
Diverticulum intestinal
diverticulosis of the sigmoid
colon
Dry mouth
DRYMOUTH SECONDARY TO DOSING
Dry Mouth
Dry mouth
dry mouth
Dyspepsia
Heartburn
Indigestion
heart burn
Gastritis
gastritis
Gastrooesophageal reflux disease
Acid Reflux
Gastroesophageal Reflux Disease
Glossitis
Glossitis
Glossodynia
Sore Tongue
sore tongue
tongue tenderness
Hiatus hernia
LARGE HIATAL HERNIA
Ileus
Abdominal Pain due to Focal Ileus
Ileus
ileus
Inguinal hernia
Left Inguinal Hernia
Protocol: ADC111114
Population: Intent-to-Treat
Page 3 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
587
General disorders and
administration site conditions
Weakness
Chest discomfort
Heavy Chest
chest discomfort
Burning Sensation in chest
Chest Pain
atypical right thorax pain
chest pain
Fatigue
Fatique
tired
Bumps on Neck
Chest Pain - Non Cardiac
Non cardiac chest pain
Bilateral Leg Edema
Edema - right ankle
FEET SWELLING
LEFT KNEE EDEMA
Lower Extremity Edema
Lower Leg Edema
Chest pain
Fatigue
Local swelling
Non-cardiac chest pain
Oedema peripheral
20APR2010 07:44
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ADC111114
Asthenia
CONFIDENTIAL
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Gastrointestinal disorders
Irritable bowel syndrome
IRRITABLE BOWEL SYNDROME
Lower gastrointestinal haemorrhage
LOWER GASTROINTESTINAL BLEED
Nausea
Nausea
nausea
slight queay stomach
Oesophagitis
Esophagitis
Toothache
TOOTH PAIN
Tooth pain
Toothache
toothache
Vomiting
INTERMITTENT VOMITTING
Vomiting
Vomitting
Protocol: ADC111114
Population: Intent-to-Treat
Page 4 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------General disorders and
Oedema peripheral
edema feet
administration site conditions
Pain
Body Aches
Pain
body aches
Pyrexia
Fever
fever of unknown origin
cholecystitis
Immune system disorders
Allergy to arthropod sting
ALLERGIC REACTION TO INSECT STING
Infections and infestations
Abscess
Abscess limb
Acute sinusitis
Body tinea
Bronchitis
Abscess on scalp
Left Leg Abcess
Acute sinusitis
TINEA CORPORIS
AECB
Acute Bronchitis
Bronchitis
bronchitis
Thrush
thrush
Cellulitis (Right and Left Lower
Legs)
self diagnosed pink eye
Bladder infection
Diverticulitis
ear infection
Yeast Infection
yeast infection
FUNGAL DERMATOSIS
boil on right leg
boil right leg
Gastric Bacterial Infection
Candidiasis
Cellulitis
Conjunctivitis infective
Cystitis
Diverticulitis
Ear infection
Fungal infection
Fungal skin infection
Furuncle
Gastric infection
20APR2010 07:44
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Cholecystitis
CONFIDENTIAL
588
Hepatobiliary disorders
Protocol: ADC111114
Population: Intent-to-Treat
Page 5 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:44
CONFIDENTIAL
589
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Infections and infestations
Gastroenteritis
Acute Gastroenteritis
Gastroenteritis
Gastroenteritis viral
Stomach Virus
Viral Gastroenteritis
stomach flu
Gastrointestinal bacterial infection GI Bacterial Infection
Gastrointestinal infection
GI Infection
Gingival infection
Gum Infection
Groin infection
Groin Infection
Herpes simplex
HSV II FLARE
Herpes zoster
Shingles herpes zoster
Hordeolum
Stye left upper eyelid
Influenza
FLU (ACHE ALL OVER)
Flu Symptoms
Laryngitis
Laryngitis
Lobar pneumonia
left lower lobe pneumonia
Localised infection
Thumb Infection
Nasopharyngitis
COLD SYMPTOMS
COMMON COLD
Cold
Cold Symptoms
Common Cold
Head Cold
Viral Headcold
cold
cold symptoms
common cold
head cold
viral cold
Oral candidiasis
Oral Thrush
Oral thrush
oral candidiasis
oral candidiasis (Thrush)
oral thrush
Protocol: ADC111114
Population: Intent-to-Treat
Page 6 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:44
CONFIDENTIAL
590
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Infections and infestations
Otitis media
Left otitis media
Pharyngitis
PHARYNGITIS
Pharyngitis
pharyngitis
Pharyngitis streptococcal
POSITIVE STREP THROAT INFECTION
Pilonidal cyst
pilonidal Cyst
Pneumonia
Pneumonia
left sided pneumonia
Pneumonia bacterial
Bacterial Pneumonia
Prostate infection
prostrate infection
Rash pustular
Pustules on Neck
Sinusitis
Sinus Infection
Sinusitis
sinusitis
Staphylococcal infection
MRSA
Tinea pedis
Foot Fungus
Fungus on right big toe
Tooth abscess
Abcess tooth root
tooth abcess
Tooth infection
tooth Infection
Upper respiratory tract infection
Acute Upper Respiratory Infection
Upper Respiratory Infection
Upper respiratory infection
Worsening of Upper Respiratory
Infection
Urinary tract infection
UTI
Urinary Tract Infection
urinary tract infection
Vaginitis bacterial
BACTERIAL VAGINOSIS
Vaginal Bactererial Infection
Viral infection
VIRAL SYNDROME
Viral Infection
Viral syndrome
viral syndrome
Protocol: ADC111114
Population: Intent-to-Treat
Page 7 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Infections and infestations
Vulvovaginal mycotic infection
Vaginal yeast infection
vaginal yeast infection
Injury, poisoning and procedural
complications
Contusion
Patient went to Mexico and tripped
over man hole cover and bruised
both hips.
left leg contusion
Left leg abrasion
Both hips bruised after tripping
over man hole in mexico
Patient went to Mexico and had
tripped over a man hole cover
Twisted right knee
Left Knee Ligamentous Sprain
Lower Back Strain
Broken Patella bone (Left Knee)
MICRODISECTOMY SITE SWELLING
Eye Pain Secondary to Cataract
Surgery
ankle pain secondary to ankle
surgery
1 bruised rib from tripping over
man hole in mexico
Contusion of Right upper ribs
Laceration, Right Foot
Fractured 8th and 9th vertebrae
(compression fracture of the 8th &
9th vertebrae per MRI results).
back pain R/T compression fracture
spinal compression fracture
Ruptured Spleen
Excoriation
Fall
591
Joint sprain
Ligament sprain
Muscle strain
Patella fracture
Post procedural swelling
Procedural pain
Skeletal injury
Skin laceration
Spinal compression fracture
Splenic rupture
20APR2010 07:44
CONFIDENTIAL
insect bite
RM2010/00132/00
ADC111114
Arthropod bite
Protocol: ADC111114
Population: Intent-to-Treat
Page 8 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Investigations
Blood pressure increased
elevated blood pressure
worsening of high blood
pressure(increase)
Heart rate increased
Rapid heart rate
Hepatic enzyme increased
elevated liver enzymes
Hepatobiliary scan abnormal
BORDERLINE DIMINISHED GALLBLADDER
EJECTION FRACTION
Weight increased
Weight gain
Dehydration
Diabetes mellitus
Type 2 diabetes mellitus
Dehydration
Steroid Induced Diabetes Mellitus
diabetes mellitus
Gout
Hypercholesterolemia
Worsening hypercholesterolemia
Borderline Hyperglycemia
hyperglycemia
steroid induced hyperglycemia
worsening of hyperlipidemia
Hypokalemia
Hypopotassemia
hypokalemia
type 2 diabetes
Arthralgia
Left Wrist Pain
592
Gout
Hypercholesterolaemia
Hyperglycaemia
Hyperlipidaemia
Hypokalaemia
Arthritis
Arthropathy
Back pain
Worsening Right Knee Pain
increased joint pain
right wrist pain
Worsening of Arthritis
increase in symptoms of arthritis
in his back
facet arthropathy
BACKACHE
20APR2010 07:44
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ADC111114
Musculoskeletal and connective
tissue disorders
CONFIDENTIAL
Metabolism and nutrition disorders
Protocol: ADC111114
Population: Intent-to-Treat
Page 9 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:44
CONFIDENTIAL
593
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Musculoskeletal and connective
Back pain
Back Ache
tissue disorders
Back Pain
Back pain
Backpain
INCREASED BACKACHE
Intermittant back Pain
Intermittent backache
Upper back pain
Worsening of Lower Back Pain
Worsening of back pain
back ache
back pain
backache
exacerbation of back pain
increased back ache
low back pain
worsening back pain
worsening of back pain
worsening of lower back pain
Bone pain
Severe Spinal Pain
Bursitis
Left subdeltoid bursitis
Costochondritis
costal chondritis
Muscle spasms
back muscle Spasms
cramps in right thigh
muscle spasms
Musculoskeletal chest pain
sub sternal musculoskeletal pain
Musculoskeletal pain
Worsening right shoulder pain
shoulder pain
Neck pain
Neck Pain
neck pain
Osteoarthritis
DEGENERATIVE JOINT DISEASE
Degenerative Joint Disease
Pain in extremity
Achy Right Leg
Protocol: ADC111114
Population: Intent-to-Treat
Page 10 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
Neoplasms benign, malignant and
unspecified (incl cysts and
polyps)
right adrenal gland adenoma
Basal cell carcinoma
Basil cell carcinoma skin lesion
on nose
recurrent invasive metastatic
transitional cell carcinoma of the
urinary bladder
Bone Carcinoma
worsening of myelodiplastic
syndrome
non-small cell carcinoma
Bladder transitional cell carcinoma
recurrent
Bone neoplasm malignant
Myelodysplastic syndrome
Non-small cell lung cancer
Nervous system disorders
Carotid artery occlusion
Carpal tunnel syndrome
Cerebrovascular accident
Right Carotid Artery Blockage
Worsening left carpal tunnel
syndrome
stroke
20APR2010 07:44
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ADC111114
Adrenal adenoma
CONFIDENTIAL
594
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Musculoskeletal and connective
Pain in extremity
Hand Pain
tissue disorders
Intermittant feet pain
Intermittant leg pain
Left Leg Pain
Left leg pain
Leg Pain
Leg pain
bilateral lower leg pain
calf ache, bilateral, intermitant
left middle finger pain
soreness in right thigh
Rheumatoid arthritis
worsening of Rhumatoid arthritis
Tendonitis
Left bicipital tendonitis
Tenosynovitis stenosans
dequervain tenosynovitis
Torticollis
TORTICOLLIS
Protocol: ADC111114
Population: Intent-to-Treat
Page 11 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
Anxiety
Confusional state
Depression
Insomnia
Acute Anxiety
anxiety
confusion
Anxiety/Depression
Worsening Depression
depression
increased depression
INSOMNIA
Inability to sleep
20APR2010 07:44
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ADC111114
Psychiatric disorders
CONFIDENTIAL
595
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Nervous system disorders
Dizziness
Dizziness
Light Headed
Light-headed
Headache
HEADACHE
Head Pain
Head ache
Headache
headache
increased headache
intermittent headache
prolonged headaches
Loss of consciousness
loss of consciousness
Migraine
Migraine
Neuropathy peripheral
Peripheral Neuropathy
Worsening Neuoropathy
right leg neuropathy
Presyncope
near sycope
Sinus headache
SINUS HEADACHE
Sinus pressure
increased sinus headache
sinus headache (intermittent)
sinus pressure
Syncope
worsening of syncope
Transient ischaemic attack
Transient Ischemic Attack
Protocol: ADC111114
Population: Intent-to-Treat
Page 12 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Psychiatric disorders
Insomnia
Insomnia
SLEEPLESSNESS
insomnia
Tension
TENSION
Renal and urinary disorders
Dysuria
Haematuria
Hypertonic bladder
Urinary retention
6x4mm Kidney stone obstructing
left proximal ureter
dysuria
hematuria
Over active bladder
urinary retention
Benign prostatic hyperplasia
benign prostatic hypertrophy
Endometriosis
Pelvic pain secondary to
Endometriosis
gynecomastia
Pelvic pain secondary to bilateral
ovarian cysts
Multiple Varicocele in Right
Testicle
Gynaecomastia
Ovarian cyst
Varicocele
Respiratory, thoracic and
mediastinal disorders
Chronic obstructive pulmonary
disease
Acute Exacerbation of COPD
Acute Exacerbation of COPD #1
Acute Exacerbation of COPD #2
COPD EXACERBAION
COPD EXACERBATION
COPD Exacerbation
COPD exacerbation
Copd Exacerbation
Mild COPD Exacerbation
copd exacerbation
Bad Cough
20APR2010 07:44
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ADC111114
Cough
CONFIDENTIAL
596
Reproductive system and breast
disorders
Calculus ureteric
Protocol: ADC111114
Population: Intent-to-Treat
Page 13 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
RM2010/00132/00
ADC111114
20APR2010 07:44
CONFIDENTIAL
597
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Respiratory, thoracic and
Cough
Cough
mediastinal disorders
Horrible cough
Increased Coughing
cough
increased cough
worsening of cough
Dry throat
DRY THROAT AFTER DOSING
Dysphonia
HOARSENESS
Raspy, Hoarse voice
hoarse throat/voice
hoarse voice
hoarseness
horseness
Dyspnoea
Increased Shortness of breath
Increased shortness of breath
Shortness of Breath
increased shortness of breath
Dyspnoea exertional
extreme shortness of breath with
any minor exertion
Epistaxis
NOSE BLEED
NOSEBLEED
Nosebleed
nosebleed
Haemoptysis
Blood tinged sputum
Increased upper airway secretion
phlegm production
Nasal congestion
Intermittent nasal congestion
Nasal Congestion
WORSENED NASAL CONGESTION
nasal congestion
stuffy nose
Oropharyngeal blistering
Blister in inner cheek
Oropharyngeal pain
SORE THROAT
Sore Throat
Protocol: ADC111114
Population: Intent-to-Treat
Page 14 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
Skin and subcutaneous tissue
disorders
Worsening Perioral Dermatitis
Dermatitis contact
contact dermatitis
poison ivy
Sweaty palms after taking study
drug
Onychocryptosis
night sweats
ITCHING ALL OVER
Itching all over
Back and Stomach Rash
Facial rash
Rash on Neck
mouth rash
GENERALIZED RASH
Hyperhidrosis
Ingrowing nail
Night sweats
Pruritus generalised
Rash
Rash generalised
20APR2010 07:44
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ADC111114
Dermatitis
CONFIDENTIAL
598
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Respiratory, thoracic and
Oropharyngeal pain
Sore throat
mediastinal disorders
sore throat
Pneumothorax
Right Pneumothroax
Postnasal drip
Post Nasal Drip
Respiratory tract congestion
CHEST CONGESTION (Respiratory)
Chest Congestion- Unknown
Repiratory chest congestion
Respiratory Chest Congestion
Respiratory Congestion
Rhinorrhoea
Rhinorhea
Sinus congestion
sinus congestion
Sinus Congestion
sinus congestion
Sleep apnoea syndrome
SEVERE OBSTRUCTIVE SLEEP APNES
Sputum increased
increase in mucous(chest)
increased sputum production
Protocol: ADC111114
Population: Intent-to-Treat
Page 15 of 15
Table 7.12
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text
System Organ Class
Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------------------------Surgical and medical procedures
Finger amputation
Partial Amputation of ring and
middle fingers
Shoulder operation
Right Shoulder Surgery
Tooth extraction
TOOTH EXTRACTION
Tooth extraction
Vascular disorders
Aortic aneurysm
Femoral artery occlusion
599
Haemorrhage
Hypertension
Hypotension
Intermittent claudication
Peripheral arterial occlusive
disease
RM2010/00132/00
ADC111114
20APR2010 07:44
CONFIDENTIAL
Haematoma
Abdominal Aortic Aneuysm
Aortic aneurysm
Arterial blockages(suspect
Femoral)
Left leg hematoma
Scalp Hematoma
HEMORRHAGE
Worsening of Hypertension
hypertension
worsening of hypertension
hypotension
worsening of intermitant
claudication
Worsening of Peripheral Artery
Disease
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 7
Table 7.13
Listing of Adverse Events Leading to Withdrawal from the Study
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
CONFIDENTIAL
600
RM2010/00132/00
ADC111114
20APR2010 07:44
Protocol: ADC111114
Population: Safety
Page 1 of 1
Table 7.14
Listing of Fatal Adverse Events (Safety Population)
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
CONFIDENTIAL
607
RM2010/00132/00
ADC111114
20APR2010 07:44
Protocol: ADC111114
Population: Safety
Page 1 of 12
Table 7.15
Listing of Non-Fatal Serious Adverse Events (Safety Population)
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
CONFIDENTIAL
608
RM2010/00132/00
ADC111114
20APR2010 07:47
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 7.16
Listing of Pneumonia Adverse Events
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
CONFIDENTIAL
620
RM2010/00132/00
ADC111114
20APR2010 07:44
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 7.17
Listing of Pneumonia Chest X-rays
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data
from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of
the GSK Clincal Study Register.
CONFIDENTIAL
621
RM2010/00132/00
ADC111114
20APR2010 07:44
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 7.18
Listing of Pneumonia Chest X-rays - Cultures and Clinical Findings
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
CONFIDENTIAL
622
RM2010/00132/00
ADC111114
20APR2010 07:45
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 7.19
Listing of Pneumonia Chest X-rays - Treatment and Outcome
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.
CONFIDENTIAL
623
RM2010/00132/00
ADC111114
20APR2010 07:45
Protocol: ADC111114
Population: Intent-to-Treat
Page 1 of 1
Table 7.20
Listing of Positive Pregnancy Tests
No data to report
CONFIDENTIAL
624
RM2010/00132/00
ADC111114
05MAR2010 10:20
CONFIDENTIAL
RM2010/00132/00
ADC111114
Synopsis
Study Number: ADC111114
Title: A Randomized, Double-Blind, Parallel-Group, 24-Week Study to Evaluate the
Efficacy and Safety of ADVAIR™ DISKUS™ (Fluticasone Propionate/Salmeterol
Combination Product 250/50mcg Inhalation Powder) BID Plus Spiriva HandiHaler
(Tiotropium Bromide Inhalation Powder 18mcg) QD Versus Spiriva QD Plus Placebo
DISKUS BID in Subjects with Chronic Obstructive Pulmonary Disease (COPD)
Investigator(s): Multi-Center Study
Study center(s): 33 centers in the United States (US)
Publication(s): None at the time of this report
Study Period: 01Dec2008 -08Dec2009
Phase of Development: IV
Objectives: The primary objective was to evaluate the effectiveness and safety of
Flutiasone Propionate/Salmeterol Combination (FSC) 250/50mcg plus Tiotropium 18mcg
compared to Tiotropium 18mcg and placebo DISKUS in patients with COPD.
Methodology: This was a multicenter, randomized, double-blind, parallel-group, study
with a 24-week treatment period. Eligible subjects completed approximately a 4 week
run-in period during which subjects received open-label Tiotropium 18mcg QD.
Following run-in, only subjects who had a modified Medical Research Council (mMRC)
score of ≥2 were eligible for randomization. Subjects were randomized 1:1 to FSC
250/50 BID plus Tiotropium 18mcg QD or Tiotropium 18mcg QD (active comparator)
plus Placebo DISKUS BID. Albuterol was provided as rescue medication to subjects for
use throughout the study. Treatments were stratified according to forced expiratory
volume in one second (FEV1) reversibility to albuterol at Visit 1. There were a total of 6
visits (conducted at Screening, Randomization, and after 4, 8, 16, and 24 weeks of
treatment). A post-treatment follow-up phone call was conducted approximately 14 days
following the last dose of study medication. A variety of lung function as well as quality
of life (QOL) measures were evaluated.
Number of subjects: 350 subjects planned; 342 subjects recruited and analyzed
Diagnosis and main criteria for inclusion:
Inclusion Criteria:
1.
Informed Consent: Signed and written informed consent from the subject and/or
subject’s legally acceptable representative prior to study participation
2.
Age: ≥40 years of age
3.
Sex: Male or Female
1
CONFIDENTIAL
RM2010/00132/00
ADC111114
A female is eligible to enter and participate in this study if she is of:
a
non-child bearing potential (i.e., physiologically incapable of becoming
pregnant, including any female who is post-menopausal); or,
b
child-bearing potential, has a negative pregnancy test (urine) at screening, and
one of the following apply:
•
Abstinence from intercourse, or,
•
Male partner was sterile prior to the female subject’s entry into the study, or,
•
Use of implants of levonorgestrel; or,
•
Injective progesterone; or,
•
Oral contraceptive (combined or progesterone only), contraceptive patch,
vaginal ring; or,
•
Any intrauterine device (IUD) with published data showing that the highest
expected failure rate is less than 1% per year (e.g., Paragard), or,
•
Double barrier technique simultaneously using two of the following:
spermicide, male condom, diaphragm, or female condom
Female subjects, with the exception of post-menopausal females and surgically
sterile females, will undergo a urine pregnancy test at every study visit and the
Premature Discontinuation Visit if applicable. Any female who becomes pregnant
during the study will be withdrawn. Female subjects should not be enrolled if they
plan to become pregnant during the time of study participation.
4.
Diagnosis: An established clinical history of COPD in accordance with the
following definitions by the American Thoracic Society (ATS).
COPD is a preventable and treatable disease state characterized by airflow limitation
that is not fully reversible. The airflow limitation is usually progressive defined as a
disease state characterized by the presence of airflow obstruction and an abnormal
inflammatory response of the lungs to noxious particles or gasses, primarily caused
by cigarette smoking. Although COPD affects the lungs, it also produces significant
systemic consequences.
5.
Severity of Disease: A post-albuterol FEV1 ≥40 to ≤80% of predicted normal and a
post-albuterol FEV1/forced vital capacity (FVC) ratio of ≤ 0.70 based on NHANES
III reference values.
6.
Smoking History: Current or previous smokers with a history of smoking of ≥ 10
pack-years where pack-years are defined as the number of packs of cigarettes
smoked per day multiplied by the number of years smoked. All current smokers
considered for the study may be counselled at the investigator’s discretion regarding
hazards of continuing to smoke and the benefits of cessation. Ex-smokers are defined
as subjects who have discontinued smoking for ≥ 6 months prior to Visit 1.
Exclusion Criteria:
1.
Asthma: A current diagnosis of asthma
2
CONFIDENTIAL
RM2010/00132/00
ADC111114
2.
Other Diseases/Abnormalities: Any significant disease that, in the opinion of the
investigator, would put the safety of the subject at risk through study participation, or
which would affect the efficacy analysis if the disease/condition exacerbated during
the study.
3.
Other Respiratory Disorders: Has a respiratory disorder other than COPD (e.g.,
lung cancer, sarcoidosis, active or quiescent tuberculosis, bronchiectasis, pulmonary
fibrosis, cystic fibrosis, or alpha-1-antitrypsin deficiency)
4.
History of Alcohol or Drug Abuse: Has a known or suspected history of alcohol or
drug abuse within the past 2 years
5.
12-Lead Electrocardiogram (ECG): At Visit 1, 12-lead ECG is abnormal and
clinically significant. The investigator will determine the clinical significance of the
abnormality and determine if a subject is precluded from entering the study.
6.
Chest X-Ray: Chest X-ray (posteroanterior) or computed tomography (CT) scan
reveals evidence of clinically significant abnormalities not believed to be due to the
presence of COPD. A chest X-ray must be taken if the subject has not had one within
6 months of Visit 1.
7.
Drug Allergy: Any adverse reaction including immediate or delayed
hypersensitivity to any beta2-agonist, sympathomimetic drug, or corticosteroid
(intranasal, inhaled, or systemic including any components of the formulations [e.g.
lactose or milk protein]), or atropine or its derivatives, including ipratropium.
8.
Body Mass Index: A BMI of ≥40kg/m2
9.
Use of strong P450 3A4 inhibitors (e.g., Ritonavir)
10. Taking the following medications before the timeframe prior to Visit 1:
Medication
Long-acting beta agonist (LABA)/ Inhaled
corticosteroid (ICS) combination products
(e.g, ADVAIR™, Symbicort)
Inhaled corticosteroids
Oral or parenteral corticosteroids
Any investigational drug
Theophylline preparations
Tiotropium
Salmeterol
Formoterol
Oral beta-agonists
Ipratropium
Ipratropium/albuterol combination
products (e.g., Combivent)
Short-acting beta-agonists (e.g., albuterol)
Washout period prior to Visit 1
30 days
30 days
30 days
30 days
48 hours
48 hours
24 hours
24 hours
12 hours
6 hours
6 hours
6 hours
11. Long –Term Oxygen Therapy (LTOT): LTOT is prohibited at any time during the
study
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12. Lung surgery: Lung resection surgery (e.g., lung volume reduction surgery or
lobectomy) within 1 year of Visit 1.
13. Pregnancy: Women who are pregnant or lactating at Visit 1
14. Cancer: Previously diagnosed cancer unless it is in complete remission for 2 years
(no evidence of tumor burden) at Visit 1. Localized carcinomas of the skin that have
been resected for cure are not exclusionary.
15. Affiliation with investigator site: Subject is a study Investigator, sub-Investigator,
study coordinator, or employee of a participating Investigator or immediate family
member of the aforementioned
16. Questionable Validity of Consent: Any intellectual deficiency including illiteracy,
psychiatric illness, or any other condition which will limit the validity of informed
consent to participate in the study
Treatment administration:
The following double-blind study medications were used in this study:
•
Fluticasone propionate/salmeterol 250/50mcg per inhalation via DISKUS
(formulated with lactose) twice-daily
•
Matching Placebo DISKUS (formulated with lactose) DISKUS one inhalation twicedaily
The following open-label study medication was used in this study:
•
Tiotropium Bromide (18mcg) per inhalation via the HandiHaler device once-daily
Criteria for evaluation:
Endpoints:
Primary
•
AM Pre-dose Forced Expiratory Volume in One Second (FEV1) at Endpoint
Secondary
•
2 hour post-dose FEV1 at Endpoint
•
AM Pre-dose Forced Vital Capacity (FVC) at Endpoint
•
2 hour post-dose FVC at Endpoint
•
AM Pre-Dose Inspiratory Capacity (IC) at Endpoint
•
Scores on the Clinical Respiratory Questionnaire-Self-Administered Standardized
(CRQ-SAS) at Endpoint
Other(s)
•
Supplemental albuterol use
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•
Rate of Health Care Utilization (HCU) for COPD exacerbations (i.e.,use of systemic
corticosteroids and/or antibiotics, unscheduled or urgent care physician /clinic office
visits, and/or emergency room visits)
•
HCU (i.e., hospitalizations) for COPD exacerbations
Exploratory
•
Scores on the Quick Inventory of Depressive Symptomatology-Self Report (QIDSSR) scale
•
Scores on the Hospital Anxiety and Depression Scale (HADS)
Safety
•
Type and incidence of adverse events (AEs)
•
Type and incidence of pneumonia
Statistical methods: It was estimated that 133 subjects per treatment group would
provide approximately 90% power for detection of a significant difference of 100 mL in
pre-dose FEV1 change from baseline at Endpoint with a significance level of 0.05 based
on a two-sample two-sided t-test with a standard deviation estimate of 250 mL.
Approximately 350 subjects were to be randomized to allow for a 30% study withdrawal
rate. The analysis population for this study was the Intent-to-Treat (ITT) Population
which included all subjects randomized to study drug.
The primary efficacy measure (change from baseline in pre-dose FEV1 at Endpoint) and
secondary efficacy measures of pre-dose FVC and IC, 2-hour post-dose FEV1 and FVC,
and CRQ-SAS scores were compared between treatment groups using analysis of
covariance (ANCOVA).
The Hochberg method was used at the 0.05 significance level to control the overall type I
error rate across the secondary efficacy measures. Other efficacy measures were nested
under a secondary efficacy measure, and the secondary efficacy measure served as a
gatekeeper for the other measures. Other efficacy measures were supplemental albuterol
use and HCU for COPD exacerbations and were nested under the secondary efficacy
measure of pre-dose IC. Exploratory measures were QIDS-SR and HADS scores.
The analysis of COPD exacerbations compared the rate of exacerbations per subject per
the 24-week treatment period between treatment groups using a Poisson regression
model. Healthcare utilization was summarized by treatment group in terms of the
number of healthcare contacts (physician office visits, urgent care visits, emergency room
visits and hospitalizations) as related to exacerbations during the 24-week study.
Supplemental albuterol use and QIDS-SR and HADS scores were compared between
treatment groups with an ANCOVA model. The proportion of subjects reporting AEs
was summarized for each treatment group using the Medical Dictionary for Regulatory
Activities (MedDRA) primary system organ class (SOC) and preferred term.
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Summary:
The key findings from this study were that the combination of FSC + Tiotropium (Tio)
resulted in statistically significant improvements in lung function compared to
Tiotropium alone. However, FSC + Tio did not differ statistically from Tiotropium alone
on QOL domain scores as measured by the CRQ-SAS.
FSC + Tio
N=173
AM Pre-Dose FEV1 at Endpoint
LS Mean Difference, (SE)
p value
2 Hour Post-Dose FEV1 at Endpoint
LS Mean Difference, (SE)
p value
AM Pre-Dose FVC at Endpoint
LS Mean Difference, (SE)
p value
2 Hour Post-Dose FVC at Endpoint
LS Mean Difference, (SE)
p value
AM Pre-Dose IC at Endpoint
LS Mean Difference, (SE)
p value
Tio
N=169
115 (29.5)
<0.001
154 (30.1)
<0.001
122 (44.0)
0.006
175 (46.4)
<0.001
141 (41.0)
<0.001
Conclusions:
•
Triple therapy with FSC + Tio resulted in statistically significant improvements on
various lung function measures including AM pre-dose FEV1, 2 hour post-dose
FEV1, AM pre-dose FVC, 2 hour post-dose FVC, and pre-dose IC compared to
Tiotropium alone.
•
There were no statistically significant differences between groups on any domain
score of the CRQ-SAS.
•
Triple therapy with FSC + Tio resulted in a statistically significant reduction in
albuterol use compared to Tiotropium alone.
•
The number of COPD exacerbations in each group was low; thus, rate of HCU for
COPD exacerbations could not be calculated.
•
There were no statistically significant differences between groups on depression or
depression/anxiety measured via the QIDS-SR and HADS, respectively.
•
Triple therapy was well-tolerated and did not result in any significant safety risks.
Date of Report: April 2010
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The GlaxoSmithKline group of companies
RM2010/00132/00
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Division: Worldwide Development
Retention Category: GRS019
Information Type: Clinical Protocol
Title:
A Randomized, Double-Blind, Parallel-Group, 24-Week Study
to Evaluate the Efficacy and Safety of ADVAIR DISKUS
(Fluticasone Propionate/Salmeterol Combination Product
250/50mcg Inhalation Powder) BID Plus Spiriva HandiHaler
(Tiotropium Bromide Inhalation Powder 18mcg) QD Versus
Spiriva QD Plus Placebo DISKUS BID in Subjects with Chronic
Obstructive Pulmonary Disease (COPD)
Compound Number: CCI18781+GR33343
Development Phase
IV
Effective Date:
24-JUN-2008
Description: This is a multicenter, randomized, double-blind, parallel-group study. The
purpose of this study is to evaluate the efficacy and safety of combination treatment with
Fluticasone Propionate/Salmeterol Combination (FSC) 250/50mcg via DISKUS BID plus
Tiotropium 18mcg QD Compared to Tiotropium 18mcg QD plus Placebo DISKUS BID
in subjects with COPD. After a 4-week run-in period on Tiotropium 18mcg QD, subjects
(n=350) will be randomized to one of the two treatment arms. All subjects will be
provided with albuterol for relief medication as needed throughout the study. Subjects
will complete a total of 6 visits. The primary endpoint is AM pre-dose forced expiratory
volume in one second (FEV1) at Endpoint. Secondary measures include 2 hour post-dose
FEV1, AM pre-dose forced vital capacity (FVC), 2 hour post dose FVC, AM pre-dose
inspiratory capacity (IC), and scores on the Chronic Respiratory Questionnaire-Self
Administered Standardized (CRQ-SAS) at Endpoint. Safety will be assessed by adverse
events (AEs) and the type and incidence of pneumonia.
Subject: ADVAIR DISKUS, Spiriva, COPD, FEV1, Fluticasone Propionate, Salmeterol,
Tiotropium
Author(s):
Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.
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SPONSOR INFORMATION PAGE
Clinical Study Identifier:
ADC111114
GlaxoSmithKline
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone:
Sponsor Contact Information:
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate
company (or designee). Where applicable, the details of the Sponsor and contact person
will be provided to the relevant regulatory authority as part of the clinical trial submission
Sponsor Serious Adverse Events (SAE) Contact Information:
, MD
GlaxoSmithKline
Five Moore Drive
Research Triangle Park, NC 27709-3398, USA
Telephone:
Case Management Group, GCSP
Email:
Fax:
Regulatory Agency Identifying Number(s): 50,703
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
Required Standard Wording:
I confirm agreement to conduct the study in compliance with the protocol.
Investigator Name: _____________________________
Investigator Signature
Date
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TABLE OF CONTENTS
Page
ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
PROTOCOL SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2. Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
12
14
2. OBJECTIVE(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
3. INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Discussion of Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
14
15
4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA. . . . . . . . . . . . . .
4.1. Number of Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. Randomization Criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5. Withdrawal Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
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15
17
18
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5. STUDY TREATMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Investigational Product and Reference Therapy . . . . . . . . . . . . . . . .
5.2. Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3. Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4. Product Accountability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5. Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6. Concomitant Medications and Non-Drug Therapies . . . . . . . . . . . . .
5.6.1. Permitted Medications and Non-Drug Therapies . . . . . . . . . . .
5.6.2. Prohibited Medications and Non-Drug Therapies . . . . . . . . . .
5.7. Treatment after the End of the Study . . . . . . . . . . . . . . . . . . . . . . . . .
5.8. Treatment of Investigational Product Overdose . . . . . . . . . . . . . . . . .
19
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21
21
21
22
22
23
23
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6. STUDY ASSESSMENTS AND PROCEDURES . . . . . . . . . . . . . . . . . . . . .
6.1. Critical Baseline Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2. Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.1. Primary Efficacy Measure . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.2. Secondary Efficacy Measure . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.3. Other Efficacy Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.4. Exploratory Efficacy Measures. . . . . . . . . . . . . . . . . . . . . . . . .
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26
26
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6.3. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.1. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.2. Safety Assessment Abnormalities Reported as AEs and
SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.3. Disease-Related Events and/or Disease-Related Outcomes
Not Qualifying as SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.4. Time Period and Frequency of Detecting AEs and SAEs . . . .
6.3.5. Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.6. Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.7. Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.8. Prompt Reporting of Serious Adverse Events and Other
Events to GSK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4. Health Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4.1. Summary Assessment of CRQ-SAS . . . . . . . . . . . . . . . . . . . .
6.4.2. Summary Assessment of the QIDS-SR . . . . . . . . . . . . . . . . . .
6.4.3. Summary Assessment of the Hospital Anxiety and
Depression Scale (HADS) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.5. Pharmacogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
30
7. DATA MANAGEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS . . . . . . . . . . .
8.1. Hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2. Study Design Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.1. Sample Size Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.2. Sample Size Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.3. Sample Size Re-estimation . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3. Data Analysis Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.1. Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.2. Analysis Data Sets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.3. Treatment Comparisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.4. Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.5. Key Elements of Analysis Plan . . . . . . . . . . . . . . . . . . . . . . . .
34
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34
35
35
35
35
35
35
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9. STUDY CONDUCT CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . .
9.1. Regulatory and Ethical Considerations, Including the Informed
Consent Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.2. Quality Control (Study Monitoring) . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.3. Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.4. Study and Site Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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9.5. Records Retention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.6. Provision of Study Results and Information to Investigators . . . . . . .
9.7. Independent Data Monitoring Committee (IDMC) . . . . . . . . . . . . . . .
38
39
39
10. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40
11. APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1. Appendix 1: PGx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2. Appendix 2: Country Specific Requirements . . . . . . . . . . . . . . . . . .
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ABBREVIATIONS
AE
ANCOVA
ATS
BID
COPD
CRQ-SAS
ECG
eCRF
ERS
FEV1
FSC
FVC
GCSP
GOLD
GSK
HADS
HAM-D
HCU
IB
IC
IEC
IRB
IDMC
IVRS
LABA
LAMA
LTOT
MDI
MMRC
PGx
QIDS-SR
QD
SAE
SGRQ
SPM
US
Adverse Event
Analysis of Covariance
American Thoracic Society
Twice-Daily
Chronic Obstructive Pulmonary Disease
Chronic Respiratory Questionnaire-Self-Administered
Standardized
Electrocardiogram
Electronic Case Report Form
European Respiratory Society
Forced Expiratory Volume in One Second
Fluticasone Propionate/Salmeterol Combination
Forced Vital Capacity
Global Clinical Safety and Pharmacovigilance
Global Initiative for Obstructive Lung Disease
GlaxoSmithKline
Hospital Anxiety and Depression Scale
Hamilton Depression Rating Scale
Health Care Utilization
Investigator Brochure
Inspiratory Capacity
Independent Ethics Committee
Institutional Review Board
Independent Data Monitoring Committee
Interactive Voice Recognition System
Long-Acting Beta Agonist
Long-Acting Muscarinic Antagonist
Long-Term Oxygen Therapy
Metered Dose Inhaler
Modified Medical Research Council
Pharmacogenetics
Quick Inventory of Depressive Symptomatology-Self
Report
Once-Daily
Serious Adverse Event
St. George’s Respiratory Questionnaire
Study Procedures Manual
United States
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Trademark Information
Trademarks of the GlaxoSmithKline
group of companies
Trademarks not owned by the
GlaxoSmithKline group of companies
ADVAIR DISKUS
Spiriva HandiHaler
Combivent
Norvir
Paragard
Symbicort
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PROTOCOL SUMMARY
Rationale
Both Fluticasone Propionate/Salmeterol Combination (FSC) and tiotropium are indicated
for the maintenance treatment of COPD. FSC contains fluticasone propionate, an inhaled
corticosteroid (ICS) and salmeterol, a bronchodilator which is an agonist at betaadrenergic receptors [long-acting beta-agonist, (LABA)] in a combination inhaler to be
administered BID. Tiotropium, like salmeterol, is a long-acting bronchodilator but is an
antagonist at muscarinic cholinergic receptors [long-acting muscarinic antagonist
(LAMA)] and is administered once-daily. These medications are frequently coprescribed in clinical practice, but few studies have examined the“triple”combination
therapy of an ICS/LABA and LAMA for the treatment of COPD. Furthermore, no
studies have examined the “triple” combination of the FSC 250/50 strength combined
with tiotropium, and FSC 250/50mcg is the only approved dosage for COPD in the
United States (US). This study will provide information on the efficacy and safety of
add-on therapy with FSC 250/50 to tiotropium compared with tiotropium alone. The
results of this study may give health care providers an additional arsenal of combination
therapies that are safe and result in better COPD symptom control than tiotropium alone
for patients with COPD.
Objective(s)
The primary objective is to evaluate the effectiveness and safety of FSC 250/50mcg BID
plus tiotropium 18mcg QD compared with tiotropium 18mcg QD and Placebo DISKUS
BID in patients with COPD.
Study Design
This is a multicenter, randomized, double-blind, parallel-group, study with a 24-week
treatment period. Eligible subjects will complete approximately a 4 week run-in period
during which subjects will receive tiotropium 18mcg QD. Following run-in, only
subjects who have a Modified Medical Research Council (MMRC) score of ≥2 will be
eligible for randomization. Subjects will be randomized 1:1 to FSC 250/50 BID plus
tiotropium 18mcg QD or tiotropium 18mcg QD (active comparator) plus Placebo
DISKUS BID. Albuterol will be provided as rescue medication to subjects for use
throughout the study. Treatments will be stratified according to FEV1 reversibility to
albuterol at Visit 1. There will be a total of 6 visits (conducted at Screening,
Randomization, and after 4, 8, 16, and 24 weeks of treatment). A post-treatment followup phone call will be conducted approximately 14 days following the last dose of study
medication. Approximately 350 subjects total will be randomized to obtain 245
completed subjects.
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Study Endpoints/Assessments
Endpoints:
Primary
•
AM Pre-dose Forced Expiratory Volume in One Second (FEV1) at Endpoint
Secondary
•
2 hour post-dose FEV1 at Endpoint
•
AM Pre-dose Forced Vital Capacity (FVC) at Endpoint
•
2 hour post-dose FVC at Endpoint
•
AM Pre-Dose Inspiratory Capacity (IC) at Endpoint
•
Scores on the Clinical Respiratory Questionnaire-Self-Administered Standardized
(CRQ-SAS) at Endpoint
Other(s)
•
Supplemental albuterol use
•
Rate of Health Care Utilization (HCU) for COPD exacerbations (i.e.,use of systemic
corticosteroids and/or antibiotics, unscheduled or urgent care physician /clinic office
visits, and/or emergency room visits)
•
HCU (i.e., hospitalizations) for COPD exacerbations
Exploratory
•
Scores on the Quick Inventory of Depressive Symptomatology-Self Report (QIDSSR) scale
•
Scores on the Hospital Anxiety and Depression Scale (HADS)
Safety
•
Type and incidence of adverse events (AEs)
•
Type and incidence of pneumonia
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1.
INTRODUCTION
1.1.
Background
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Chronic Obstructive Pulmonary Disease (COPD) is one of the leading causes of
morbidity and mortality worldwide. Currently, COPD is the fifth leading cause of death
worldwide; and by the year 2020, it is estimated that COPD will become the third leading
cause of death worldwide [Urbano, 2005]. The most distinguishing feature of COPD is
dyspnea which can be related to airflow obstruction as documented by spirometric
evaluation. Exacerbations of COPD are also an important cause of the mortality and
morbidity associated with COPD and frequent exacerbations are associated with quality
of life impairment and frequent hospitalizations [Seemungal, 1998; Andersson, 2002].
Smoking cessation is the only therapy that has been shown to slow the rate of decline in
lung function in COPD [Anzueto, 2006]. However, effective treatments to manage
symptoms and improve health status are available. Long-acting bronchodilators are
among the most effective medications for COPD and are recommended for moderate to
very severe COPD [Global Initiative for Obstructive Lung Disease (GOLD), 2007].
Tiotropium (Spiriva) is a long-acting bronchodilator which acts by antagonism of
muscarinic (particularly M3) receptors (long-acting muscarinic antagonist, LAMA).
Tiotropium is indicated for the long-term maintenance treatment of bronchospasm
associated with COPD including chronic bronchitis and emphysema [Spiriva Product
Information, 2007]. Tiotropium has been shown to be effective in improving trough
forced expiratory volume in one second (FEV1), dyspnea, health status, and exacerbations
compared to placebo after 1 year of treatment [Casaburi, 2002]. Also, in a 6-month
study, tiotropium significantly reduced the number of and health care utilization for
exacerbations [Niewoehner, 2005].
Salmeterol, a long-acting beta-agonist (LABA) is another effective bronchodilator for
COPD, but is most commonly prescribed for COPD as a component of a dry powder
inhaler consisting of the inhaled corticosteroid (ICS) fluticasone propionate and
salmeterol (FSC) DISKUS. Randomized trials have shown treatment with FSC at
strengths of 250/50mcg and 500/50mcg BID results in greater improvement in lung
function and dyspnea compared with the individual components in patients with COPD
[Mahler, 2002; Hanania, 2003; Calverley, 2003]. Recent studies have also demonstrated
that both the 500/50 and 250/50 strengths of FSC significantly reduce the rate of
exacerbations in COPD [Calverley, 2007; see report for study SCO40043,
RM2006/00845/00 and study SCO100250, RM2007/00469/00]. In the United States
(US), only the 250/50 strength of FSC is indicated for the twice-daily maintenance
treatment of airflow obstruction in patients with COPD associated with chronic bronchitis
or emphysema.
Recent COPD guidelines have recommended that combining bronchodilators with
different mechanisms and durations of action may increase the degree of bronchodilation
for equivalent or lesser side effects [GOLD, 2007]. In effect, combining different
treatments can potentially produce greater improvements in COPD than individual
treatments alone. The bronchodilator component of FSC (salmeterol) and the
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bronchodilator tiotropium each have different effects on bronchodilation and may work
synergistically to improve bronchodilation when given together. The ICS component of
FSC (fluticasone propionate) works through a different mechanism by reducing
inflammation in COPD.
Tiotropium and FSC are the two most prescribed medications for the treatment of COPD,
and are frequently co-prescribed in clinical practice. While intuitively, the combination
of FSC with confer additional benefit in COPD compared to single bronchodilator (i.e,
tiotropium) alone, there are only a few empirical studies to support this. A 3-month pilot
study of treatment of FSC 500/50 plus placebo, tiotropium plus placebo, or FSC 500/50
plus tiotropium showed that all groups had significant improvements in trough FEV1 at
the end of the study compared to baseline. However, the greatest difference occurred in
the FSC 500/50 plus tiotropium group [Cazzola, 2007]. Another recent study [Aaron,
2007] compared the effect of FSC 250/25 plus tiotropium, tiotropium plus salmeterol,
and tiotropium plus placebo. The study was not adequately powered to show a
statistically significant difference among groups on the primary endpoint of
exacerbations. However, the FSC plus tiotropium group improved lung function,
hospitalizations for exacerbations and St. George’s Respiratory Questionnaire (SGRQ)
scores compared to tiotropium plus placebo. Of note, the tiotropium plus salmeterol
group did not improve these endpoints compared to tiotropium plus placebo which
suggests that dual bronchodilator therapy was no better than a single bronchodilator in
this study. This finding, along with the aforementioned studies indicating the benefit of
FSC versus the individual components alone, may indicate the further benefit achieved
when an ICS is added to bronchodilator therapy compared to dual bronchodilatory
therapy alone. A recent GSK study [Singh, 2008] examined the effect of FSC 500/50
plus tiotropium compared with either treatment alone. This study showed that the triple
therapy was superior to either agent alone in AUC0-4hr sGAW and sRAW at 14 days and
other lung function measurements as well as improvement in symptomatic endpoints
such as the Transition Dyspnea Index (TDI) and the use of rescue medication.
Of note, the triple combination studies mentioned above all showed statistically
significant differences with triple combination therapy on a variety of lung function and
symptomatic endpoints in COPD. In addition, the patient populations in these studies
ranged from moderate (FEV1 ≤75% predicted normal) to severe (FEV1 <50% predicted
normal) indicating that a wide range of COPD severities do benefit from triple
combination therapy compared to dual or single bronchodilator therapy alone. However,
larger and adequately powered studies are needed to confirm these results.
The addition of FSC 250/50 to tiotropium may also indirectly improve other endpoints
which are considered exploratory for this study. It has been well-documented that
patients with COPD have co-morbidities such as depression and anxiety which adds to
the economic burden associated with COPD [Mannino, 2007]. Recent guidelines
[GOLD, 2007] suggest that these comorbidities are frequent in COPD patients and should
be actively identified. These co-morbidities are associated with poorer survival and
quality of life [Ng, 2007]. Furthermore, studies in COPD have shown significant
associations between depression and physical symptoms of COPD such as dyspnea
[Katon, 2007]. In addition, one study found that treatment with an antidepressant
decreased comorbid depression in COPD but had no effect on physical symptoms such as
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dyspnea and lung function [Borson, 1992]. A non-pharmacological, non-antidepressant
treatment (pulmonary rehabilitation) also resulted in improvement in depression, anxiety,
and dyspnea in COPD patients [Diaz, 2007].
We hypothesize that improving respiratory symptoms in COPD with the addition of a
pharmacological regimen of FSC 250/50 plus tiotropium may also lead to an
improvement in those subjects who demonstrate depression and/or anxiety as assessed by
validated psychometric questionnaires.
The purpose of this study is to evaluate the effects on lung function and quality of life
with FSC 250/50 plus tiotropium compared with tiotropium plus placebo. In addition,
these treatments will be evaluated to determine their effect on the exploratory endpoints
of depression and anxiety. The aim is to examine the effect of the 250/50 strength of
FSC which is the only approved dosage for COPD treatment in the US plus tiotropium
compared with tiotropium plus placebo. The results of this study may support the use of
triple therapy in COPD patients to augment the benefits of tiotropium alone.
1.2.
Rationale
Both Fluticasone Propionate/Salmeterol Combination (FSC) and tiotropium are indicated
for the maintenance treatment of COPD. FSC contains fluticasone propionate, an inhaled
corticosteroid (ICS) and salmeterol, a bronchodilator which is an agonist at betaadrenergic receptors [long-acting beta-agonist, (LABA)] in a combination inhaler to be
administered BID. Tiotropium, like salmeterol, is a long-acting bronchodilator but is an
antagonist at muscarinic cholinergic receptors [long-acting muscarinic antagonist
(LAMA)] and is administered once-daily. These medications are frequently coprescribed in clinical practice, but few studies have examined the“triple”combination
therapy of an ICS/LABA and LAMA for the treatment of COPD. Furthermore, no
studies have examined the “triple” combination of the FSC 250/50 strength combined
with tiotropium, and FSC 250/50mcg is the only approved dosage for COPD in the
United States (US). This study will provide information on the efficacy and safety of
add-on therapy with FSC 250/50 to tiotropium compared with tiotropium alone. The
results of this study may give health care providers an additional arsenal of combination
therapies that are safe and result in better COPD symptom control than tiotropium alone
for patients with COPD.
2.
OBJECTIVE(S)
The primary objective is to evaluate the effectiveness and safety of FSC 250/50mcg plus
tiotropium 18mcg compared to tiotropium 18mcg alone in patients with COPD.
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
This is a multicenter, randomized, double-blind, parallel group study. Subjects will
complete a 4-week run-in period in which open-label tiotropium will only be given.
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Albuterol will be supplied as rescue medication during run-in and throughout the rest of
the study. Following run-in, only subjects who have an MMRC score of ≥2 will be
eligible for randomization. The run-in period will be followed by a 24 week treatment
period. Subjects will be randomized 1:1 to open-label tiotropium 18mcg once-daily plus
double-blind FSC 250/50 mcg BID or open-label tiotropium 18mcg once daily plus
double-blind matching Placebo DISKUS BID.
There will be a total of 6 study visits Screening, Randomization, and after 4, 8, 16, and 24
weeks of treatment. A follow-up phone contact for collection of AE and pregnancy (if
applicable) information will be conducted approximately 14 days following the last study
visit. Study completion will be defined as completion of the follow-up phone call.
The magnitude of bronchodilator response to FSC DISKUS 250/50 is generally larger in
subjects with COPD who demonstrate FEV1 reversibility to albuterol compared with nonreversible subjects [Hanania, 2003]. Therefore, the treatment groups will be stratified by
albuterol reversibility assessed at Visit 1 to ensure the proportion of reversible to nonreversible subjects is similar across groups.
Supplementary study conduct information not mandated to be present in this protocol is
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide
the site personnel with administrative and detailed technical information that does not
impact subject safety.
3.2.
Discussion of Design
Both tiotropium and FSC 250/50 are approved as maintenance treatment for
bronchospasm associated with COPD. No placebo group was chosen as the value of addon therapy (FSC 250/50) to an existing therapy (tiotropium) is to be assessed. The
18mcg dose is the only approved dose of tiotropium. While a few studies have been
conducted combining tiotropium with FSC500/50, no studies have been conducted with
the 250/50 dose of FSC which is the only dose currently approved for COPD in the US.
The 6 month duration of treatment is consistent with other studies and allows enough of a
treatment period to evaluate the effects of FSC 250/50 added to tiotropium therapy
compared with tiotropium alone.
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
Assuming a 30% premature discontinuation rate, 350 subjects will be randomized to
obtain 245 completed/evaluable subjects.
4.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other
pertinent information on the investigational product that may impact subject eligibility is
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provided in the Investigator Brochure [IB/IB supplement(s)], product label, add other
pertinent documents.
Subjects eligible for enrolment in the study must meet all of the following criteria:
1.
Informed Consent: Signed and written informed consent from the subject and/or
subject’s legally acceptable representative prior to study participation
2.
Age: ≥40 years of age
3.
Sex: Male or Female
A female is eligible to enter and participate in this study if she is of:
a
non-child bearing potential (i.e., physiologically incapable of becoming
pregnant, including any female who is post-menopausal); or,
b
child-bearing potential, has a negative pregnancy test (urine) at screening, and
one of the following apply:
•
Abstinence from intercourse, or,
•
Male partner was sterile prior to the female subject’s entry into the study, or,
•
Use of implants of levonorgestrel; or,
•
Injective progesterone; or,
•
Oral contraceptive (combined or progesterone only), contraceptive patch,
vaginal ring; or,
•
Any intrauterine device (IUD) with published data showing that the highest
expected failure rate is less than 1% per year (e.g., Paragard), or,
•
Double barrier technique simultaneously using two of the following:
spermicide, male condom, diaphragm, or female condom
Female subjects, with the exception of post-menopausal females and surgically
sterile females, will undergo a urine pregnancy test at every study visit and the
Premature Discontinuation Visit if applicable. Any female who becomes pregnant
during the study will be withdrawn. Female subjects should not be enrolled if they
plan to become pregnant during the time of study participation.
4.
Diagnosis: An established clinical history of COPD in accordance with the
following definitions by the American Thoracic Society (ATS) [Celli, 2004].
COPD is a preventable and treatable disease state characterized by airflow limitation
that is not fully reversible. The airflow limitation is usually progressive defined as a
disease state characterized by the presence of airflow obstruction and an abnormal
inflammatory response of the lungs to noxious particles or gasses, primarily caused
by cigarette smoking. Although COPD affects the lungs, it also produces significant
systemic consequences.
5.
Severity of Disease: A post-albuterol FEV1 ≥40 to ≤80% of predicted normal and a
post-albuterol FEV1/FVC ratio of ≤ 0.70 based on NHANES III reference values
[Hankinson, 1999].
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6.
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Smoking History: Current or previous smokers with a history of smoking of ≥ 10
pack-years where pack-years are defined as the number of packs of cigarettes
smoked per day multiplied by the number of years smoked. All current smokers
considered for the study may be counselled at the investigator’s discretion regarding
hazards of continuing to smoke and the benefits of cessation. Ex-smokers are defined
as subjects who have discontinued smoking for ≥ 6 months prior to Visit 1.
4.3.
Exclusion Criteria
Subjects meeting any of the following criteria must not be enrolled in the study:
1.
Asthma: A current diagnosis of asthma
2.
Other Diseases/Abnormalities: Any significant disease that, in the opinion of the
investigator, would put the safety of the subject at risk through study participation, or
which would affect the efficacy analysis if the disease/condition exacerbated during
the study.
3.
Other Respiratory Disorders: Has a respiratory disorder other than COPD (e.g.,
lung cancer, sarcoidosis, active or quiescent tuberculosis, bronchiectasis, pulmonary
fibrosis, cystic fibrosis, or alpha-1-antitrypsin deficiency)
4.
History of Alcohol or Drug Abuse: Has a known or suspected history of alcohol or
drug abuse within the past 2 years
5.
12-Lead Electrocardiogram (ECG): At Visit 1, 12-lead ECG is abnormal and
clinically significant. The investigator will determine the clinical significance of the
abnormality and determine if a subject is precluded from entering the study.
6.
Chest X-Ray: Chest X-ray (posteroanterior) or computed tomography (CT) scan
reveals evidence of clinically significant abnormalities not believed to be due to the
presence of COPD. A chest X-ray must be taken if the subject has not had one within
6 months of Visit 1.
7.
Drug Allergy: Any adverse reaction including immediate or delayed
hypersensitivity to any beta2-agonist, sympathomimetic drug, or corticosteroid
(intranasal, inhaled, or systemic including any components of the formulations [e.g.
lactose or milk protein]), or atropine or its derivatives, including ipratropium.
8.
Body Mass Index: A BMI of ≥40kg/m2
9.
Use of strong P450 3A4 inhibitors (e.g., Ritonavir)
10. Taking the following medications before the timeframe prior to Visit 1:
Medication
LABA/ICS combination products (e.g,
ADVAIR, Symbicort)
Inhaled corticosteroids
Oral or parenteral corticosteroids
Any investigational drug
Theophylline preparations
Tiotropium
Washout period prior to Visit 1
30 days
30 days
30 days
30 days
48 hours
48 hours
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Salmeterol
Formoterol
Oral beta-agonists
Ipratropium
Ipratropium/albuterol combination
products (e.g., Combivent)
Short-acting beta-agonists (e.g., albuterol)
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24 hours
24 hours
12 hours
6 hours
6 hours
6 hours
11. Long –Term Oxygen Therapy (LTOT): LTOT is prohibited at any time during the
study
12. Lung surgery: Lung resection surgery (e.g., lung volume reduction surgery or
lobectomy) within 1 year of Visit 1.
13. Pregnancy: Women who are pregnant or lactating at Visit 1
14. Cancer: Previously diagnosed cancer unless it is in complete remission for 2 years
(no evidence of tumor burden) at Visit 1. Localized carcinomas of the skin that have
been resected for cure are not exclusionary.
15. Affiliation with investigator site: Subject is a study Investigator, sub-Investigator,
study coordinator, or employee of a participating Investigator or immediate family
member of the aforementioned
16. Questionable Validity of Consent: Any intellectual deficiency including illiteracy,
psychiatric illness, or any other condition which will limit the validity of informed
consent to participate in the study
4.4.
Randomization Criteria
The randomization criteria listed below must be reviewed for each subject prior to
randomization to blinded study drug:
•
Must have a score of ≥2 on the MMRC dyspnea scale
•
Did not experience a COPD exacerbation or respiratory tract infection that required
treatment with antibiotics, systemic corticosteroids, or hospitalization during the runin period (including Visit 2).
4.5.
Withdrawal Criteria
Reasons for subject withdrawal from the study will include the following: AE, lost-to
follow up, lack of efficacy, protocol violation, non-compliance, subject decided to
withdraw from the study, Investigator decision, or other.
The reason for subject withdrawal will be recorded in the electronic case report form
(eCRF) and study source documents.
Study drug should not be discontinued for >14 days. If a subject discontinues use of
blinded study medication for >14 consecutive days or has a calculated compliance to
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study medication of <75.0% at any study visit, the study sponsor/site monitor must be
contacted to discuss subject eligibility for continued participation in the study.
Subjects prematurely withdrawn from the study will not be replaced.
Any female who becomes pregnant during the study will be withdrawn.
5.
STUDY TREATMENTS
5.1.
Investigational Product and Reference Therapy
The following double-blind study medication will be used in this study:
•
Fluticasone propionate/salmeterol 250/50mcg per inhalation via DISKUS
(formulated with lactose) twice-daily
•
Matching Placebo DISKUS (formulated with lactose) DISKUS one inhalation twicedaily
The following open-label study medication will be used in this study:
•
Tiotropium Bromide (18mcg) per inhalation via the HandiHaler device once-daily
Double-blind study medication will be manufactured by GlaxoSmithKline (GSK).
Clinical Trial Supplies of GSK Research and Development will provide the FSC 250/50
DISKUS and Placebo DISKUS. Sites will be supplied with Spiriva (Tiotropium Bromide
Inhalation Powder) HandiHaler 18mcg manufactured by Boehringer Ingelheim
(Ingelheim, Germany).
All subjects will receive albuterol as relief medication. GSK Clinical Trial Supplies will
provide each investigative site with a bulk supply of albuterol Metered Dose Inhaler
(MDI) and nebules.
Each subject will be instructed to self administer blinded study drug during the doubleblind treatment period as follows:
•
Each morning (approximately 6-9AM) take 1 inhalation from the DISKUS followed
by 1 inhalation from the Spiriva HandiHaler Device. Each evening (approximately
6-9PM), approximately 12 hours after morning dosing with the DISKUS, take 1
inhalation from the DISKUS
In order to obtain accurate pre-dose FEV1 assessments, subjects must be instructed to
withhold their morning dose of study drug at study Visits 3, 4, 5, and 6 corresponding to
weeks 4, 8, 16, and 24 respectively. The first dose of study drug will be administered in
the clinic at Visit 2, and the morning dose of study drug will be administered in the clinic
for all other visits (Visits 3 through 6) following completion of pre-dose pulmonary
function tests. Study visits must be re-scheduled if the subject does not withhold their
morning dose of study drug.
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Subjects will record the total number of inhalations administered from the DISKUS and
HandiHaler each day in their diary card.
All subjects will receive supplemental albuterol as relief medication. Albuterol must be
withheld for at least 6 hours prior to all visits. If a subject has taken albuterol within 6
hours prior to a visit, the visit must be rescheduled.
The contents of the label will be in accordance with all applicable regulatory
requirements.
Under normal conditions of handling and administration, investigational product is not
expected to pose significant safety risks to site staff. Take adequate precautions to avoid
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of
any unintentional occupational exposure. A Material Safety Data Sheet (MSDS)
describing the occupational hazards and recommended handling precautions will be
provided to site staff if required by local laws or will otherwise be available from GSK
upon request.
Investigational product must be stored in a secure area under the appropriate physical
conditions for the product. Access to and administration of the investigational product
will be limited to the investigator and authorized site staff. Investigational product must
be dispensed or administered only to subjects enrolled in the study and in accordance
with the protocol.
5.2.
Treatment Assignment
After obtaining written informed consent and completing at least one additional screening
procedure [including making any change in subject medication use (e.g., drug washout)],
a unique subject identifier will be assigned for each subject and will be used to identify
individual subjects during the course of the study.
Subjects will be assigned to study treatment in accordance with a randomization
schedule.
This study will utilize an interactive voice recognition service (IVRS) which will provide
a means for central allocation of drug. Each Investigator will be supplied with sufficient
supplies to conduct the trial. Additional treatment packs will be supplied as needed to the
sites. Each subject will be assigned a unique randomization number. Once a
randomization number has been assigned it must not be re-assigned.
All study medication will be supplied by GSK. After all appropriate regulatory and
ethical approval documents have been received and approved by GSK, study medication
will be sent to the site.
Subjects will be stratified based on FEV1 reversibility to albuterol. Within each stratum
(reversible or non-reversible), subjects will be randomly assigned to FSC 250/50
DISKUS twice daily plus tiotropium once-daily or Placebo DISKUS twice-daily plus
tiotropium once-daily at a ratio of 1:1.
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5.3.
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Blinding
The investigator or treating physician may unblind a subject’s treatment assignment only
in the case of an emergency, when knowledge of the study treatment is essential for the
appropriate clinical management or welfare of the subject. Whenever possible, the
investigator must first discuss options with the GSK Medical Monitor or appropriate
GSK study personnel before unblinding the subject’s treatment assignment. If this is
impractical, the investigator must notify GSK as soon as possible, but without revealing
the treatment assignment of the unblinded subject, unless that information is important
for the safety of subjects currently in the study. The date and reason for the unblinding
must be recorded in the appropriate data collection tool.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the
treatment assignment for any subject with a Serious Adverse Event (SAE). If the SAE
requires that an expedited regulatory report be sent to one or more regulatory agencies, a
copy of the report, identifying the subject’s treatment assignment, may be sent to clinical
investigators in accordance with local regulations and/or GSK policy.
If a subject’s treatment assignment in unblinded, the subject must be prematurely
discontinued from the study.
5.4.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff,
or head of the medical institution (where applicable) must document the amount of GSK
investigational product dispensed and/or administered to study subjects, the amount
returned by study subjects, and the amount received from and returned to GSK, when
applicable. Product accountability records must be maintained throughout the course of
the study.
The subject must return all used and unused study medication and the Investigator or
designee must reconcile or resolve any discrepancies in the number of study treatment
inhalers dispensed and returned.
5.5.
Treatment Compliance
Treatment compliance with blinded study drug will be evaluated at Visits 3, 4, 5, and 6.
Treatment compliance with the study HandiHaler and DISKUS will be determined by
dividing total number of inhalations recorded in the subject diary card by the total
number of inhalations prescribed X 100.
Study drug should not be discontinued for greater than 14 consecutive days. If a subject
discontinues use of blinded study drug for >14 consecutive days or has a calculated
compliance to study drug of <75.0% at any study visit, the study Sponsor must be
contacted to discuss subject eligibility for continued participation in the study.
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5.6.
Concomitant Medications and Non-Drug Therapies
5.6.1.
Permitted Medications and Non-Drug Therapies
All COPD medications taken ≤ 30 days prior to Visit 1 should be recorded in the eCRF.
All concomitant medications (COPD and other) taken during the study will be recorded
in the eCRF. The minimum requirement is that drug name and the dates of
administration are to be recorded.
The following relevant medications are permitted during this study:
•
Inhaled albuterol
•
Systemic corticosteroids for the acute treatment of a COPD exacerbation not to
exceed 10 days (See Section 6.2.4.7)
•
Systemic corticosteroids for non-respiratory-related medical treatment; however,
GSK or designee must be notified if this occurs to determine subject eligibility
•
Systemic antibiotics for treatment of a COPD exacerbation or treatment of an upper
or lower respiratory tract infection not to exceed 10 days (See Section 6.2.4.8)
•
Systemic antibiotics for non-respiratory related medical treatment
•
Antihistamines, nasal decongestants and/or other intranasal medications including
intranasal corticosteroids for the treatment of rhinitis
•
Leukotriene modifiers/ receptor antagonists
•
Beta-blocker eye drops
•
Systemic beta-blockers are allowed for those subjects who have been on a stable
regimen for at least 30 days prior to Visit 1 and judged capable to continue this
regimen until discharged from the study. Initiation of systemic beta-blocker
medications within 30 days prior to Visit 1 and during the study is not allowed.
•
Immunotherapy for the treatment of allergies provided that the subject has received a
constant dose for 30 days prior to Visit 1 and the dose is maintained during the study
•
Treatment for smoking cessation
•
Mucolytics
•
Flu shots
•
Monoamine oxidase inhibitors and tricyclic antidepressants are permitted but should
be used with extreme caution as these may potentiate the effects of
fluticasone/salmeterol 250/50 or salmeterol on the vascular system.
Participation in a pulmonary rehabilitation program is permitted provided subjects have
not begun or discontinued enrolment in a pulmonary rehabilitation program within 60
days of Visit 1 or during the study. Subjects who are enrolled in a pulmonary
rehabilitation program at study start should maintain participation in the program for the
duration of the study.
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Prohibited Medications and Non-Drug Therapies
The following medications are not permitted during the study and must not have been
taken for the indicated times prior to Visit 1 (Screening):
Medication
Exclusion Period
Ritonavir (Norvir)
No use at any time during the study
Long-acting beta-agonist/inhaled corticosteroid
compounds (e.g., ADVAIR or Symbicort)
30 days prior to Visit 1 and no use at
any time during the study
Inhaled corticosteroids
30 days prior to Visit 1 and no use at
any time during the study
Oral or parenteral corticosteroids
30 days prior to Visit 1 and no use
during the study except for treatment of
COPD exacerbations
Any Investigational drug
30 days prior to Visit 1 and no use at
any time during the study
Theophylline preparations
48 hours prior to Visit 1 and no use at
any time during the study
Tiotropium
48 hours prior to Visit 1 and no use at
any time during the study
Salmeterol and formoterol
24 hours prior to Visit 1 and no use
during the study
Oral beta-agonists
12 hours prior to Visit 1 and no use
during the study
Ipratropium and ipratropium/albuterol combination
products (e.g., Atrovent or Combivent)
6 hours prior to Visit 1 and no use during
the study
Initiation of systemic beta-blocker medications within 30 days prior to Visit 1 is not
allowed.
Use of nocturnal positive pressure devices [e.g., continuous positive airway pressure or
bi-level positive airway pressure] is not allowed.
LTOT is not allowed.
If a prohibited medication is used by a study subject, the study Sponsor must be contacted
to discuss the subject’s eligibility for continued participation in the study.
5.7.
Treatment after the End of the Study
After discharge from the study, subjects will return to usual COPD therapy as determined
by their healthcare provider. GSK will not provide post study treatment.
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Treatment of Investigational Product Overdose
An overdose is defined as a dose greater than the total doses described in Section 5.1
(Investigational Product and Reference Therapy), which results in clinical signs and
symptoms. In the event of an overdose of study medication, the Investigator should use
clinical judgment in treating the overdose and contact the study medical monitor. GSK is
not recommending specific treatment guidelines for overdose and toxicity management.
The Investigator should refer to the relevant document(s) for detailed information
regarding warnings, precautions, contraindications, AEs, and other significant data
pertaining to the study drug(s) being used in this study. Such documents may include,
but not be limited to, the approved product labelling for FSC DISKUS, tiotropium
Bromide, and albuterol and IBs.
6.
Table 1
STUDY ASSESSMENTS AND PROCEDURES
Time and Events Table
Procedures
Screen/
Run-in
Randomi
zation
Week
Visit
Written Informed
Consent1
Subject Demography
Medical History/Smoking
History
Smoking Status
Medication History2
Concomitant Medication
Review
Physical Examination
Chest x-ray or review3
ECG4
Inclusion/Exclusion
Criteria
Albuterol Reversibility
Issue Diary Card
Collect/Review Diary
Card
Issue Albuterol
MMRC5
Efficacy Assessments
CRQ-SAS6
QIDS6
HADS6
Pre/Post-Dose PFTs
Trough IC
Safety Assessments
Adverse Events
Serious Adverse Events
Incidence/Type of
Pneumonia7
Visit 1
x
Double-Blind Treatment
Week 4
Week 8
Visit 2
Visit 3
x
Early
Withdrawal
Visit 4
Week
16
Visit 5
Week
24
Visit 6
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
X
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Follow
-up
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
24
x
x
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Procedures
Screen/
Run-in
Randomi
zation
Week
Visit
Laboratory
Assessments
PGx Sampling8
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Visit 1
Visit 2
Double-Blind Treatment
Week 4
Week 8
Visit 3
Visit 4
Week
16
Visit 5
Early
Withdrawal
Follow
-up
Week
24
Visit 6
PGx sample to be taken any time after obtaining the PGx informed consent
and after randomization. It is recommended that the PGx sample be collected
at Visit 3
x
x
x
x
x
x
Pregnancy Test
x
Investigational product
Dispense Invest. Product.
x
x
x
x
Collect Invest. Product
x
x
x
x
x
Assess Invest. Product
x
x
x
x
x
compliance
IVRS9
x
x
x
x
x
x
x
x
Review DISKUS and
x
x
x
x
x
HandiHaler Inhalation
Technique
Follow-up phone call10
x
1. Written informed consent for study participation must be obtained before performing any study procedures or
making any study-related changes in subject medication use.
2. Record all COPD medications used ≤ 30 days prior to Visit 1
3. Chest X-ray must be taken if a subject has not had one within 6 months of Visit 1
4. The Investigator will determine the clinical significance of any ECG abnormality and determine if a subject is
precluded from entering the study
5. Subjects must have a score of ≥2 on the MMRC at Visit 2 to be eligible for randomization.
6. Questionnaires must be completed prior to any other study assessments.
7. Pneumonia diagnosis must be confirmed by chest x-ray.
8. A separate pharmacogenetics (PGx) specific written informed consent must be obtained before PGx sampling.
9. Subjects will be randomized to blinded study drug using a telephone based IVRS system (RAMOS) which will be
used by the investigator or designate to register the subject, randomize the subject and provide medication
assignment information.
10. The follow-up phone contact is for collection of post-treatment AE and pregnancy information
6.1.
Critical Baseline Assessments
The following critical baseline assessments will be conducted at Visit 1:
•
Demographic information for sex, ethnic origin, date of birth, and height and weight
•
COPD history comprising duration of COPD, COPD type (emphysema and/or
chronic bronchitis), COPD exacerbation history, smoking history, and smoking
status
•
Albuterol FEV1 reversibility
•
Concomitant Medication Assessment
The following critical baseline assessments are conducted at Visit 2:
•
Baseline spirometry assessments for FEV1, FVC, and trough IC
•
MMRC Dyspnea Scale
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6.2.
Efficacy
6.2.1.
Primary Efficacy Measure
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The primary efficacy measure is AM pre-dose FEV1 at Endpoint.
6.2.2.
Secondary Efficacy Measure
Secondary efficacy measures are as follows:
•
2 hour post-dose FEV1 at Endpoint
•
AM Pre-dose FVC at Endpoint
•
2 hour post-dose FVC at Endpoint
•
AM Pre-Dose IC at Endpoint
•
Scores on the CRQ-SAS at Endpoint
6.2.3.
Other Efficacy Measures
Other efficacy measures are as follows:
•
Supplemental albuterol use
•
Rate of HCU for COPD exacerbations (i.e.,use of systemic corticosteroids and/or
antibiotics, unscheduled or urgent care physician /clinic office visits, and/or
emergency room visits)
•
HCU (i.e., hospitalization) for COPD
6.2.4.
Exploratory Efficacy Measures
Exploratory efficacy measures are as follows:
•
Scores on the QIDS-SR scale
•
Scores on the HADS
6.2.4.1.
Spirometry Assessment of FEV1 and FVC
Spirometry equipment that meets or exceeds the minimal performance recommendations
of the American Thoracic Society (ATS) [Miller, 2005] will be provided by a centralized
vender to be used for all study related spirometry assessments. Spirometry equipment
must be calibrated prior to spirometry testing. Calibration results will be maintained in a
calibration log, which will routinely be monitored for compliance during monitoring
visits. Subjects will be required to wear nose clips during spirometry testing.
Spirometry will be performed after withholding medications as described in Section
5.6.2. Additionally at Visits 3, 4, 5, and 6, the morning dose of blinded study drug should
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be withheld prior to performing spirometry and spirometry at these visits should be
obtained between 6 AM and 12 PM.
For FEV1 and FVC determinations, at least 3 acceptable spirometry efforts will be
obtained. Acceptable spirometry efforts should be free from artifacts due to cough, early
termination, poor effort, obstructed mouthpiece, equipment malfunction, or other reasons
[Miller, 2005].
The following repeatability criteria should be met [Miller, 2005]:
•
The two largest FVC values must be within 0.150L of each other
•
The two largest FEV1 values must be with 0.150L of each other (or 0.100L for
subjects with FVC < 1.0L)
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they
do not come from the same effort.
If 3 acceptable efforts are not obtained or the above repeatability criteria are not met, the
Sponsor or Sponsor representative should be contacted for discussion.
The subject’s position during spirometry measurements (sitting or standing) must remain
constant for the duration of the study. To verify that the spirometry efforts met the study
acceptability and repeatability standards, the spirometry results for each subject at all
visits where spirometry is obtained must be initialled and dated by the Investigator or
designated sub-Investigator.
6.2.4.2.
Albuterol Reversibility
At Visit 1, both pre- and post-albuterol spirometry will be obtained. Spirometry may be
performed at any time of day.
Following pre-albuterol spirometry, the subject will self-administer 4 puffs (360mcg) of
the albuterol MDI supplied by GSK. For consistency, spacer use is not allowed.
Triplicate spirometry efforts will be performed 15 to 30 minutes after albuterol
administration, and the highest FEV1 from three valid forced expiratory curves will be
used to determine post-albuterol assessments of FEV1 and FEV1/FVC.
Percent reversibility will be calculated as follows:
% reversibility = (FEV1 after albuterol– FEV1 before albuterol)
FEV1 before albuterol
X 100
Assignment to blinded study medication will be stratified based on albuterol response
using the following definitions:
•
Non-reversible: defined as a post-albuterol increase in FEV1 of <200mL or an
increase of ≥200mL that is <12% from the pre-albuterol baseline
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Reversible: defined as a post-albuterol increase in FEV1 of ≥200mL and ≥12% from
the pre-albuterol baseline
A full description of the timing and conduct of spirometry procedures is provided in the
study procedures manual (SPM).
6.2.4.3.
Summary Assessment of Trough (AM pre-dose) IC
Inspiratory capacity will be obtained via spirometry. At least 3 acceptable IC
measurements will be obtained with the 2 largest ICs within 150 mLs of each other. The
largest of 3 acceptable ICs will be recorded. A full description of the procedures for
obtaining IC is providing in the SPM.
6.2.4.4.
Modified Medical Research Council (MMRC) Dyspnea Scale
Assessment of the general perception of breathlessness will be made using the MMRC
dyspnea scale (See the SPM for details). Dyspnea score will be assessed at Visit 2 and a
score of ≥ 2 is required. Subjects who do not meet this criterion at Visit 2 will not be
eligible for randomization into the study.
6.2.4.5.
Diary Card Assessments
Subjects will be instructed to record on diary cards:
•
Daily records of supplemental albuterol use as number of puffs from the MDI or
number of nebules used.
•
Daily use of blinded study drug as number of inhalations from the DISKUS and
daily use of open-label tiotropium as number of inhalations from the HandiHaler
•
Any medical problems the subject may have experienced and any medications used
to treat those medical problems
Subjects will be instructed to return completed diary cards at each clinic visit. The study
coordinator must review the diary cards at each clinic visit for completeness and
consistency with subject-reported AEs. Signs and symptoms of COPD included on the
diary cards will not be considered AEs and will not be recorded in the eCRF.
6.2.4.6.
COPD Exacerbations
Worsening symptoms of COPD should be treated as deemed necessary by the study
investigator. However, use of prohibited medications (Section 5.6.2) for the treatment of
COPD exacerbations may result in subject withdrawal. If a prohibited medication is used
for the treatment of a COPD exacerbation, the study sponsor/site monitor must be
contacted to discuss subject eligibility for continued participation in the study.
A COPD exacerbation is defined as ‘an event in the natural course of the disease
characterized by a change in the patient’s baseline dyspnea, cough, and/or sputum that is
beyond normal day-to-day variations, is acute in onset, and may warrant a change in
regular medication in a patient with underlying COPD” [GOLD, 2007]. For this study,
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COPD exacerbations will be recorded as AEs. Subjects will be instructed to contact the
Investigator if they have worsening symptoms of COPD. COPD exacerbations will be
categorized by the number of health care utilizations [i.e., physician office visits,
emergency room visits, and/or hospitalizations] for acute increased symptoms of COPD.
At each visit, the study coordinator will ask the patient if any such visits have occurred (if
the visit for worsening symptoms did not occur at the Investigative site), record the
symptom(s) that led to the exacerbation, record any changes in medication, and record if
the subject was hospitalized for worsening COPD symptoms in the eCRF.
During run-in, subjects who experience a COPD exacerbation requiring treatment with
systemic corticosteroids and/or antibiotics will be discontinued from the study and may
be re-screened with the approval of GSK or designee.
6.2.4.7.
Guidelines for Treatment with Corticosteroids
If in the opinion of the investigator/treating physician the exacerbation is severe enough
to warrant the need for systemic corticosteroids (with or without antibiotics) the
following guidelines should be used.
•
The duration of treatment with corticosteroids should be no longer than 10
consecutive days (dose and type according to local practice)
6.2.4.8.
Guidelines for Treatment with Antibiotics
If there is evidence of respiratory infection that in the opinion of the investigator or
treating physician warrants the need for antibiotics the following guidelines should be
followed:
•
The duration of treatment with antibiotics should be no longer than 10 days (dose
and type according to local practice).
Use of antibiotics for the treatment of upper or lower respiratory tract infections is not
considered a COPD exacerbation unless the subject experiences worsening symptoms of
COPD.
6.3.
Safety
Study safety will be assessed by adverse events and type and incidence of pneumonia.
Pneumonia diagnosis must be confirmed by chest X-ray. Confirmed diagnoses of
pneumonia must be recorded as AEs or SAEs if the pneumonia meets the criteria of an
SAE (See Section 6.3.1.2).
Information regarding chest X-ray confirmed cases of pneumonia will be recorded in the
eCRF. Details regarding the information to be captured for pneumonias are provided in
the SPM.
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Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting
events that meet the definition of an AE or SAE.
6.3.1.1.
Definition of an AE
Any untoward medical occurrence in a patient or clinical investigation subject,
temporally associated with the use of a medicinal product, whether or not considered
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of a medicinal product. For marketed medicinal products, this
also includes failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.
6.3.1.2.
Definition of an SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in
which the subject was at risk of death at the time of the event. It does not refer to an
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the subject has been detained
(usually involving at least an overnight stay) at the hospital or emergency ward for
observation and/or treatment that would not have been appropriate in the physician’s
office or out-patient setting. Complications that occur during hospitalization are
AEs. If a complication prolongs hospitalization or fulfills any other serious criteria,
the event is serious. When in doubt as to whether “hospitalization” occurred or was
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen
from baseline is not considered an AE.
d.
Results in disability/incapacity, or
NOTE: The term disability means a substantial disruption of a person’s ability to
conduct normal life functions. This definition is not intended to include experiences
of relatively minor medical significance such as uncomplicated headache, nausea,
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may
interfere or prevent everyday life functions but do not constitute a substantial
disruption.
e.
Is a congenital anomaly/birth defect
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Medical or scientific judgement should be exercised in deciding whether reporting is
appropriate in other situations, such as important medical events that may not be
immediately life-threatening or result in death or hospitalization but may jeopardize
the subject or may require medical or surgical intervention to prevent one of the
other outcomes listed in the above definition. These should also be considered
serious. Examples of such events are invasive or malignant cancers, intensive
treatment in an emergency room or at home for allergic bronchospasm, blood
dyscrasias or convulsions that do not result in hospitalization, or development of
drug dependency or drug abuse.
6.3.2.
Safety Assessment Abnormalities Reported as AEs and SAEs
Safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including
those that worsen from baseline, and felt to be clinically significant in the medical and
scientific judgement of the investigator are to be recorded as AEs or SAEs. However,
any clinically significant safety assessments that are associated with the underlying
disease, unless judged by the investigator to be more severe than expected for the
subject’s condition, are not to be reported as AEs or SAEs.
6.3.3.
Disease-Related Events and/or Disease-Related Outcomes Not
Qualifying as SAEs
There are no disease-related events and/or disease-related outcomes in this study that do
not qualify as SAEs.
6.3.4.
Time Period and Frequency of Detecting AEs and SAEs
From the time a subject consents to participate in and completes the study (including any
follow-up period), all SAEs will be reported promptly to GSK. All AEs will be collected
from Visit 1 (Screening) until completion of the follow-up phone contact.
6.3.5.
Pneumonia
Pneumonia diagnosis must be confirmed by chest X-ray. Confirmed diagnoses of
pneumonia must be recorded as AEs.
Information regarding chest X-ray confirmed cases on pneumonia will be recorded in the
eCRF. Details regarding the information to be captured for pneumonias are provided in
the SPM.
6.3.6.
Pregnancy
Any pregnancy that occurs during study participation must be reported using a clinical
trial pregnancy form. To ensure subject safety, each pregnancy must be reported to GSK
within 2 weeks of learning of its occurrence. The pregnancy must be followed up to
determine outcome (including premature termination) and status of mother and child.
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Pregnancy complications, and elective terminations for medical reasons must be reported
as an AE or SAE. Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigator’s
attention after the subject has completed the study and considered by the investigator as
possibly related to the investigational product, must be promptly reported to GSK.
In addition, the investigator must attempt to collect pregnancy information on any female
partners of male study subjects who become pregnant while the subject is enrolled in the
study. Pregnancy information must be reported to GSK as described above.
6.3.7.
Medical Devices
No medical devices are being provided by GSK for use in this study.
6.3.8.
Prompt Reporting of Serious Adverse Events and Other Events
to GSK
SAEs, pregnancies, medical device incidents and near-incidents, and liver function
abnormalities meeting pre-defined criteria will be reported promptly to GSK as described
in the following table once the investigator determines that the event meets the protocol
definition for that event.
Initial Reports
Type of Event
All SAEs
Time Frame
24 hours
Pregnancy
2 Weeks
Documents
“SAE” data
collection tool
Pregnancy Form
Follow-up Information on a
Previous Report
Time Frame
Documents
24 hours
Updated “SAE”
data collection tool
2 Weeks
Updated
Pregnancy Form
The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus
procedures for completing and transmitting SAE reports to GSK are provided in the
SPM. Procedures for post-study AEs/SAEs are provided in the SPM.
6.4.
Health Outcomes
6.4.1.
Summary Assessment of CRQ-SAS
The CRQ-SAS will be completed by the subject at Visits 2, 4, 6, and premature
discontinuation. The CRQ-SAS includes 20 items across four domains: dyspnea (5
items), fatigue (4 items), emotional function (7 items), and mastery (4 items). When
completing this instrument, subjects rate their experience on a 7-point scale ranging from
1 (maximum impairment) to 7 (no impairment). The CRQ-SAS should be administered
before any other study procedures are performed (including concomitant medication
assessment or AE assessment, etc.) at visits in which the CRQ-SAS is performed. The
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CRQ-SAS has demonstrated excellent measurement properties for both discriminative
and evaluative purposes and served as a model in numerous methodological studies in
chronic airflow limitation and COPD [Schumemann, 2005]. Each domain will be treated
as an individual score as part of a larger domain of “quality of life”. A full description of
the CRQ-SAS is provided in the SPM.
6.4.2.
Summary Assessment of the QIDS-SR
The QIDS-SR will be completed by the subject at Visits 2, 4, 6, and premature
discontinuation. This is a 16 item test that measures 9 different criterion domains of
major depression and was derived from the long form (30 item test) of the Inventory of
Depression Symptomatology (IDS). The QIDS-SR has been shown to be sensitive to
treatment measures of symptom severity in depressed patients [Trivedi, 2004].
Furthermore, the QIDS-SR total scores are highly correlated with and as sensitive to
change as the IDS and the Hamilton Depression Rating Scale (HAM-D) [Rush, 2003]. A
full description of the QIDS is provided in the SPM.
6.4.3.
Summary Assessment of the Hospital Anxiety and Depression
Scale (HADS)
The HADS will be completed by the subject at Visits 2, 4, 6, and premature
discontinuation. A full description of this scale is provided in the SPM.
6.5.
Pharmacogenetics
Information regarding pharmacogenetic research is included in Appendix 1. The
IEC/IRB and, where required, the applicable regulatory agency must approve the PGx
assessments before these can be conducted at the site. The approval(s) must be in writing
and will clearly specify approval of the PGx assessments (i.e., approval of Appendix 1).
In some cases, approval of the PGx assessments can occur after approval is obtained for
the rest of the study. If so, then the written approval will clearly indicate approval of the
PGx assessments is being deferred and in most cases, the study, except for PGx
assessments, can be initiated. When PGx assessments will not be approved, then the
approval for the rest of the study will clearly indicate this and therefore, PGx assessments
will not be conducted.
7.
DATA MANAGEMENT
Data Management will identify and implement the most effective data acquisition and
management strategy for each clinical trial protocol and deliver datasets which support
the protocol objectives.
For this study subject data will be entered into GSK defined electronic Case Report
Forms (eCRFs), transmitted electronically to GSK and combined with data provided from
other sources (e.g., diary data) in a validated data system.
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Clinical data management will be performed in accordance with applicable GSK
standards and data cleaning procedures with the objective of removing errors and
inconsistencies in the data which would otherwise impact on the analysis and reporting
objectives, or the credibility of the Clinical Study Report. Adverse events and
concomitant medications terms will be coded using Medical Dictionary for Regulatory
Activities (MedDRA) and GSKDrug, internal validated dictionaries. eCRFs will be
retained by GSK, while copies of eCRFs (including queries and audit trails) will be sent
to the investigator for retention at the site. In all cases, subject initials will not be
collected nor transmitted to GSK.
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
The null hypothesis for this study is that there is no difference between FSC250/50 plus
tiotropium and tiotropium in AM pre-dose FEV1 change from baseline. The alternative
hypothesis is that there is a difference between FSC250/50 plus tiotropium and
tiotropium in AM pre-dose FEV1 change from baseline. The study is designed to show
superiority.
8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
Data from a 24-week GSK COPD study (SFCA3007) indicate that a reasonable estimate
of the standard deviation of change in AM pre-dose FEV1 is 0.250 L. It is estimated that
133 subjects per treatment group will provide 90% power for detection of a significant
difference of 0.100 L in pre-dose FEV1 change from baseline at Endpoint between the
two treatment groups based on a two-sample two-sided t-test with a significance level of
0.05. Approximately 350 subjects will be randomized to allow for a 30% study
withdrawal rate.
8.2.2.
Sample Size Sensitivity
The sensitivity of the sample size calculation has been considered in order to assess the
impact on the power of the study should the observed standard deviation for AM pre-dose
FEV1 be higher or should the observed treatment difference for AM pre-dose FEV1 be
lower than expected. Given the sample size of 133 subjects per treatment group and the
estimated difference between the treatment groups of 0.100 L in AM pre-dose FEV1, the
study would have ≥80% power if the standard deviation is 0.290 L or less. Alternatively,
given the sample size of 133 subjects per treatment group and estimated standard
deviation of 0.250 L, the study would have ≥80% power if the treatment difference is
0.086 L or more.
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Sample Size Re-estimation
No sample size re-estimation is planned for this study.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
The analysis population for this study is the Intent-to-Treat (ITT) population. The ITT
population will include all subjects randomized to study drug.
8.3.2.
Analysis Data Sets
Data collected to the time of study discontinuation for subjects who withdraw from the
study prematurely will be included in analysis. Efficacy data collected during a clinic
visit will be reported by visit at which the data are collected. No interpolation of missing
data is planned.
8.3.3.
Treatment Comparisons
8.3.3.1.
Primary Comparisons of Interest
The primary comparison of interest in this study is the treatment comparison of
FSC250/50 plus tiotropium and tiotropium.
8.3.3.2.
Other Comparisons of Interest
There is one primary efficacy measure analysis for this study with all secondary efficacy
measure and other efficacy measure analyses considered supportive. Statistical tests of
all efficacy measures will be two-sided alternative hypothesis tests conducted at the 0.05
significance level. Overall Type I error rate for the secondary efficacy measures will be
managed using Hochberg adjusted p-values. Other efficacy measures are nested under
secondary efficacy measures. Each secondary efficacy measure will serve as a
gatekeeper for its nested measure. A single primary analysis of each efficacy measure is
defined with comparisons at other time points to be interpreted as supporting.
8.3.4.
Interim Analysis
An interim analysis is not planned for this study.
8.3.5.
Key Elements of Analysis Plan
8.3.5.1.
Efficacy Analyses
The primary efficacy measure is AM pre-dose FEV1 at Endpoint. Mean change from
baseline values will be compared between treatment groups at Endpoint using analysis of
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covariance (ANCOVA) with terms for treatment, investigator, reversibility stratum and
baseline in the model. Endpoint will be defined as the last scheduled measurement of
pre-dose FEV1 during the 24-week treatment period and baseline will be defined as the
pre-dose FEV1 measure from Visit 2 (Randomization). The secondary efficacy measures
of 2 hour post-dose FEV1 and FVC and pre-dose FVC and IC will be compared between
treatment groups in the same manner as pre-dose FEV1. Health-related quality of life
will be assessed through the subject-completed CRQ-SAS which is another secondary
efficacy measure for this study. Scoring of the questionnaire will be conducted per the
developers’ scoring guidelines. Change from baseline values will be compared between
treatment groups with an ANCOVA model that includes terms for treatment group,
investigator, reversibility stratum and baseline score. The primary analysis will be the
total score compared between treatment groups at Endpoint, defined from the last
questionnaire collected during the 24-week treatment period or at the early withdrawal
visit.
Other efficacy measures are supplemental albuterol use and rate of HCU for COPD
exacerbations. Treatment comparisons for supplemental albuterol use mean change from
baseline values will be based on ANCOVA models that include terms for treatment,
investigator, reversibility stratum and baseline. The primary analysis will be at Endpoint.
Supplemental albuterol use will be analyzed as the number of puffs taken per day.
Healthcare utilization for COPD exacerbations will be summarized by treatment group in
terms of use of systemic corticosteroids and/or antibiotics, the number of healthcare
contacts (unscheduled or urgent care physician /clinic office visits, and/or emergency
room visits) or number of hospitalizations. Rate of HCU for COPD exacerbations will be
compared between treatment groups using a negative binomial regression model with
terms for treatment, investigator, reversibility stratum, and baseline severity.
Supplemental albuterol use and rate of HCU will be nested under the secondary efficacy
measure of pre-dose IC.
Exploratory measures are the QIDS-SR and the HADS. Scoring of these scales will be
conducted per the developers’ guidelines. Scores and change from baseline values will
be summarized and compared between treatment groups with an ANCOVA model that
includes terms for treatment group, investigator, reversibility stratum and baseline score.
Exploratory analyses will be conducted for subjects meeting depression and anxiety
criteria as determined by the QIDS-SR scale and HADS, respectively.
8.3.5.2.
Safety Analyses
The proportion of subjects reporting AEs will be tabulated by treatment group by
MedDRA system organ class and preferred term. All AEs occurring during the study,
AEs leading to study withdrawal, drug-related AEs and SAEs will be summarized.
Adverse events will be reported by study treatment period (during run-in, during
treatment, post-treatment). Pneumonia adverse events and x-ray findings will also be
summarized by treatment group.
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9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Regulatory and Ethical Considerations, Including the
Informed Consent Process
Prior to initiation of a study site, GSK will obtain approval from the appropriate
regulatory agency to conduct the study in accordance with applicable country-specific
regulatory requirements, including those required under a US IND.
The study will be conducted in accordance with all applicable regulatory requirements,
including an U.S. IND 50,703 for ADVAIR DISKUS.
The study will be conducted in accordance with Good Clinical Practice (GCP), all
applicable subject privacy requirements, and the guiding principles of the declaration of
Helsinki, including, but not limited to:
•
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and
approval of study protocol and any subsequent amendments.
•
Subject informed consent.
•
Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the
study.
9.2.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors
will contact the site prior to the start of the study to review with the site staff the protocol,
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK
requirements. When reviewing data collection procedures, the discussion will include
identification, agreement and documentation of data items for which the CRF will serve
as the source document.
GSK will monitor the study to ensure that the:
•
Data are authentic, accurate, and complete.
•
Safety and rights of subjects are being protected.
•
Study is conducted in accordance with the currently approved protocol and any other
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to
allow the monitor direct access to all relevant documents
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Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may
conduct a quality assurance audit of the site records, and the regulatory agencies may
conduct a regulatory inspection at any time during or after completion of the study. In the
event of an audit or inspection, the investigator (and institution) must agree to grant the
auditor(s) and inspector(s) direct access to all relevant documents and to allocate their
time and the time of their staff to discuss any findings/relevant issues.
9.4.
Study and Site Closure
Upon completion or termination of the study, the GSK monitor will conduct site closure
activities with the investigator or site staff (as appropriate), in accordance with applicable
regulations, GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for
reasons including (but not limited to) safety issues, ethical issues, or severe noncompliance. If GSK determines that such action is required, GSK will discuss the
reasons for taking such action with the investigator or head of the medical institution
(where applicable). When feasible, GSK will provide advance notice to the investigator
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all
investigators, heads of the medical institutions (where applicable),and/or institutions
conducting the study. GSK will also promptly inform the relevant regulatory authorities
of the suspension/termination along with the reasons for such action. Where required by
applicable regulations, the investigator or head of the medical institution must inform the
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
9.5.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where
applicable) must maintain all site study records (except for those required by local
regulations to be maintained elsewhere) in a safe and secure location. The records must
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and
must be available for review in conjunction with assessment of the facility, supporting
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the
records may be maintained in a format other than hard copy (e.g., microfiche, scanned,
electronic); however, caution must be exercised before such action is taken. The
investigator must ensure that all reproductions are legible and are a true and accurate
copy of the original. In addition, they must meet accessibility and retrieval standards,
including regeneration of a hard copy, if required. The investigator must also ensure that
an acceptable back-up of the reproductions exists and that there is an acceptable quality
control procedure in place for creating the reproductions.
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GSK will inform the investigator of the time period for retaining the site records in order
to comply with all applicable regulatory requirements. The minimum retention time will
meet the strictest standard applicable to a particular site, as dictated by local
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including,
but not limited to archival of records at an off-site facility or transfer of ownership of the
records in the event that the investigator is no longer associated with the site.
9.6.
Provision of Study Results and Information to Investigators
Where required by applicable regulatory requirements, an investigator signatory will be
identified for the approval of the clinical study report. The investigator will be provided
reasonable access to statistical tables, figures, and relevant reports and will have the
opportunity to review the complete study results at a GSK site or other mutuallyagreeable location.
Upon completion of the clinical study report, GSK will provide the investigator with the
full summary of the study results. The investigator is encouraged to share the summary
results with the study subjects, as appropriate.
GSK will provide the investigator with the randomization codes for their site only after
completion of the full statistical analysis.
9.7.
Independent Data Monitoring Committee (IDMC)
There will be no IDMC for this study.
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REFERENCES
Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M,
O'Donnell D, Mclvor A, Sharma S, Bishop G, Anthony J, Cowie R, field S, Hirsch A,
Hernandez P, Rivington R, Road J, Hoffstein V, Hodder R, Marciniuk D, McCormack D,
Fox G, Cox G, Prins HB, Ford G, Bleskie D, Doucette S, Mayers I, Chapman K, Zamel
N, FitzGerald M, for the Canadian Thoracic Society/Canadian Respiratory Clinical
Research Consortium. Tiotropium in Combination with Placebo, Salmeterol, or
Fluticasone-Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease. Ann Int
Med. 2007;146:545-555.
Andersson F, Borg S, Jansson SA, Jonsson AC, Ericsson A, Prutz C, Ronmark E,
Lundback B. The Costs of Exacerbations in Chronic Obstructive Pulmonary Disease.
Repir Med. 2002;96:700-708.
Anzueto A. Clinical Course of Chronic Obstructive Pulmonary Disease: Review of
Therapeutic Interventions. Am. J. Med. 2006;119:S46-S53.
Borson S, McDonald GJ, Gayle T, Deffebach M, Lakshminarayan S, VanTuinen C.
Improvement in Mood, Physical Symptoms, and Function with Nortriptyline for
Depression in Patients with Chronic Obstructive Pulmonary Disease. Psychosomatics.
1992;33:190-201.
Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C.
Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary
disease: a randomized controlled trial. Lancet. 2003;361:449-456.
Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates J,
Vestbo J, for the TORCH Investigators. Salmeterol and Fluticasone Propionate and
Survival in Chronic Obstructive Pulmonary Disease. New Engl J Med. 2007;356:775789.
Casaburi R, Mahler DA, Jones PW, Wanner A, San Pedro GS, ZuWallack RL, Menjoge
SS, Serby CW, Witek Jr T. A Long-Term Evaluation of Once-Daily Inhaled Tiotropium
in Chronic Obstructive Pulmonary Disease. Eru Respir J. 2002;19:217-224.
Cazzola M, Ando F, Santus P, Ruggeri P, Di Marco F, Sanduzzi A, D'Amato M. A pilot
study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium
on the airflow obstruction of patients with severe-to-very severe COPD. Pulm.
Pharmacol. Ther. 2007;20:556-561.
Celli BR, MacNee W, ATS/ERS Task Force. Standards for the Diagnosis and Treatment
of Patients with COPD: A Summary of the ATS/ERS Position Paper. Eur Respir J.
2004;23:932-946.
Diaz PD, Montes de Oca M, Lopez JM, Celli BR. Pulmonary Rehabilitation Improves
Depression, Anxiety, Dyspnea, and Health Status in Patients with COPD. Am J Phys Med
Rehabil. 2007;86:30-36.
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GlaxoSmithKline Document Number RM2006/00845/00 Study ID SCO40043. A
randomized, double-blind, parallel-group, 52-week study to compare the effect of
fluticasone propionate/salmeterol DISKUS 250/50mcg BID with salmeterol DISKUS
50mcg BID on the annual rate of moderate/severe exacerbations in subjects with chronic
obstructive pulmonary disease. Report Date 03-May-2007.
GlaxoSmithKline Document Number RM2007/00469/00 Study ID SCO100250. A
randomized, double-blind, parallel-group, 52-week study to compare the effect of
fluticasone propionate/salmeterol DISKUS 250/50mcg BID with salmeterol DISKUS
50mcg BID on the annual rate of moderate/severe exacerbations in subjects with chronic
obstructive pulmonary disease. Report Date 11-Sep-2007.
GOLD (Global Strategy for the Diagnosis, Management, and Prevention of COPD,
Global Initiative for Chronic Obstructive Lung Disease), 2007. Available from
http://www.goldcopd.org.
Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, Shah T. The Efficacy
and Safety of Fluticasone Propionate (250mcg)/Salmeterol(50mcg) Combined in the
DISKUS Inhaler for the Treatment of COPD. Chest. 2003;124:834-843.
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric Reference Values from a Sample
of the General U.S. Population. Am J Respir Crit Care Med. 1999;159:179-187.
Katon W, Lin EHB, Kroenke K. The Association of Depression and Anxiety with
Medical Symptom Burden in Patients with Chronic Medical Illness. Gen Hosp Psych.
2007;29:147-155.
Mahler DA, Wire P, Horstmann D, Chang CN, Yates J, Fischer T, Shah T. Effectiveness
of Fluticasone Propionate and Salmeterol Combination Delivered via the Diskus Device
in the Treatment of Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med.
2002;166:1084-1091.
Mannino DM, Braman S. The Epidemiology and Economics of Chronic Obstructive
Pulmonary Disease. Proc Am Throac Soc. 2007;4:502-506.
Miller MR, Hankinson J, Brusasco V, Burgos R, Casaburi R. Standardisation for
spirometry. Eru Respir J. 2005;26:319-338.
Ng TP, Niti M, Tan WC, Cao Z, Ong KC, Eng P. Depressive Symptoms and Chronic
Obstructive Pulmonary Disease: Effect on Mortality, Hosptial Readmission, Symptom
Burden, Functional Status, and Quality of Life. Arch Intern Med. 2007;167:60-67.
Niewoehner DE, Rice K, Cote C, Paulson D, Cooper Jr A, Korducki L, cassino C, Kesten
S. Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with
Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator. Ann Int Med.
2005;143:317-326.
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Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Dlein DN, Markowitz JC,
Ninan PT, Kornstein S, Manber R, Thase ME, Kocsis JH, Keller MB. The 16-Item Quick
Invesntory of Depressive Symptomatology (QIDS), Clinician Rating (QIDS-C), and SelfReport (QIDS-SR): A Psychometric Evaluation in Patients with Chronic Major
Depression. Biol Psychiatry. 2003;54:573-583.
Schumemann JH, Puhan M, Goldstein R, Jaeschke R, Guyatt GH. Measurement
properties and interpretibility of the Chronic Respiratory Questionnaire (CRQ). J COPD.
2005; 2:81-89.
Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of
Exacerbation on Quality of Life in Patients with Chronic Obstructive Pulmonary Disease.
Respir Crit Care Med. 1998:157;157:1418-1422.
Singh D, Brooks J, Hagan G, cahn T, O'Connor B. Triple therapy with
salmeterol/fluticasone propionate and tiotropium bromide versus individual components
in moderate to severe COPD. Thorax.
2008:http://thorax.bmj.com/cgi/content/abstract/thx.2007.087213v1.
Spiriva (Tiotropium Bromide Inhalation Powder) Product Information. August, 2007.
Trivedi MH, Rush AJ, Ibrahim HM, Carmody TJ, Biggs MM, Suppes T, Crismon ML,
Shores-Wilson K, Toprac MG, Dennehy EB, Witte B, Kashner TM. The Inventory of
Depressive Symptomatology, Clinician Rating (IDS-C), and Self-Report (IDS-SR), and
the Quick Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and
Self-Report (QIDS-SR) in Public Sector Patients with Mood Disorders: A Psychometric
Evaluation. Psychol Med. 2004;34:73-82.
Urbano FL, Pascual RM. Contemporary Issues in the Care of Patients with Chronic
Obstructive Pulmonary Disease. J. Manag Care Pharm. 2005;11 (suppl):S2-S13.
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11.
APPENDICES
11.1.
Appendix 1: PGx
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Pharmacogenetic Research
Pharmacogenetics - Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary
factors in different populations. There is increasing evidence that an individual's genetic
composition (i.e., genotype) may impact the pharmacokinetics (absorption, distribution,
metabolism, elimination), pharmacodynamics (relationship between concentrations and
pharmacologic effects or the time course of pharmacologic effects) and/or clinical
outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of
PGx analysis include:
Drug
Abacavir
Tranilast
ABT-761
Disease
HIV
[Hetherington,
2002; Mallal,
2002]
Restenosis
prevention
following
coronary bypass
[Roses, 2002]
Asthma [Drazen,
1999]
Gene
HLA (human
leukocyte
antigen)
Outcome
Caucasian males with HLA B57 variant were
at increased risk for experiencing
hypersensitivity to abacavir
UGT1A1
Drug induced hyperbilirubinemia explained
by high proportion of affected patients
having 7/7 TA repeat genotype, consistent
with clinically benign Gilbert’s Syndrome
ALOX5
ALOX5 Sp1 promoter genotype (x,x)
associated with reduced response to 5lipoxygenase inhibitor ABT-761
A key component to successful PGx research is the collection of samples during the
conduct of clinical studies.
Collection of samples, even when no a priory hypothesis has been identified, may enable
PGx analysis to be conducted if at any time it appears that there is a potential unexpected
or unexplained variation in handling or response to FSC and/or tiotropium.
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained
variation) is to investigate a possible genetic relationship to handling or response to FSC
and/or tiotropium. If at any time it appears there is potential variability in response in
this clinical study or in a series of clinical studies with FSC that may be attributable to
genetic variations of subjects, the following objectives may be investigated:
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•
Relationship between genetic variants and the pharmacokinetics of investigational
product
•
Relationship between genetic variants and safety and/or tolerability of investigational
product
•
Relationship between genetic variants and efficacy of investigational product
Study Population
Any subject who has given informed consent to participate in the clinical study, has met
all the entry criteria for the clinical study, and receives investigational product may take
part in the PGx research. Any subject who has received an allogeneic bone marrow
transplant must be excluded from the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not
indicate withdrawal from the clinical study. Refusal to participate will involve no
penalty or loss of benefits to which the subject would otherwise be entitled.
Study Assessments and Procedures
No blood sample will be necessary for the pharmacogenetic analysis. DNA will be extracted
from cells obtained from the subject’s saliva. Saliva (2ml) is spit into the DNA self-collection
kit. A single sample will be taken but can be duplicated if the first sample is unusable. It
is recommended that the saliva sample be collected as soon as practical after
randomization although it can be collected at any time during study participation
The PGx sample is labelled (or “coded”) with a study specific number that can be traced or
linked back to the subject by the investigator or site staff. Coded samples do not carry
personal identifiers (such as name or social security number). The saliva sample will be
taken on a single occasion unless a duplicate sample is required due to inability to utilize the
original sample.
If deoxyribonucleic acid (DNA) is extracted from the saliva sample, the DNA may be
subjected to sample quality control analysis. This analysis will involve the genotyping of
several genetic markers to confirm the integrity of individual samples. The sample may
be destroyed if inconsistencies are noted in the analysis.
The need to conduct PGx analysis may be identified after a study (or set of studies) of the
investigational product has been completed and the study data reviewed. For this reason,
samples may be kept for up to 15 years after the last subject completes the study unless
GSK destroys the samples earlier. In special cases, the samples may not be studied. This
might happen if there are not enough subjects, if the study is stopped for other reasons, or
if no questions arise concerning response to the investigational product. GSK or those
working with GSK (for example, other researchers) will analyse these samples only as
stated in the protocol and in the informed consent form. Samples will be stored securely.
Subjects can request destruction of their sample at any time.
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Subject Withdrawal from Study
If a subject who has consented to participate in PGx research and has a sample taken for
PGx research withdraws from the clinical study for any reason other than lost to followup, the subject will be given the following options:
1.
The sample is retained for PGx research
2.
Any PGx sample is destroyed
If a subject withdraws consent from the PGx research or requests sample destruction for
any reason, the investigator must complete the appropriate documentation to request
sample destruction within the timeframe specified by GSK and maintain the
documentation in the site study records. In either case, GSK will only use study
information collected/generated up to that point.
Screen and Baseline Failures
If a saliva sample for PGx research has been collected and it is determined that the
subject does not meet the entry criteria for participation in the clinical study, then the
investigator must complete the appropriate documentation to request sample destruction
within the timeframe specified by GSK and maintain the documentation in the site study
records.
Pharmacogenetics Analyses
Generally GSK will utilize two approaches to explore genetic variation in drug response.
1. Specific sections of DNA may be selected from areas of the genome (e.g., candidate
genes) known to encode the drug target, drug metabolizing enzymes, areas associated
with mechanisms underlying adverse events, and those linked to study disease and,
thus, linked to drug response. The candidate genes that may be investigated in this
study will include the following: the GSK Absorption, Distribution, Metabolism and
Excretion (ADME) panel. Absorption, distribution, metabolism and excretion
(ADME) genes play a central role in drug pharmacokinetics and pharmacodynamics
(PK-PD). The GSK ADME panel contains genetic markers from one hundred and
thirty-five enzymes, transporters and other genes involved in drug absorption,
distribution, metabolism and excretion. The ADME panel may be used to investigate
the relationship between genetic variants on the panel and pharmacokinetics, safety
and efficacy of the investigational product.
2. By evaluating large numbers of polymorphic markers (e.g., single nucleotide
polymorphisms or SNPs) throughout the genome, sets of markers may be identified
that correspond to differential drug response. These will include:
Hardy-Weinberg Equilibrium testing.
The genotypic frequencies of each polymorphism will be evaluated for conformity to
those expected under normal conditions by employing Hardy-Weinberg Equilibrium
testing.
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Comparison of Demographic and Baseline Characteristics by Genotype
Differences in baseline clinical characteristics and potential contributing covariates may
be summarized and compared among genotype (or haplotype) subgroups.
Evaluation of Genotypic Effects
Analyses may be carried out to evaluate the degree of association between subject
genotype (or haplotype) and selected parameters (e.g., pharmacokinetics, efficacy and
safety). Where such genotypic tests are inappropriate (for example, where the number of
marker genotypes is too large and/or the frequency of individual genotypes too small),
allelic tests may be conducted. Allelic tests evaluate whether the frequency of each
marker allele is the same in responders and non-responders.
Evaluation of Treatment by Genotype and Gene-Gene Interaction
In addition to evaluating the main effects of the genotypes (haplotypes or alleles) on the
selected parameters, the possibility of a treatment group by genotype (haplotype or allele)
interaction will also be explored. If appropriate, the joint effects of multiple markers
(gene-gene interactions) may also be evaluated.
Linkage Disequilibrium
For pairs of polymorphisms, the degree to which alleles from the two sites are correlated
(linkage disequilibrium) may also be evaluated. If the genotypes at two polymorphic
sites within a gene are shown to be statistically associated with a response to
investigational product, the degree of linkage disequilibrium will aid interpretation in that
it will indicate the extent to which the two sites are exerting independent effects.
Multiple Comparisons and Multiplicity
Adjustment to observed p-values may be made to limit erroneous conclusions due to
multiple tests when multiple markers are evaluated (especially in the case of a genome
scan for association).
Power and Sample Size Considerations
The ability to detect differential drug response among genotypes at a polymorphic site
depends on the total number of subjects genotyped and the frequency distribution of the
different genotypes. Consequently, genotyping analyses are plausible for those
polymorphic sites where the number of subjects comprising the genotypic groups is
sufficiently large; however, these frequencies will not be known until sufficient samples
have been collected and genotyping is complete.
Estimates of sample sizes required to demonstrate genotype effects vary considerably,
depending on the assumptions made about allele frequency, genetic effect size, and
mechanism of inheritance [Cardon, 2000]. In the work by Palmer and Cookson [Palmer,
2001], which assumed a genotype relative risk of 1.5, it was estimated that more than 300
cases and 600 controls would be needed to conduct a genetic association analysis. In
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contrast, McCarthy and Hilfiker [McCarthy, 2000] showed that with a genotype relative
risk of 2.16 and a relatively commonly occurring genotype, only 30 cases and 30 controls
would be needed to demonstrate an association.
Published PGx examples include abacavir hypersensitivity reaction [Hetherington, 2002;
Mallal, 2002] and tranilast induced hyperbilirubinemia [Roses, 2002] where genetic
markers have been found to significantly associate with hypersensitivity reaction
(abacavir) and hyperbilirubinemia (tranilast). These examples show that small sample
sizes typically encountered in Phase I and Phase II studies may be sufficient to identify
clinically relevant genetic associations.
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the
clinical study. PGx informed consent must be obtained prior to any sample being taken
for PGx research.
Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarize the cumulative PGx research results in the clinical study report. In
general, GSK does not inform the investigator, subject or anyone else (e.g., family
members, study investigators, primary care physicians, insurers, or employers) of the
PGx research results because the information generated from PGx studies is preliminary
in nature, and the significance and scientific validity of the results are undetermined at
such an early stage of research, under any circumstance unless required by law.
References
Cardon LR, Idury RM, Harris TJR, Witte JS, Elston RC. Testing drug response in the
presence of genetic information: sampling issues for clinical trials. Pharmacogenetics.
2000; 10:503-10.
Drazen JM, Yandava CN, Dube L, Szcerback N, Hippensteel R, Pillari A, Israel E,
Schork N, Silverman ES, Katz DA, Drajesk J. Pharmacogenetic association between
ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet.
1999; 22:168-70.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E,
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir.
Lancet. 2002; 359:1121-2.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte
C, Maxwell D, James I. Association between presence of HLA-B*5701, HLA-DR7, and
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.
Lancet. 2002; 359:727-32.
McCarthy JJ, Hilfiker R. The use of single-nucleotide polymorphism maps in
pharmacogenomics. Nat Biotechnol. 2000; 18:505-8.
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Palmer LJ, Cookson WO. Using single nucleotide polymorphisms as a means to
understanding the pathophysiology of asthma. Respir Res. 2001; 2:102-12.
Roses AD. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev
Drug Discov. 2002; 1:541-9.
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Appendix 2: Country Specific Requirements
Since this study will be conducted in the US only, there are no specific country
requirements.
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The GlaxoSmithKline group of companies
RM2009/00553/00
ADC111114
Division: World Wide Development
Retention Category: GRS019
Information Type: Reporting and Analysis Plan
Title:
Reporting and Analysis Plan for ADC111114: A Randomized,
Double-Blind, Parallel-Group, 24-Week Study to Evaluate the
Efficacy and Safety of ADVAIR DISKUS (Fluticasone
Propionate/Salmeterol Combination Product 250/50mcg
Inhalation Powder) BID Plus Spiriva HandiHaler (Tiotropium
Bromide Inhalation Powder 18mcg) QD Versus Spiriva QD Plus
Placebo DISKUS BID in Subjects with Chronic Obstructive
Pulmonary Disease (COPD)
Compound Number: CCI18781+GR33343
Effective Date:
22-DEC-2009
Description: This document details the planned statistical analyses for ADC111114 in
support of the clinical study report.
Identifier/Version Number: [RM2009/00553/00]
Subject: ADVAIR DISKUS, Spiriva, COPD, FEV1, Fluticasone Propionate, Salmeterol,
Tiotropium
Author’s Name, Title and Functional Area:
Manager Statistics
and Programming, Respiratory & Immuno-Inflammation Medical Development Center
Approved through email by
Date
Director Clinical Development
Respiratory & Immuno-Inflammation Medical
Development Center
Copyright 2009 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.
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TABLE OF CONTENTS
PAGE
ABBREVIATIONS ...........................................................................................................4 1. INTRODUCTION......................................................................................................5 2. STUDY OBJECTIVE(S) AND ENDPOINT(S) ...........................................................5 2.1. Study Objective(s) ........................................................................................5 2.2. Study Endpoint(s) .........................................................................................5 2.3. Statistical Hypotheses...................................................................................6 3. STUDY DESIGN ......................................................................................................6 4. PLANNED ANALYSES ............................................................................................7 4.1. Interim Analyses ...........................................................................................7 4.2. Final Analysis ...............................................................................................7 5. SAMPLE SIZE CONSIDERATIONS .........................................................................8 5.1. Sample Size Assumptions ............................................................................8 5.2. Sample Size Sensitivity.................................................................................8 5.3. Sample Size Re-estimation...........................................................................8 6. ANALYSIS POPULATIONS .....................................................................................8 7. TREATMENT COMPARISONS................................................................................9 7.1. Data Display Treatment and Other Sub-group Descriptors ...........................9 8. GENERAL CONSIDERATIONS FOR DATA ANALYSES.........................................9 8.1. Multicentre Studies .....................................................................................10 8.2. Other Strata and Covariates .......................................................................10 8.3. Examination of Subgroups..........................................................................10 8.4. Multiple Comparisons and Multiplicity ......................................................... 11 9. DATA HANDLING CONVENTIONS .......................................................................11 9.1. Premature Withdrawal and Missing Data ....................................................11 9.2. Derived and Transformed Data...................................................................11 9.2.1. Treatment Exposure ....................................................................11 9.2.2. COPD Exacerbations...................................................................12 9.2.3. Diary Measures............................................................................12 9.2.4. Subject Rating Scales and Questionnaires ..................................12 9.2.5. Body Mass Index (BMI)................................................................14 9.2.6. FEV1 Calculated Measures ..........................................................14 10. STUDY POPULATION ...........................................................................................14 10.1. Disposition of Subjects................................................................................14 10.2. Protocol Deviations.....................................................................................15 10.3. Demographic and Baseline Characteristics.................................................15 10.4. Treatment Compliance................................................................................16 11. EFFICACY ANALYSES..........................................................................................17 2
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11.1. Primary Efficacy Analysis(es)......................................................................17 11.2. Secondary Efficacy Analysis(es).................................................................17 11.3. Other Efficacy Analysis(es) .........................................................................17 12. SAFETY ANALYSES .............................................................................................19 12.1. Extent of Exposure .....................................................................................19 12.2. Adverse Events...........................................................................................19 12.3. Deaths and Serious Adverse Events........................................................... 20 12.4. Adverse Events Leading to Discontinuation of Investigational
Product and/or Withdrawal from the Study and Other Significant
Adverse Events...........................................................................................20 12.5. Pregnancies (as applicable)........................................................................ 20 13. REFERENCES.......................................................................................................21 14. ATTACHMENTS ....................................................................................................22 14.1. Table of Contents for Data Display Specifications....................................... 22 3
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ABBREVIATIONS
AE
AM
ANCOVA
ATC
BID
BMI
COPD
CRQ-SAS
CSR
eCRF
FEV1
FSC
FVC
GSK
HADS
HARP
HCU
IC
ICH
IDSL
ITT
kg
m
Mcg
MedDRA
mL
MMRC
NHANES
QD
QIDS-SR
RAP
SOC
US
Adverse Event
Morning
Analysis of covariance
Anatomical Therapeutic Chemical
Twice daily
Body Mass Index
Chronic Obstructive Pulmonary Disease
Chronic Respiratory Questionnaire-Self-Administered
Standardized
Clinical Study Report
Electronic Case Report Form
Forced Expiratory Volume in one second
Fluticasone propionate/Salmeterol Combination
Forced Vital Capacity
GlaxoSmithKline
Hospital Anxiety and Depression Scale
Harmonization for Analysis and Reporting Program
Health Care Utilization
Inspiratory capacity
International Conference on Harmonization
International Data Standards Library
Intent-to-Treat
Kilogram
Meter
Microgram
Medical Dictionary for Regulatory Activities
Milliliter
Modified Medical Research Council
National Health and Nutrition Examination Survey
Once-Daily
Quick Inventory of Depressive Symptomatology-Self
Report
Reporting and Analysis Plan
System Organ Class
United States
Trademark Information
Trademarks of the GlaxoSmithKline
group of companies
Trademarks not owned by the
GlaxoSmithKline group of companies
ADVAIR
DISKUS
SAS
S-Plus
Spiriva
HandiHaler
Unix
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INTRODUCTION
This Reporting and Analysis Plan (RAP) describes in detail the statistical methods that
will be used to summarize and analyze the demographic/background, efficacy and safety
data from ADC111114 on which the clinical study report (CSR) will be based. All
decisions regarding analysis, as defined in this document, have been made prior to
unblinding the study database. Any deviations from this RAP will be documented in the
CSR and all study results will be included in the CSR. Refer to the protocol
[GlaxoSmithKline Document Number RM2007/00725/00] for more details concerning
this study.
2.
STUDY OBJECTIVE(S) AND ENDPOINT(S)
2.1.
Study Objective(s)
The primary objective is to evaluate the effectiveness and safety of FSC 250/50mcg BID
plus tiotropium 18mcg QD compared with tiotropium 18mcg QD and Placebo DISKUS
BID in patients with COPD.
2.2.
Study Endpoint(s)
Primary
•
AM pre-dose Forced Expiratory Volume in One Second (FEV1) at Endpoint
Secondary
•
2-hour post-dose FEV1 at Endpoint
•
AM pre-dose Forced Vital Capacity (FVC) at Endpoint
•
2-hour post-dose FVC at Endpoint
•
AM pre-pose Inspiratory Capacity (IC) at Endpoint
•
Scores on the Clinical Respiratory Questionnaire-Self-Administered Standardized
(CRQ-SAS) at Endpoint
Other(s)
•
Supplemental albuterol use
•
Rate of Health Care Utilization (HCU) for COPD exacerbations (i.e.,use of systemic
corticosteroids and/or antibiotics, unscheduled or urgent care physician /clinic office
visits, and/or emergency room visits)
•
HCU (i.e., hospitalizations) for COPD exacerbations
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Exploratory
•
Scores on the Quick Inventory of Depressive Symptomatology-Self Report (QIDSSR) scale
•
Scores on the Hospital Anxiety and Depression Scale (HADS)
Safety
•
Type and incidence of adverse events (AEs)
•
Type and incidence of pneumonia
2.3.
Statistical Hypotheses
The null hypothesis for this study is that there is no difference between FSC 250/50 mcg
DISKUS plus tiotropium and tiotropium in pre-dose FEV1 change from baseline at
Endpoint. The alternative hypothesis is that there is a difference between FSC 250/50
mcg DISKUS plus tiotropium and tiotropium in pre-dose FEV1 change from baseline at
Endpoint. The study is designed to show superiority of FSC 250/50 mcg DISKUS plus
tiotropium over tiotropium.
H0: µFSC+Tio = µTio
HA: µFSC+Tio > µTio or µFSC+Tio < µTio
where µFSC+Tio and µTio are mean results for FSC250/50 + Tiotropium and Tiotropium,
respectively.
Statistical tests for all efficacy measures will test two-sided hypotheses of no difference
between treatment groups. The nominal significance level for all statistical tests will be
0.05. Inferential significance levels are defined in Section 8.4 Multiple Comparisons and
Multiplicity.
3.
STUDY DESIGN
This is a multi-center, randomized, double-blind, parallel-group study with a 24-week
treatment period. Eligible subjects are 40 years of age or older with a diagnosis of
COPD, a smoking history of ≥10 pack-years, a post-bronchodilator FEV1 ≥40 to ≤ 80%
of predicted normal, and a post-bronchodilator FEV1/FVC ratio of ≤0.7. Subjects
meeting the entry criteria begin a 4-week run-in period and receive open-label tiotropium
18mcg QD. The run-in period serves to assess the subject’s eligibility for randomization,
compliance with study procedures and study drug regimen, and provides a baseline for
the subject-recorded diary efficacy measure.
Following the run-in period, only subjects who have a Modified Medical Research
Council (MMRC) score of ≥2 are eligible for randomization. Subjects are randomly
assigned in a 1:1 ratio to either FSC 250/50 mcg BID plus tiotropium 18 mcg QD or
tiotropium 18 mcg QD plus Placebo DISKUS BID for 24 weeks. The first dose of
blinded study drug (DISKUS) is administered at the site at Visit 2 (Randomization).
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Albuterol will be provided as rescue medication to subjects for use throughout the study.
During the study, clinic visits occur at Screening (Visit 1), Randomization (Visit 2), and
after 4, 8, 16 and 24 weeks of treatment (Visits 3-6, respectively). Subjects withdrawing
from the study prematurely are to complete an Early Withdrawal visit. All subjects are to
be contacted by telephone approximately 14 days following the last dose of study
medication to follow-up with adverse event reporting since the last visit.
The randomization schedule for this study was generated for a stratified, parallel group
study design using RandALL (an intranet based clinical trials randomization system used
at GSK for the generation of random numbers). Assignment to blinded study drug is
stratified based on albuterol reversibility (reversible or non-reversible). Each treatment
number is allocated to one of the two treatment groups using appropriate blocking within
each stratum. Randomization to study drug is center-based (i.e., sites are allocated blocks
of treatment numbers for each stratum).
Reversibility testing with albuterol is assessed at Screening (Visit 1) and each subject’s
response is used to determine the appropriate randomization stratum. A subject is
classified as reversible if the subject has a post-albuterol increase in FEV1 that is ≥200mL
and ≥12% above the pre-albuterol FEV1 measurement. Otherwise the subject is
classified as non-reversible. Percent reversibility is calculated as [(post-albuterol FEV1 –
pre-albuterol FEV1) / pre-albuterol FEV1]*100.
The treatment codes and corresponding treatment allocations are supplied only to GSK
Clinical Supplies (for packaging of study drug) and GSK Global Clinical Safety and
Pharmacovigilance (for monitoring of serious adverse events). Each subject completing
the run-in period and meeting the randomization criteria is assigned a treatment number
(lowest available at the site from the appropriate stratum of the randomization schedule)
at Randomization (Visit 2) by the investigator, who has no knowledge of the treatment
allocated to that treatment number. In the event of a serious adverse event that requires
knowledge of the subject’s treatment regimen, the investigator is to unblind the subject’s
treatment. Once unblinded, the investigator is to withdraw the subject from the study.
4.
PLANNED ANALYSES
4.1.
Interim Analyses
No interim analyses will be performed for this study.
4.2.
Final Analysis
Final statistical analysis will be conducted after the RAP has been finalized, all protocol
deviations have been identified, all data queries have been resolved and the study
database has been locked by GSK Data Management, and treatment assignments have
been unblinded.
Once the study database is locked by GSK Data Management, the treatment allocations
will be unblinded in RandALL. A SAS data set will be generated that includes treatment
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number and the corresponding unblinded treatment assignment. This data set will then
become part of the reporting database for the study. Treatment number will serve as the
link between a subject’s treatment assignment and his/her study data.
5.
SAMPLE SIZE CONSIDERATIONS
5.1.
Sample Size Assumptions
Data from a 24-week GSK COPD study (SFCA3007) indicated that a reasonable estimate
of the standard deviation of change in AM pre-dose FEV1 is 250 mL. It was estimated
that 133 subjects per treatment group would provide 90% power for detection of a
significant difference of 100 mL in pre-dose FEV1 change from baseline at Endpoint
between the two treatment groups based on a two-sample two-sided t-test with a
significance level of 0.05. Approximately 350 subjects were to be randomized to allow
for a 30% study withdrawal rate.
5.2.
Sample Size Sensitivity
The sensitivity of the sample size calculation has been considered in order to assess the
impact on the power of the study should the observed standard deviation for AM pre-dose
FEV1 be higher or should the observed treatment difference for AM pre-dose FEV1 be
lower than expected. Given the sample size of 133 subjects per treatment group and the
estimated difference between the treatment groups of 100 mL in AM pre-dose FEV1, the
study would have ≥80% power if the standard deviation is 290 mL or less. Alternatively,
given the sample size of 133 subjects per treatment group and estimated standard
deviation of 250 mL, the study would have ≥80% power if the treatment difference is 86
mL or more.
5.3.
Sample Size Re-estimation
No sample size re-estimation was performed for this study.
6.
ANALYSIS POPULATIONS
Four populations will be defined for this study: Safety Population, Screen Failure
Population, Run-In Failure Population and Intent-to-Treat (ITT) Population. The
population used in each summary and listing will be noted in the upper left corner of each
data display.
Safety Population
The Safety population will include all subjects screened in the study (i.e., assigned a
subject number and performed at least one study procedure). This population will
include screen failures, run-in failures and randomized subjects. This population will be
used for listings of serious adverse events and for a summary of the analysis populations.
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Screen Failure Population
The Screen Failure population will include all subjects screened for inclusion in the study
but were discontinued from the study at Screening (Visit 1). Reasons for screen failure
and inclusion/exclusion criteria not met will be summarized for this population.
Run-In Failure Population
The Run-In Failure population will include all subjects screened for inclusion in the study
but were discontinued from the study after screening and prior to randomization to
blinded study drug at Visit 2. Adverse events and reasons for run-in failure will be
summarized for this population.
Intent-to-Treat Population
The ITT population will include all subjects who have been randomized to study drug.
For all subjects in the ITT population, it will be assumed that at least one dose of blinded
study drug was taken since the first dose was to be administered at the site following
randomization. Treatment group assignment will be based only on randomization
(regardless of any inadvertent errors in dispensing of study drug that may occur during
the study). The ITT population will be the primary analysis population for summaries
and analyses of demographic/background, efficacy and safety data.
7.
TREATMENT COMPARISONS
7.1.
Data Display Treatment and Other Sub-group Descriptors
The treatment comparison of interest in this study is between the two treatment groups,
FSC250/50 DISKUS + tiotropium and tiotropium. The following treatment descriptions
will be used on all data displays (summaries and listings):
•
•
8.
FSC250/50 mcg BID via DISKUS + Tiotropium 18 mcg QD – > FSC250/50+Tio
Placebo via DISKUS + Tiotropium 18mcg QD– > Tiotropium
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Statistical programming and reporting will be performed in a UNIX environment using
SAS Version 9.1 and the GSK HARP (Harmonization for Analysis and Reporting
Program) reporting environment. Figures for the CSR will be generated using SAS
and/or S-Plus. Reporting conventions will follow the GSK International Data Standards
Library (IDSL) guidelines. In general, categorical measures will be summarized using
frequency distributions (n, %) and continuous measures will be summarized with
descriptive statistics including the number of observations, mean, standard deviation or
standard error, median, minimum and maximum. Other descriptive statistics such as the
upper and lower quartiles may be included, if appropriate. The fit of the negative
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binomial regression models evaluating rates of exacerbations will be assessed by
examining Q-Q plots of standardized residuals.
8.1.
Multicentre Studies
Due to the large number of investigational sites participating in this study and the
possibility of small numbers of subjects randomized at some sites, sites will be combined
by geographical region to ensure centers are of a reasonable size for statistical analysis.
This study is conducted in the US and sites will be pooled on a regional basis according
to the following:
Region 1 (Northeast): Sites in
Region 2 (Mid-Atlantic): Sites in
Region 3 (Southeast): Sites in
Region 4 (North): Sites in
Region 5 (Mid/Midwest): Sites in
Region 6 (South): Sites in
Region 7 (West): Sites in
All references to ‘pooled investigator’ will be based on this geographical combination of
sites.
8.2.
Other Strata and Covariates
Randomization to blinded study drug is stratified by reversibility (reversible or nonreversible) to ensure treatment allocation is balanced within these groups. All analyses
will include a term for reversibility stratum as a covariate. The baseline value of each
continuous efficacy measure will also serve as a covariate in analyses of change from
baseline values for that measure. Other covariates include terms for disease severity
(defined as FEV1 percent predicted at baseline (Randomization / Visit 2)), as well as
terms for treatment group and pooled investigative site (into regions) as described above.
8.3.
Examination of Subgroups
For the primary efficacy measure of pre-dose FEV1, the extent to which the treatment
response varies across levels of the covariates will be examined through interaction tests.
A separate statistical model will be used for each interaction term (treatment by pooled
investigator, treatment by reversibility stratum) with all main effects in the model to
explore the significance of the interaction. If an interaction term is found to be
statistically significant at the 0.10 significance level at multiple time points, then the
interaction will be explored further by presenting summaries for each level of the
subgroup. A subgroup of subjects will also be defined as those with FEV1 % predicted
values >50% at baseline. Demographic/background summaries and efficacy measure
analyses will be provided for this subgroup.
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Multiple Comparisons and Multiplicity
A single primary efficacy measure is defined for this study with all other efficacy
measures defined as secondary, other or exploratory. A primary analysis of each efficacy
measure is also specified with comparisons at any other time points to be interpreted as
supportive. Similarly there is only one treatment comparison of interest in this study.
The inferential significance level for all statistical tests will be 0.05. All statistical tests
will test two-sided hypotheses of no difference between treatment groups.
For interpretation of results and to control overall Type I error rate, step-down principles
for testing of efficacy measures will be implemented. The primary efficacy measure will
act as gatekeeper for analysis of the secondary efficacy measures. The secondary
efficacy measure for the set of related, other measures (nested below the secondary
measure) will act as gatekeeper. Additionally, the Hochberg method will be used at the
0.05 significance level to control the Type I error rate across the secondary efficacy
measures [Hochberg, 1988].
If for the primary efficacy measure, the statistical test fails to reject the null hypothesis of
no treatment difference at the significance level of 0.05, then all subsequent analyses of
the secondary efficacy measures and related other efficacy measures will be interpreted
as descriptive only. If statistical tests fail to reject the null hypothesis of no treatment
difference at the significance level of 0.05 for a secondary efficacy measure, then all
subsequent analyses of related efficacy measures (nested under the secondary efficacy
measure) will be interpreted as descriptive only. No further multiplicity adjustment is
planned for the related or exploratory efficacy endpoints.
9.
DATA HANDLING CONVENTIONS
9.1.
Premature Withdrawal and Missing Data
Data collected up to the time of study discontinuation for subjects who withdraw from the
study prematurely will be included in analyses. A subject will be included in analyses
wherever his/her data is available. Therefore, the number of subjects evaluated at each
visit and time point, as well as across demographic/background, efficacy and safety
measures, will vary. In order to account for subjects withdrawing from the study in the
analysis of efficacy measures, an Endpoint analysis will be performed where Endpoint
will be determined from last post-baseline measurements for each subject as defined
below in Section 9.2.3 (for diary measures) and Section 11 (for pulmonary function test
measures and subject reported questionnaires).
9.2.
Derived and Transformed Data
9.2.1.
Treatment Exposure
Days on blinded study drug will be calculated for each subject as treatment stop date treatment start date + 1. If the treatment stop date is missing then the subject’s last visit
date will be used for treatment stop date. (Treatment start date is assumed to not be
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missing as the first dose of study drug is administered at the site at Randomization (Visit
2)). This imputation of treatment exposure (with last visit date serving as a proxy for
missing treatment stop date) will be used for efficacy analyses.
9.2.2.
COPD Exacerbations
In this study, COPD exacerbations are also recorded as adverse events. For the efficacy
analysis of COPD exacerbations, exacerbations will only be obtained from the electronic
case report form (eCRF) exacerbation log data. In accordance with previous analyses of
COPD exacerbations [Ferguson, 2008], if 2 exacerbations recorded for the same subject
have ≤7 days between the date of resolution of the first exacerbation and the date of onset
of the second exacerbation, then this event will be considered as a single exacerbation,
rather than as 2 separate exacerbations. If separate exacerbations are associated with
health care utilization (e.g., OCS use, antibiotic use or a hospitalization), then any
combined exacerbation from these events will also be associated with OCS use, antibiotic
use and hospitalization as well.
9.2.3.
Diary Measures
Supplemental albuterol use is an efficacy measure derived from the subject-recorded
daily diaries and will be summarized as the number of puffs (with nebule use converted
to puffs as 1 nebule = 2 puffs) taken per day. Supplemental albuterol use will be
summarized at baseline week, each 4-week interval of the 24-week treatment period, at
Endpoint, and for the overall 24-week treatment period. Each set of 7 days during the
treatment period will be defined as 1 week and each set of 28 days during the treatment
period will be defined as a 4-week interval. Endpoint is defined as the last week of the
treatment period for which a subject provided data. Baseline values will be calculated as
the mean of the daily diary values recorded on the 7 preceding days to Randomization
(Visit 2). Treatment period intervals will begin with the day after Randomization (Visit
2) since the daily diary recordings are assessments for a 24-hour period.
A subject must have at least 3 days of diary data in any time interval (including baseline)
to contribute a non-missing mean of daily values for that time interval. Otherwise, the
mean value for that time interval will be considered missing. Diary data collected prior
to the 7-day baseline period or after 24 weeks of treatment or after the treatment stop date
will not be included in analyses. Also, obvious errors (albuterol puffs and nebules >50)
included in the diary data due to subject entry error will be excluded from analysis. If
duplicate diary data is collected (i.e., 2 diary records with the same diary date in the
database), then the most conservative value for this date will be included in data analysis.
The most conservative supplemental albuterol use value is defined as the maximum from
the values recorded.
9.2.4.
Subject Rating Scales and Questionnaires
CRQ-SAS
The CRQ-SAS is a self-administered questionnaire including 20 items with 4 domains:
Dyspnea (5 items; Questions 1-5), Fatigue (4 items; Questions 8, 11, 15, 17), Emotional
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Function (7 items; Questions 6, 9, 12, 14, 16, 18, 20), and Mastery (4 items; Questions 7,
10, 13, 19) [CRQ-SAS, 2006]. Each item is scored on a 7-point scale ranging from 1
(worst) to 7 (best) so that higher scores indicate better health-related quality of life.
Individual items within the CRQ-SAS are equally weighted and domain scores are
calculated as the mean across the non-missing items within each domain (so that domain
scores will be calculated although an individual item score is missing). (Scores of 8 (Not
done) for the questions of the Dyspnea domain will be considered missing).
QIDS-SR 16
The QIDS-SR 16 is a self-reported rating scale that assesses symptom severity diagnostic
criterion for major depressive disorder [Rush, 2003]. The QIDS-SR 16 contains 16
separate items which correspond to 9 symptom criterion domains: [sad mood,
concentration, self-criticism, suicidal ideation, interest, energy/fatigue, sleep disturbance,
decrease/increase in appetite/weight, and psychomotor agitation/retardation].
The QIDS-SR total score is calculated by summing the following items:
•
The highest score obtained on any of the four sleep items (Items 1, 2, 3 and 4)
•
Item 5 (feeling sad)
•
The highest score obtained on any of the four appetite/weight items (Items 6, 7,
8 and 9)
•
Item 10 (concentration/decision making)
•
Item 11 (view of myself)
•
Item 12 (thoughts of death or suicide)
•
Item 13 (general interest)
•
Item 14 (energy level)
•
The highest score obtained on either of the two psychomotor items (Items 15
and 16)
Each item is rated from 0 to 3. The highest possible score is 27, which represents the
most severe measure of depression; the lowest possible score is 0, which represents an
absence of depression. In the 3 situations above where an item score is obtained from the
highest score of a number of questions, as long as 1 question is present, the item score
will be calculated. If any of the 9 items to be summed for a total score are missing, the
total score will not be calculated.
HADS
The HADS is a 14-item self-administered scale used to assess levels of anxiety and
depression [Hermann, 1997]. The 7 even-numbered questions relate to depression and
the 7 odd-numbered questions relate to anxiety. Responses for each question are scored
on a scale from 3 to 0. The maximum score is 21 for both the anxiety and depression
subscales with higher scores indicating worse levels of anxiety and depression. The
HADS Anxiety score will be calculated by summing the responses for items 1, 3, 5, 7, 9,
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11, and 13. The HADS Depression score will be calculated by summing the responses
for items 2, 4, 6, 8, 10, 12, and 14. If any of the 7 items to be summed for a subscale
score are missing, the subscale score will not be calculated.
9.2.5.
Body Mass Index (BMI)
BMI will be calculated as weight (in kilograms) divided by height (in meters) squared.
Height and weight are collected at Screening (Visit 1).
BMI = Weight (kg)
Height (m)2
9.2.6.
FEV1 Calculated Measures
All sites will use standardized spirometry equipment provided by an external vendor who
will provide the spirometry measurements electronically to GSK. Spirometry
measurements provided by the vendor include calculated measures of FEV1 percent
predicted, FEV1 percent reversibility and FEV1/FVC ratio. The percent predicted values
for FEV1 are calculated using the reference values based on NHANES III
[Hankinson, 1999]. Spirometry measurements provided electronically from the vendor
will be used in analyses and will not be re-calculated. FEV1 percent predicted, FEV1
percent reversibility and FEV1/FVC ratio are calculated as:
* 100
% Predicted =
FEV1 (L)
Predicted FEV1 (L)
% Reversibility = FEV1 after albuterol– FEV1 before albuterol * 100
FEV1 before albuterol
FEV1/FVC = FEV1 (L)
FVC (L)
10.
STUDY POPULATION
10.1.
Disposition of Subjects
The disposition of subjects in the Safety population (including all subjects screened in the
study) will be tabulated. Subject disposition will be summarized in terms of:
•
•
•
•
the number of subjects screened (Safety population)
the number (%) of screen failures (Screen Failure population)
the number (%) of subjects per screen failure reason (Screen Failure population)
the number (%) of subjects not meeting each inclusion/exclusion criteria (Screen
Failure population)
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the number (%) of run-in failures (Run-In Failure population)
the number (%) of subjects per run-in failure reason (Run-In Failure population)
the number (%) of subjects randomized (ITT population)
Subject disposition in the ITT population will also be summarized overall and by
treatment group in terms of:
•
•
•
•
the number (%) of subjects randomized at each investigative site
the number (%) of subjects who complete the study
the number (%) of subjects who withdraw prematurely from the study
the number (%) of subjects per reason for withdrawal
A subject listing of premature study withdrawals, including reasons for study withdrawal
and days on treatment will also be provided.
10.2.
Protocol Deviations
Protocol deviations will be determined prior to unblinding treatment assignments. Data
supporting the determinations of protocol deviations will be collected in the eCRF.
Protocol deviations will include the following:
•
•
•
violation of inclusion/exclusion criteria
use of a prohibited medication
non-compliance with study drug
Violations of inclusion/exclusion criteria will be obtained from the eligibility responses
from Screening (Visit 1). Use of prohibited medications will be obtained from the
concomitant medication logs of the eCRF. Prohibited medications, taken for any
indication, are those as defined in the protocol (Section 5.6.2 Prohibited Medications and
Non-Drug Therapies). Non-compliance with study drug regimen is defined as
medication usage <75% and will be calculated as described below in Section 10.4 of the
RAP.
Protocol deviations will be tabulated by treatment group and for the overall ITT
population in a summary table as well as reported in a listing. A separate summary and
listing of subjects violating the inclusion/exclusion criteria and a listing of subjects for
whom the treatment blind was broken during the study for the ITT population will also be
provided per IDSL standards. Data collected following a protocol deviation will not be
excluded from the ITT analysis.
10.3.
Demographic and Baseline Characteristics
Demographic characteristics of age, sex, ethnicity, race, height, weight and BMI will be
summarized by treatment group and for the overall ITT population. Subject listings of
demographic attributes will also be provided.
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Disease characteristics, current medical conditions and screening pulmonary function
tests will also be summarized by treatment group and for the overall ITT population.
COPD baseline characteristics will include the following:
•
•
•
•
•
•
COPD duration
COPD type (chronic bronchitis and/or emphysema)
exacerbation history
smoking status (current or former)
pack-years
MMRC dyspnea score
The summary of screening pulmonary function measurements will include:
•
•
•
•
•
•
pre- and post-bronchodilator FEV1
pre- and post-bronchodilator FEV1 percent predicted
FEV1 percent reversibility
distribution (n, %) of subjects reversible or non-reversible
pre- and post-bronchodilator FVC
post-bronchodilator FEV1/FVC ratio
Prior COPD medications taken within 30 days of Screening (Visit 1) and concomitant
medications taken during the study will be assigned codes using the GSK Drug dictionary
and will be reported using the Anatomical Therapeutical Chemical (ATC) Level 1
classification and drug components. Treatment groups will be summarized by reporting
the number (%) of subjects taking any medication, the number (%) of subjects taking a
medication by ATC classification, and the number (%) of subjects taking a medication by
each drug component. Combination medications will be summarized as combined drug
components. A listing will be provided to outline the relationship between GSK Drug
dictionary terms and verbatim drug text. Summaries will be generated for prior COPD
medications, COPD concomitant medications, and non-COPD concomitant medications
as collected in the eCRF.
10.4.
Treatment Compliance
Compliance with the study drug regimen will be calculated from the diary records of
number of daily inhalations taken from the open-label HandiHaler and number of daily
inhalations taken from the double-blind DISKUS and will be summarized with
descriptive statistics by treatment group. Treatment compliance will be expressed as an
overall percentage of compliance calculated as the total number of doses used during the
treatment period (based on treatment start and stop dates) divided by the total expected
use during this time period, multiplied by 100. If duplicate diary data is collected, then
the maximum from the values recorded will be included in data analysis. Per IDSL
reporting standards, a subject listing of randomization details by investigative site will
also be provided.
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11.
EFFICACY ANALYSES
11.1.
Primary Efficacy Analysis(es)
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The primary efficacy analysis is mean change from baseline in pre-dose FEV1 at
Endpoint compared between treatment groups. Pre-dose FEV1 measures and change
from baseline values will be summarized with descriptive statistics by treatment group at
Endpoint and at each clinic visit. Endpoint will be defined as the last scheduled
measurement of pre-dose FEV1 during the 24-week treatment period and baseline will be
defined as the pre-dose FEV1 measure from Randomization (Visit 2). An analysis of
covariance (ANCOVA) model with terms for treatment group, pooled investigator,
reversibility stratum and baseline pre-dose FEV1 will be used to test statistical differences
between treatment groups at each time point. Treatment differences from the ANCOVA
model will be presented as least square means and standard errors with the corresponding
p-values and 95% confidence intervals. Pre-dose FEV1 values will also be presented in a
figure.
11.2.
Secondary Efficacy Analysis(es)
Secondary efficacy measures are 2-hour post-dose FEV1, pre-dose FVC, 2-hour post-dose
FVC, pre-dose IC and CRQ-SAS scores.
Post-dose FEV1 and FVC, Pre-dose FVC and IC: The secondary efficacy measures of
2 hour post-dose FEV1 and FVC and pre-dose FVC and IC will be compared between
treatment groups in the same manner as pre-dose FEV1
CRQ-SAS: The CRQ-SAS is administered at Randomization (Visit 2), Week 8 (Visit 4),
and Week 24 (Visit 6) or the Early Withdrawal visit. Baseline will be determined from
the Randomization (Visit 2) questionnaire and Endpoint will be determined from the last
questionnaire collected during the treatment period or at the Early Withdrawal visit.
Scoring of the questionnaire will follow the developers’ guidelines (see Section 9.2.4.).
The primary analysis will be mean change from baseline scores compared between
treatment groups at Endpoint. CRQ-SAS domain scores and change from baseline values
will be summarized with descriptive statistics at Endpoint and each visit for which the
CRQ-SAS is administered. An ANCOVA model, including terms for treatment group,
pooled investigator, reversibility stratum and baseline, will be used to test statistical
differences in treatment group mean changes from baseline at Endpoint and each visit.
Treatment differences from the ANCOVA model will be presented as least square means
and standard errors with the corresponding p-values and 95% confidence intervals.
11.3.
Other Efficacy Analysis(es)
Other efficacy measures for this study are defined as related efficacy measures nested
below a secondary efficacy measure as described in Section 8.4. Other efficacy measures
are supplemental albuterol use and HCU for COPD exacerbations and are nested under
the secondary efficacy measure of pre-dose IC. Exploratory measures are QIDS-SR and
HADS scores.
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Supplemental albuterol use: The primary analysis of supplemental albuterol use is
mean change from baseline compared between treatment groups at Endpoint. Mean
supplemental albuterol use and mean change from baseline values will be summarized
with descriptive statistics by treatment group for the overall 24-week treatment period,
each 4-week treatment period and at Endpoint. An ANCOVA model, including terms for
treatment group, pooled investigator, reversibility stratum and baseline, will be used to
test statistical differences in treatment group mean changes from baseline for the overall
24-week treatment period, each 4-week period and at Endpoint. Treatment differences
from the ANCOVA model will be presented as least square means and standard errors
with the corresponding p-values and 95% confidence intervals. Baseline week will also
be summarized with descriptive statistics.
HCU for COPD exacerbations: The analysis of HCU for COPD exacerbations will
compare the rate of exacerbations between treatment groups using a generalized linear
model. The number of exacerbations occurring during the 24-week treatment period will
be assumed to follow the negative binomial distribution. The model will include terms
for treatment group, pooled investigator, reversibility stratum and baseline severity
(baseline FEV1 percent predicted), with log (time of treatment) as an offset variable.
The number (%) of subjects experiencing an exacerbation and the number of
exacerbations will be tabulated by treatment group. The frequency (n, %) of physician
office visits, urgent care visits, emergency room visits and hospitalizations associated
with COPD exacerbations will also be summarized by treatment group. Exacerbations
will further be described by tabulating the number (%) of exacerbations by severity (mild,
moderate, severe); symptoms (dyspnea, sputum volume, cough/wheeze); primary cause
or trigger (e.g., common cold, lower respiratory infection, etc.); outcome (resolved, not
resolved, fatal); leading to study withdrawal (Yes/No); and requiring hospitalization
(Yes/No), oral corticosteroid use (Yes/No) and antibiotic use (Yes/No). A subject listing
of COPD exacerbations will also be provided.
QIDS-SR and HADS: The QIDS-SR and HADS are administered at Randomization
(Visit 2), Week 8 (Visit 4), and Week 24 (Visit 6) or the Early Withdrawal visit.
Baseline will be determined from the Randomization (Visit 2) rating scales and Endpoint
will be determined from the last rating scale collected during the treatment period or at
the Early Withdrawal visit. Scoring of the scales will follow the developers’ guidelines
(see Section 9.2.4.). QIDS-SR total scores and HADS anxiety and depression subscale
scores will be summarized and compared between treatment groups in the same manner
as the CRQ-SAS The QIDS-SR and HADS will be summarized for the ITT population
as well as for subjects meeting depression criteria (score of ≥6 indicating at least mild
disease state at baseline) as determined by the QIDS-SR scale and depression and anxiety
criteria (scores of ≥8 indicating at least mild disease state at baseline) as determined by
the HADS depression and anxiety scales, respectively.
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SAFETY ANALYSES
12.1.
Extent of Exposure
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Extent of exposure to study drug will be calculated as the number of days between start
of treatment and end of treatment for each subject and will be summarized with
descriptive statistics by treatment group. A subject listing of treatment exposure will also
be provided.
12.2.
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) and will be reported using the primary System Organ Class (SOC) and
preferred term. The relationship of primary SOC, preferred terms and verbatim adverse
event text will be outlined in a listing.
Adverse event summaries will report the number (%) of subjects experiencing any
adverse event, the number (%) of subjects with an adverse event by SOC, and the number
(%) of subjects with an adverse event by preferred term within each SOC. Adverse event
summaries will be provided for both the ITT and Run-In Failure populations.
Separate summaries of all adverse events occurring during the study will be reported by
treatment group for the ITT population. Summaries will be generated for adverse events
occurring pre-treatment (during the run-in period), during treatment (during the doubleblind treatment period), and post-treatment (post treatment stop date and/or during the 2week follow-up period). (An adverse event occurring after the treatment start date for
which the corresponding treatment stop date is missing will be set to as having occurred
during treatment). The following summaries of all adverse events and drug-related
adverse events (those with a reasonable possibility that they may have been caused by
study drug as assessed by the investigator) will be provided:
•
•
•
•
•
•
All Adverse Events During Run-In (ITT population)
All Adverse Events During Treatment (ITT population)
Most Common (>2%) Adverse Events During Treatment (ITT population)
All Adverse Events Post-Treatment (ITT population)
Drug-Related Adverse Events (ITT population)
All Adverse Events (Run-In Failure population)
The summary of most common adverse events will report events experienced by >2%
(after rounding) of subjects in either treatment group. A subject listing of all reported
adverse events (those reported pre-treatment, during treatment and post-treatment) will be
provided. In addition, an adverse event listing will be generated for each reported
adverse event and the corresponding subjects who experienced the event during the
study. These listings will be provided for the ITT population.
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12.3.
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Deaths and Serious Adverse Events
Serious adverse events occurring during the study will be summarized for the ITT
population in an adverse event summary table. Separate subject listings will be provided
of all serious non-fatal adverse events and of all fatal adverse events for the Safety
population (screen failures, run-in failures and randomized subjects).
12.4.
Adverse Events Leading to Discontinuation of
Investigational Product and/or Withdrawal from the Study
and Other Significant Adverse Events
Adverse events leading to withdrawal from the study will be reported both in a summary
table and subject listing for the ITT population.
Pneumonia adverse events will be determined by the following MedDRA preferred
terms:
Pneumonia
Lobar pneumonia
Bronchopneumonia
Lung infection
Superinfection lung
Pneumonia primary atypical
Pneumocystis jiroveci pneumonia
Pneumonia necrotising
Bronchopneumopathy
Pneumonia bacterial
Pneumonia staphylococcal
Lung infection pseudomonal
Pneumonia chlamydial
Pneumonia streptococcal
Pneumonia pneumococcal
Pneumonia escherichia
Pneumonitis
Pneumonia adverse events occurring during the study will be reported in an adverse event
summary table and listing for the ITT population. For this study, pneumonia diagnosis is
to be confirmed with a chest x-ray. Chest x-ray data corresponding to a pneumonia
adverse event will be reported in a subject listing.
12.5.
Pregnancies (as applicable)
Any pregnancies reported during the study will be presented in a listing.
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REFERENCES
GlaxoSmithKline Document Number RM2007/00725/00 Protocol A Randomized,
Double-Blind, Parallel-Group, 24-Week Study to Evaluate the Efficacy and Safety of
ADVAIR™ DISKUS™ (Fluticasone Propionate/Salmeterol Combination Product
250/50mcg Inhalation Powder) BID Plus Spiriva HandiHaler (Tiotropium Bromide
Inhalation Powder 18mcg) QD Versus Spiriva QD Plus Placebo DISKUS BID in
Subjects with Chronic Obstructive Pulmonary Disease (COPD). Effective Date: 24-JUN2008.
Ferguson GT, Anzueto A, Fei R, et al. Effect of fluticasone propionate/salmeterol
(250/50 mcg) or salmeterol (50 mcg) on COPD exacerbations. Respir Med 2008;
102:1099-1108.
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of
the general U.S. population. Am J Respir Crit Care Med. 1999; 159:179-187.
Hermann C. International experiences with the Hospital Anxiety and Depression Scale –
a review of validation data and clinical results. J Psychosom Res. 1997; 42:17-41.
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance.
Biometrika 1988; 5:800-802.
Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-item Quick Inventory of Depressive
Symptomatology (QIDS), Clinician Rating (QIDS-C), and Self-Report (QIDS-SR): a
psychometric evaluation in patients with chronic major depression. Biol Psychiatry.
2003; 54:573-583.
The Self-Administered Chronic Respiratory Questionnaire Standardized (CRQ-SAS) and
Individualized Version (CRQ-SAI) Background Information and Suggestions for
Application. Department of Clinical Epidemiology & Biostatistics McMaster University,
Faculty of Health Sciences, Hamilton, ON. February 2006.
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14.
ATTACHMENTS
14.1.
Table of Contents for Data Display Specifications
Study Population
1.
Summary of Analysis Populations
2.
Summary of Inclusion/Exclusion Criteria Not Met (Screen Failure
Population)
3.
Summary of Enrollment by Investigator
4.
Summary of End of Study Record
5.
Summary of Protocol Deviations
6.
Summary of Inclusion/Exclusion Criteria Deviations
7.
Summary of Demographic Characteristics
8.
Summary of Race and Racial Combinations
9.
Summary of Race and Racial Combination Details
10.
Summary of Disease Characteristics
11.
Summary of Screening Pulmonary Function Tests
12.
Summary of Current Medical Conditions
13.
Summary of Prior COPD Medication Use
14.
Summary of COPD Concomitant Medications
15.
Summary of Non-COPD Concomitant Medications
16.
Summary of Treatment Compliance
17.
Listing of End of Study Record
18.
Listing of Subjects for Whom the Treatment Blind was Broken
19.
Listing of Protocol Deviations
20.
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
21.
Relationship of Medication Class, Dictionary Term and Verbatim Text
22.
Listing of Demographic Characteristics
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Listing of Race
Efficacy
1.
Summary of Pre-dose FEV1 (mL)
2.
Summary of 2-hour Post-dose FEV1 (mL)
3.
Summary of Pre-dose FVC (mL)
4.
Summary of 2-hour Post-dose FVC (mL)
5.
Summary of Pre-dose IC (mL)
6.
Summary of CRQ-SAS
7.
Summary of Supplemental Albuterol Use (puffs/day)
8.
Summary of Health Care Utilization for COPD Exacerbations
9.
Analysis of Rate of COPD Exacerbations
10.
Listing of COPD Exacerbations
11.
Summary of QIDS-SR
12.
Summary of HADS
Safety
1.
Summary of Exposure to Study Drug
2.
Summary of All Adverse Events (Run-In Failure Population)
3.
Summary of All Adverse Events During Run-In
4.
Summary of All Adverse Events During Treatment
5.
Summary of Most Common (>2%) Adverse Events During Treatment
6.
Summary of All Adverse Events Post-Treatment
7.
Summary of Drug-Related Adverse Events
8.
Summary of Serious Adverse Events
9.
Summary of Adverse Events Leading to Withdrawal from the Study
10.
Summary of Pneumonia Adverse Events
11.
Listing of Exposure to Study Drug
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12.
Listing of All Adverse Events
13.
Listing of Subject Numbers for Individual Adverse Events
14.
Listing of Fatal Serious Adverse Events (Safety Population)
15.
Listing of Non-Fatal Serious Adverse Events (Safety Population)
16.
Listing of Adverse Events Leading to Withdrawal from the Study
17.
Listing of Pneumonia Adverse Events
18.
Listing of Pneumonia Chest X-rays
19.
Relationship of Adverse Event System Organ Class, Preferred Term and
Verbatim Text
20.
Listing of Positive Pregnancy Tests
Figures
1.
Mean Change from Baseline Pre-dose FEV1 (mL)
2.
Mean Change from Baseline 2-hour Post-dose FEV1 (mL)
3.
Mean Change from Baseline Pre-dose FVC (mL)
4.
Mean Change from Baseline 2-hour Post-dose FVC (mL)
5.
Mean Change from Baseline Pre-dose IC (mL)
ICH
1.
Listing of Randomized and Actual Treatments
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Protocol Identifier
Subject Identifier
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{{{{{{}
Date of assessment
Day
Month
Final - 26 SEP 08
Visit Description
WORKSHEET
Visit 2 (Randomization)
Year
MODIFIED MEDICAL RESEARCH COUNCIL (mMRC) DYSPNEA SCALE
[0]b
Not troubled with breathlessness except with strenuous exercise
[1]b
Troubled by shortness of breath when hurrying on the level or walking up a slight hill
[2]b
Walks slower than people of the same age on the level because of breathlessness or has to stop for
breath when walking at own pace on the level
[3]b
Stops for breath after walking about 100 yards or after a few minutes on the level
[4]b
Too breathless to leave the house or breathless when dressing or undressing
US:ENG (United States/English)
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Subject Visit 1 (Screening/Run-In) Diary
Confidential
Subject Identifier
{{{{{{}
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REMINDERS:
• Bring this diary and all study medications with you to your next clinic visit.
• Do not take any new COPD medications without first contacting the study
investigator or research coordinator.
• Do not write your name or initials anywhere on this diary.
• Withhold albuterol for at least 6 hours prior to your Visit 2 clinic visit. If you have
taken albuterol within 6 hours prior to a visit, contact the clinic to reschedule the visit.
Date of Visit 2 Clinic Visit:
Day
Month
Year
Study contact name: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Study site telephone number: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
US:ENG (United States/English)
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Protocol Identifier
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Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
DAILY DIARY INSTRUCTIONS
Reminders:
• Bring this Diary and all study medication to each clinic visit.
• Do not take any new medications without first contacting the study doctor.
• Do not write your name or initials anywhere on this diary.
General rules for Diary completion:
• Print neatly using only black or blue ink. Do NOT use pencil.
• Draw one line through any changes or mistakes and re-enter the correct information above/beside.
• DO NOT use correction fluid or tape.
Record the following information in this diary every day.
1. Date. Record dates in DD MMM YY format (for example: 15 OCT 08).
2. Daily Albuterol Use. If you required rescue albuterol for COPD symptoms during the last 24 hour period, record
the total number of puffs administered. If none, enter zero (0).
3. Daily Albuterol Nebule Use. If you required rescue albuterol nebules for COPD symptoms during the last 24
hour period, record the total number of nebules administered. If none, enter zero (0).
4. Morning (AM) Study Medication Taken. Each morning (approximately 6:00-9:00 AM) take 1 inhalation from
the SPIRIVA® HANDIHALER ® Device. Record the total number of inhalations of open-blind study
medication you took each day from the SPIRIVA® HANDIHALER® Device.
5. Medical Problems/Medications Taken Worksheet. Record all medical problems which may have occurred
on that date, AND all medication(s) you took on that date to treat the problem on the separate Medical Problems/
Medications Taken Worksheet page. Do not include study-related medications.
US:ENG (United States/English)
SPIRIVA® and HANDIHALER® are trademarks of Boehringer Ingelheim.
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Protocol Identifier
Subject Identifier
Visit Description
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{{{{{{}
Visit 1
(Screening/Run-In)
SUBJECT DAILY DIARY
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations
Number of
Number of puffs
of open-label
rescue albuterol
of rescue
SPIRIVA®
albuterol taken nebules used
HANDIHALER®
during the last during the last
study medication taken
24 hours
24 hours
during the last 24 hours
(AM dosing only)
2
0
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 101 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
77
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 1
(Screening/Run-In)
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
78
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*101*
CONFIDENTIAL
use only
Page
101
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 1
(Screening/Run-In)
SUBJECT DAILY DIARY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations
Number of
Number of puffs
of open-label
rescue albuterol
of rescue
SPIRIVA®
albuterol taken nebules used
HANDIHALER®
during the last during the last
study medication taken
24 hours
24 hours
during the last 24 hours
(AM dosing only)
2
0
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 102 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
79
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 1
(Screening/Run-In)
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
80
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*102*
CONFIDENTIAL
use only
Page
102
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 1
(Screening/Run-In)
SUBJECT DAILY DIARY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations
Number of
Number of puffs
of open-label
rescue albuterol
of rescue
SPIRIVA®
albuterol taken nebules used
HANDIHALER®
during the last during the last
study medication taken
24 hours
24 hours
during the last 24 hours
(AM dosing only)
2
0
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
81
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 1
(Screening/Run-In)
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
82
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Subject Visit 2 (Randomization) Diary
Confidential
Subject Identifier
{{{{{{}
ADC111114
REMINDERS:
• Bring this diary and all study medications with you to your next clinic visit.
• Do not take any new COPD medications without first contacting the study
investigator or research coordinator.
• Do not write your name or initials anywhere on this diary.
• Withhold albuterol for at least 6 hours prior to your Visit 3 clinic visit. If you have
taken albuterol within 6 hours prior to the visit, contact the clinic to reschedule Visit 3.
• Withhold your morning dose of blinded study medication prior to the Visit 3 clinic
visit. If you have taken your morning dose of blinded study medication prior to Visit 3,
contact the clinic to reschedule the visit.
Date of Visit 3 Clinic Visit:
Day
Month
Year
Study contact name: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Study site telephone number: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
US:ENG (United States/English)
83
RM2010/00132/00
ADC111114
CONFIDENTIAL
CONFIDENTIAL
Protocol Identifier
ADC111114
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
DAILY DIARY INSTRUCTIONS
Reminders:
• Bring this Diary and all study medications to each clinic visit.
• Do not take any new medications, other than the study medication provided for this study, without first
contacting the study doctor.
• Do not write your name or initials anywhere on this diary.
General rules for Diary completion:
• Print neatly using only black or blue ink. Do NOT use pencil.
• Draw one line through any changes or mistakes and re-enter the correct information above/beside.
• DO NOT use correction fluid or tape.
Record the following information in this diary every day.
1. Date. Record dates in DD MMM YY format (for example: 15 OCT 08).
2. Daily Albuterol Use. If you required albuterol for COPD symptoms during the last 24 hour period, record the total
number of puffs administered. If none, enter zero (0).
3. Daily Albuterol Nebule Use. If you required albuterol nebules for COPD symptoms during the last 24 hour
period, record the total number of nebules administered. If none, enter zero (0).
4. Morning (AM) and Evening (PM) Study Medication Taken. Each morning (approximately 6:00-9:00 AM)
take 1 inhalation from the DISKUS followed by 1 inhalation from the SPIRIVA® HANDIHALER® Device.
Each evening (approximately 6:00-9:00 PM) approximately 12 hours after the morning dosing with the
DISKUS, take 1 inhalation from the DISKUS. Record the total number of inhalations of double-blind
study medication you took each day from the DISKUS and the total number of inhalations of open-blind
study medication you took each day from the SPIRIVA® HANDIHALER® Device.
5. Medical Problems/Medications Taken Worksheet. Record all medical problems which may have occurred
on that date, AND all medication(s) you took on that date to treat the problem on the separate Medical Problems/
Medications Taken Worksheet page. Do not include study-related medications.
US:ENG (United States/English)
SPIRIVA® and HANDIHALER® are trademarks of Boehringer Ingelheim.
84
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*200*
CONFIDENTIAL
use only
Page
200
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 2
SUBJECT DAILY DIARY
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 201 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
85
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 2
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
86
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*201*
CONFIDENTIAL
use only
Page
201
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 2
SUBJECT DAILY DIARY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 202 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
87
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 2
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
88
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*202*
CONFIDENTIAL
use only
Page
202
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 2
SUBJECT DAILY DIARY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
89
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 2
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
90
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Subject Visit 3 Diary
Confidential
Subject Identifier
{{{{{{}
ADC111114
REMINDERS:
• Bring this diary and all study medications with you to your next clinic visit.
• Do not take any new COPD medications without first contacting the study
investigator or research coordinator.
• Do not write your name or initials anywhere on this diary.
• Withhold albuterol for at least 6 hours prior to your Visit 4 clinic visit. If you have
taken albuterol within 6 hours prior to the visit, contact the clinic to reschedule Visit 4.
• Withhold your morning dose of blinded study medication prior to the Visit 4 clinic
visit. If you have taken your morning dose of blinded study medication prior to Visit 4,
contact the clinic to reschedule the visit.
Date of Visit 4 Clinic Visit:
Day
Month
Year
Study contact name: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Study site telephone number: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
US:ENG (United States/English)
91
RM2010/00132/00
ADC111114
CONFIDENTIAL
CONFIDENTIAL
Protocol Identifier
ADC111114
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
DAILY DIARY INSTRUCTIONS
Reminders:
• Bring this Diary and all study medications to each clinic visit.
• Do not take any new medications, other than the study medication provided for this study, without first
contacting the study doctor.
• Do not write your name or initials anywhere on this diary.
General rules for Diary completion:
• Print neatly using only black or blue ink. Do NOT use pencil.
• Draw one line through any changes or mistakes and re-enter the correct information above/beside.
• DO NOT use correction fluid or tape.
Record the following information in this diary every day.
1. Date. Record dates in DD MMM YY format (for example: 15 OCT 08).
2. Daily Albuterol Use. If you required albuterol for COPD symptoms during the last 24 hour period, record the total
number of puffs administered. If none, enter zero (0).
3. Daily Albuterol Nebule Use. If you required albuterol nebules for COPD symptoms during the last 24 hour
period, record the total number of nebules administered. If none, enter zero (0).
4. Morning (AM) and Evening (PM) Study Medication Taken. Each morning (approximately 6:00-9:00 AM)
take 1 inhalation from the DISKUS followed by 1 inhalation from the SPIRIVA® HANDIHALER® Device.
Each evening (approximately 6:00-9:00 PM) approximately 12 hours after the morning dosing with the
DISKUS, take 1 inhalation from the DISKUS. Record the total number of inhalations of double-blind
study medication you took each day from the DISKUS and the total number of inhalations of open-blind
study medication you took each day from the SPIRIVA® HANDIHALER® Device.
5. Medical Problems/Medications Taken Worksheet. Record all medical problems which may have occurred
on that date, AND all medication(s) you took on that date to treat the problem on the separate Medical Problems/
Medications Taken Worksheet page. Do not include study-related medications.
US:ENG (United States/English)
SPIRIVA® and HANDIHALER® are trademarks of Boehringer Ingelheim.
92
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*300*
CONFIDENTIAL
use only
Page
300
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 3
SUBJECT DAILY DIARY
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 301 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
93
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 3
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
94
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*301*
CONFIDENTIAL
use only
Page
301
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 3
SUBJECT DAILY DIARY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 302 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
95
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 3
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
96
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*302*
CONFIDENTIAL
use only
Page
302
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 3
SUBJECT DAILY DIARY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
97
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 3
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
98
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Subject Visit 4 Diary
Confidential
Subject Identifier
{{{{{{}
ADC111114
REMINDERS:
• Bring this diary and all study medications with you to your next clinic visit.
• Do not take any new COPD medications without first contacting the study
investigator or research coordinator.
• Do not write your name or initials anywhere on this diary.
• Withhold albuterol for at least 6 hours prior to your Visit 5 clinic visit. If you have
taken albuterol within 6 hours prior to the visit, contact the clinic to reschedule Visit 5.
• Withhold your morning dose of blinded study medication prior to the Visit 5 clinic
visit. If you have taken your morning dose of blinded study medication prior to Visit 5,
contact the clinic to reschedule the visit.
Date of Visit 5 Clinic Visit:
Day
Month
Year
Study contact name: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Study site telephone number: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
US:ENG (United States/English)
99
RM2010/00132/00
ADC111114
CONFIDENTIAL
CONFIDENTIAL
Protocol Identifier
ADC111114
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
DAILY DIARY INSTRUCTIONS
Reminders:
• Bring this Diary and all study medications to each clinic visit.
• Do not take any new medications, other than the study medication provided for this study, without first
contacting the study doctor.
• Do not write your name or initials anywhere on this diary.
General rules for Diary completion:
• Print neatly using only black or blue ink. Do NOT use pencil.
• Draw one line through any changes or mistakes and re-enter the correct information above/beside.
• DO NOT use correction fluid or tape.
Record the following information in this diary every day.
1. Date. Record dates in DD MMM YY format (for example: 15 OCT 08).
2. Daily Albuterol Use. If you required albuterol for COPD symptoms during the last 24 hour period, record the total
number of puffs administered. If none, enter zero (0).
3. Daily Albuterol Nebule Use. If you required albuterol nebules for COPD symptoms during the last 24 hour
period, record the total number of nebules administered. If none, enter zero (0).
4. Morning (AM) and Evening (PM) Study Medication Taken. Each morning (approximately 6:00-9:00 AM)
take 1 inhalation from the DISKUS followed by 1 inhalation from the SPIRIVA® HANDIHALER® Device.
Each evening (approximately 6:00-9:00 PM) approximately 12 hours after the morning dosing with the
DISKUS, take 1 inhalation from the DISKUS. Record the total number of inhalations of double-blind
study medication you took each day from the DISKUS and the total number of inhalations of open-blind
study medication you took each day from the SPIRIVA® HANDIHALER® Device.
5. Medical Problems/Medications Taken Worksheet. Record all medical problems which may have occurred
on that date, AND all medication(s) you took on that date to treat the problem on the separate Medical Problems/
Medications Taken Worksheet page. Do not include study-related medications.
US:ENG (United States/English)
SPIRIVA® and HANDIHALER® are trademarks of Boehringer Ingelheim.
100
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*400*
CONFIDENTIAL
use only
Page
400
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 4
SUBJECT DAILY DIARY
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 401 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
101
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 4
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
102
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*401*
CONFIDENTIAL
use only
Page
401
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 4
SUBJECT DAILY DIARY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 402 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
103
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 4
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
104
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*402*
CONFIDENTIAL
use only
Page
402
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 4
SUBJECT DAILY DIARY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 403 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
105
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 4
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
106
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*403*
CONFIDENTIAL
use only
Page
403
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 4
SUBJECT DAILY DIARY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 404 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
107
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 4
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
108
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*404*
CONFIDENTIAL
use only
Page
404
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 4
SUBJECT DAILY DIARY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
109
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 4
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
110
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Subject Visit 5 Diary
Confidential
Subject Identifier
{{{{{{}
ADC111114
REMINDERS:
• Bring this diary and all study medications with you to your next clinic visit.
• Do not take any new COPD medications without first contacting the study
investigator or research coordinator.
• Do not write your name or initials anywhere on this diary.
• Withhold albuterol for at least 6 hours prior to your Visit 6 clinic visit. If you have
taken albuterol within 6 hours prior to the visit, contact the clinic to reschedule Visit 6.
• Withhold your morning dose of blinded study medication prior to the Visit 6 clinic
visit. If you have taken your morning dose of blinded study medication prior to Visit 6,
contact the clinic to reschedule the visit.
Date of Visit 6 Clinic Visit:
Day
Month
Year
Study contact name: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Study site telephone number: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
US:ENG (United States/English)
111
RM2010/00132/00
ADC111114
CONFIDENTIAL
CONFIDENTIAL
Protocol Identifier
ADC111114
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
DAILY DIARY INSTRUCTIONS
Reminders:
• Bring this Diary and all study medications to each clinic visit.
• Do not take any new medications, other than the study medication provided for this study, without first
contacting the study doctor.
• Do not write your name or initials anywhere on this diary.
General rules for Diary completion:
• Print neatly using only black or blue ink. Do NOT use pencil.
• Draw one line through any changes or mistakes and re-enter the correct information above/beside.
• DO NOT use correction fluid or tape.
Record the following information in this diary every day.
1. Date. Record dates in DD MMM YY format (for example: 15 OCT 08).
2. Daily Albuterol Use. If you required albuterol for COPD symptoms during the last 24 hour period, record the total
number of puffs administered. If none, enter zero (0).
3. Daily Albuterol Nebule Use. If you required albuterol nebules for COPD symptoms during the last 24 hour
period, record the total number of nebules administered. If none, enter zero (0).
4. Morning (AM) and Evening (PM) Study Medication Taken. Each morning (approximately 6:00-9:00 AM)
take 1 inhalation from the DISKUS followed by 1 inhalation from the SPIRIVA® HANDIHALER® Device.
Each evening (approximately 6:00-9:00 PM) approximately 12 hours after the morning dosing with the
DISKUS, take 1 inhalation from the DISKUS. Record the total number of inhalations of double-blind
study medication you took each day from the DISKUS and the total number of inhalations of open-blind
study medication you took each day from the SPIRIVA® HANDIHALER® Device.
5. Medical Problems/Medications Taken Worksheet. Record all medical problems which may have occurred
on that date, AND all medication(s) you took on that date to treat the problem on the separate Medical Problems/
Medications Taken Worksheet page. Do not include study-related medications.
US:ENG (United States/English)
SPIRIVA® and HANDIHALER® are trademarks of Boehringer Ingelheim.
112
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*500*
CONFIDENTIAL
use only
Page
500
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 5
SUBJECT DAILY DIARY
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 501 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
113
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 5
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
114
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*501*
CONFIDENTIAL
use only
Page
501
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 5
SUBJECT DAILY DIARYY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 502 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
115
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 5
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
116
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*502*
CONFIDENTIAL
use only
Page
502
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 5
SUBJECT DAILY DIARY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 503 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
117
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 5
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
118
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
RM2010/00132/00
ADC111114
8.
RM2010/00132/00
ADC111114
CONFIDENTIAL
*ADC111114*
000001P
For
*503*
CONFIDENTIAL
use only
Page
503
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 5
SUBJECT DAILY DIARY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
TURN TO PAGE 504 TO CONTINUE RECORDING YOUR DAILY DIARY ENTRIES.
119
Final CRF Amendment 1 - 12 NOV 08
Final - 26 SEP 08
CONFIDENTIAL
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 5
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
120
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
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*ADC111114*
000001P
For
*504*
CONFIDENTIAL
use only
Page
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Final - 26 SEP 08
Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
Visit 5
SUBJECT DAILY DIARY (Continued)
Date of assessment
Day Month Year
e.g.,
15 OCT 08
Number of inhalations Number of inhalations
Number of
Number of puffs
of open-label
of double-blind
rescue albuterol
of rescue
SPIRIVA®
DISKUS
albuterol taken nebules used
HANDIHALER®
during the last during the last study medication taken
during the last 24 hours study medication taken
24 hours
24 hours
(AM and PM dosing) during the last 24 hours
(AM dosing only)
2
0
2
1
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
REMINDER: Complete the Medical Problems/Medications Taken Worksheet if you experience any medical
problems and take medication(s) for the problem(s).
US:ENG (United States/English)
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Protocol Identifier
Subject Identifier
Visit Description
ADC111114
{{{{{{}
WORKSHEET
Visit 5
MEDICAL PROBLEMS / MEDICATIONS TAKEN WORKSHEET
Record all medical problems which may have occurred on that date, AND all medication(s) you took on that date to treat the problem.
Medical Problem
Headache
1.
122
2.
3.
4.
Date Medical
Problem
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
Medication(s) Taken
for Medical Problem
2 Extra-Strength Tylenol
Date Medication
Started
Date Medication
Stopped
Day Month Year
Day Month Year
15 OCT 08
15 OCT 08
CONFIDENTIAL
e.g.,
Date Medical
Problem Started
5.
6.
7.
9.
10.
11.
12.
13.
14.
US:ENG (United States/English)
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Visit 2 (Randomization)
Confidential
Subject Identifier
{{{{{{}
ADC111114
Subject-Completed Rating Scales & Questionnaires:
•
Chronic Respiratory Questionnaire
Self-administered Standardized Activities
•
Quick Inventory Of Depressive Symptomatology
(16-item) (Self-report) (QIDS-SR16)
•
Hospital Anxiety And Depression Scale (HADS)
(US:ENG (United States/English)
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Visit 4
Confidential
Subject Identifier
{{{{{{}
ADC111114
Subject-Completed Rating Scales & Questionnaires:
•
Chronic Respiratory Questionnaire
Self-administered Standardized Activities
•
Quick Inventory Of Depressive Symptomatology
(16-item) (Self-report) (QIDS-SR16)
•
Hospital Anxiety And Depression Scale (HADS)
(US:ENG (United States/English)
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Visit 6
Confidential
Subject Identifier
{{{{{{}
ADC111114
Subject-Completed Rating Scales & Questionnaires:
•
Chronic Respiratory Questionnaire
Self-administered Standardized Activities
•
Quick Inventory Of Depressive Symptomatology
(16-item) (Self-report) (QIDS-SR16)
•
Hospital Anxiety And Depression Scale (HADS)
(US:ENG (USA/English)
155
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Early Withdrawal
Confidential
Subject Identifier
{{{{{{}
ADC111114
Subject-Completed Rating Scales & Questionnaires:
•
Chronic Respiratory Questionnaire
Self-administered Standardized Activities
•
Quick Inventory Of Depressive Symptomatology
(16-item) (Self-report) (QIDS-SR16)
•
Hospital Anxiety And Depression Scale (HADS)
(US:ENG (United States/English)
171
LIST OF INVESTIGATORS AND IECS/IRBS FOR ADC111114
Investigator
Sub-Investigator
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no
Hospital/ Institution and
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and Name of Committee
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Investigator/ Site
no
Hospital/ Institution and
Address
IEC/IRB Committee Chair
and Name of Committee
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(NO
PATIENTS RANDOMISED
Site)
Sub-Investigator
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Sub-Investigator
Investigator/ Site
no
Hospital/ Institution and
Address
IEC/IRB Committee Chair
and Name of Committee
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Investigator
Sub-Investigator
Investigator/ Site
no
Hospital/ Institution and
Address
IEC/IRB Committee Chair
and Name of Committee
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4
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Investigator
Sub-Investigator
Investigator/ Site
no
Hospital/ Institution and
Address
IEC/IRB Committee Chair
and Name of Committee
5
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,
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Investigator
Sub-Investigator
Investigator/ Site
no
Hospital/ Institution and
Address
IEC/IRB Committee Chair
and Name of Committee
(NO PATIENTS
RANDOMISED Site)
None
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,
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Investigator
Sub-Investigator
Investigator/ Site
no
Hospital/ Institution and
Address
IEC/IRB Committee Chair
and Name of Committee
United
States
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Investigator
Sub-Investigator
Investigator/ Site
no
Hospital/ Institution and
Address
IEC/IRB Committee Chair
and Name of Committee
None
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Investigator
Sub-Investigator
Investigator/ Site
no
Hospital/ Institution and
Address
IEC/IRB Committee Chair
and Name of Committee
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This section contained Principal Investigator’s Curriculum Vitae and has been excluded
to protect Principal Investigator privacy
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Study Title: A Randomized, Double-Blind, Parallel-Group, 24-Week Study to Evaluate the
Efficacy and Safety of ADVAIR DISKUS (Fluticasone Propionate/Salmeterol Combination
Product 250/50mcg Inhalation Powder) BID Plus SPIRIVA® HANDIHALER® (Tiotropium
Bromide Inhalation Powder 18mcg) QD Versus SPIRIVA® QD Plus Placebo DISKUS BID in
Subjects with Chronic Obstructive Pulmonary Disease (COPD)
Identifier: RM2007/00725/00
Sponsor:GlaxoSmithKline
SPIRIVA® and HANDIHALER® are trademarks of Boehringer Ingelheim
ADVAIR DISKUS plus SPIRIVA® compared with SPIRIVA® alone in
patients with COPD
Study Doctor:
Institution Name:
Site Address:
Phone Number:
After Hours Number:
Subject identification/number:
This paper describes a clinical trial, a type of research study. We, the study staff, will
explain the study to you. The study only includes people who choose to take part.
Some of the information in this form is required by law. This form has been reviewed
and approved by
IRB. This committee reviews research studies to protect
the rights and well being of the people taking part.
What is “consent”?
It is up to you to decide if you want to take part in this study.
If you decide to join, you must sign the pages at the end of this form to show that you
agree to be part of the study. This is called “giving consent.”
You should make your decision only after:
1. A study staff person has explained the study to you
2. You know the purpose of the study and the risks, and
3. You are willing to do what is asked of you in the study.
Talk with your family, friends, and your doctor to help you make your decision. You
can take as much time as you like.
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You may change your mind at any time during the study. You may leave the study at
any time, even if you have signed this form. You do not have to give a reason.
Who should I call if I have any questions?
You can talk with the study doctor about any questions or concerns you have about
this study. The study doctor may be contacted via the information on page 1 of this
form.
If you have any questions about the rights you have while taking part in this study,
you may call
IRB toll free at
or at
.
If you think you have been hurt from taking part in this study, or have any questions
about side effects, call the study doctor at the number listed on page 1 of this form.
Why is this study being done?
We are inviting you to join this study because you have COPD.
The purpose of this study is to see how well your COPD responds to a combination of
medicines compared with one medicine alone. It will compare using ADVAIR
DISKUS (fluticasone propionate/salmeterol dry powder inhaler) plus SPIRIVA®
(tiotropium bromide) with just taking SPIRIVA®.
You may have heard of ADVAIR DISKUS or SPIRIVA®. Both medicines are
approved for the treatment of COPD.
About 350 men and women in the United States will take part in this study. Once we
have about 350 people who agree to be part of the study, we will not invite any more.
Do I have other treatment choices?
Taking part in this study may not make your health better. You may choose to:
Continue to get regular care from your doctor
Take part in another study
Get no treatment at this time.
Talk with your doctor about your choices.
How does the study work?
This study will compare ADVAIR DISKUS plus SPIRIVA® and SPIRIVA® alone.
One group of people will take ADVAIR DISKUS plus SPIRIVA® and another group
will take only SPIRIVA®. The effects of the drugs, both good and bad, will be
compared.
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The study doctor and the people who take part won’t know which group is getting
which treatment. This way, the findings from the two groups will be handled in the
same way.
A computer will put people into groups by chance. You have a 50% chance of being
placed in either group. Neither you nor the study doctor can choose a group. During
the study, neither you nor the study doctor will know which group you are in. You
will be told only in case of emergency.
Information about how the study drug you get affects your body and your health will
be collected through a number of tests and procedures.
What am I expected to do in this study?
This study will last about 30 weeks. During this time, you will need to get tests, visit
the clinic on schedule, and tell us about any changes.
Before you begin the study:
You will need to have the following exams, tests or procedures to find out if you can
be in the study. These tests are part of regular medical care and may be done even if
you do not join the study. If you have had some of them recently, they may not need
to be repeated. This is up to the study doctor.
Medical history: We will ask about your health, and any illnesses or
medicines you are taking (including over-the-counter medicine, vitamins or
herbal treatments).
Smoking history: We will ask you how many cigarettes per day you have
smoked and for how many years you have smoked.
Physical examination: You will receive a complete physical examination.
Electrocardiogram (ECG): This will record the electrical activity of your
heart.
Vital signs: We will check your weight, height, blood pressure and pulse.
Pregnancy test: If you are a woman and can have children, a urine test will be
done to see if you are pregnant.
Lung function (breathing test): This test will measure how well your lungs
are working by breathing into a machine called a spirometer.
Reversibility test: This test measures any improvement in your breathing
when you inhale albuterol (a drug that opens the air passages in your lungs).
Your lung function will be measured before and after you inhale albuterol.
During the study:
You will be expected to do the following things during the study:
1. You will have to take the study drug ADVAIR DISKUS twice a day and the study
drug SPIRIVA® once a day. If you are in the group taking SPIRIVA® only, you
will take SPIRIVA® once a day plus a placebo DISKUS twice a day. A placebo
contains no study drug.
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2. You will need to come to our clinic/office/hospital for scheduled visits every
month for a few visits and then every 2 months for a few visits.
3. You will be asked to have the following tests or procedures done to see how the
study is affecting your body.
Smoking status (Visits 2, 3, 4, 5, 6, and early withdrawal)
Medications you are currently taking (Visits 2, 3, 4, 5, 6, and early
withdrawal).
Breathlessness rating (Visit 2): You will be asked to rate your level of
breathlessness on a scale of “0” to “4.”
Questionnaire (Visits 2, 4, 6, and early withdrawal): You will be asked
some questions about your quality of life.
Questionnaire (Visits 2, 4, 6, and early withdrawal): You will be asked
some questions about your mood such as depressive symptoms.
Questionnaire (Visits 2, 4, 6, and early withdrawal): You will be asked
some questions about your mood such as depressive and anxiety symptoms.
Lung function (Breathing tests): (Visits 2, 3, 4, 5, and 6): You will be
asked to do these tests before and 2 hours after you have taken your study
medication(s).
Urine pregnancy test: (Visits 2, 3, 4, 5, 6, and early withdrawal)
Pneumonia: (Visits 2, 3, 4, 5, 6. and early withdrawal): If you have
pneumonia during the study, you will be asked questions about your
pneumonia, any treatment you received, etc.
Diary cards (Visits 1, 2, 3, 4, and 5): You will make daily recordings on
your diary card of your albuterol use, any medical problems you have
experienced, and any medications taken to treat the medical problems.
Review of DISKUS and HANDIHALER® technique: (Visits 2, 3, 4, and
5): You will receive instructions on the proper use of the DISKUS and
HANDIHALER® from the study staff.
Questions:
You will be asked about any medical problems you have experienced (all visits and
follow-up phone call). You will be asked about any medications you may have taken
(all visits).
You will also be asked to do the following:
Keep all clinic appointments
Take all study medications as directed
Return unused study drug at each visit
Use medication for the relief of breathing symptoms as necessary
Complete a daily diary to be returned to the study staff at each study visit, as
instructed.
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After the study:
You will receive a follow-up phone call from the study doctor or study staff member
approximately 2 weeks after you stop the study to ask you about any adverse events
you may have had since you stopped the study.
Females will also be asked if they became pregnant after stopping the study. If you stop
the study early (before Visit 6) you will also receive a follow-up phone contact.
After the whole study is finished, we will tell you which drug you were given.
How will being part of this study affect my lifestyle?
When deciding whether to take part in this study, consider how the tests and visits
listed above will affect your work and family schedules. Consider if you need
transportation to get to the clinic.
You may find that these tests and visits are inconvenient and require special effort. In
addition, some tests may be uncomfortable. Ask us if you have any questions about
the tests and procedures for the study.
You will need to allow enough time for phone calls from study staff. You will need
to allow enough time each day to complete your forms/diary.
You should not take the following medicines during the study:
Ritonavir
Long-acting beta-agonist/inhaled corticosteroid compounds
Inhaled corticosteroids
Systemic corticosteroids
Any other investigational drug
Theophylline preparations
Tiotropium (SPIRIVA®)
Salmeterol (SEREVENT) or Formoterol
Oral beta-agonists
Ipratropium or ipratropium/albuterol combination products
You should not participate in this study if you started a particular type of blood
pressure medicine called a beta-blocker medication within 30 days prior to Visit 1 or
if your blood pressure is not well controlled on that medicine.
You should not participate in this study if you use night time positive pressure devices
(e.g., CPAP or Bi-PAP)
You should not participate in this study if you use long-term oxygen.
Talk with the study doctor before you start any new prescriptions.
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As part of the study and in order to take the study drug, you should:
Not drink alcohol excessively
Drink in moderation coffee or tea, and eat other foods with caffeine in
moderation
Not use recreational drugs
If you are a woman who can get pregnant, you will need to use birth control while in
this study.
Check with the study doctor about what kind of birth control methods to use and how
long to use them. Some methods may not be approved for use during this study.
Do I have to stay in the study?
You may choose to stop being in the study at any time, without giving a reason. Your
decision will not affect the future medical care you receive.
Call the study doctor if you change your mind and decide that you no longer want to
take part.
We will share with you any new information that might affect your choice to stay in
the study.
We may ask you to leave the study if:
The results of certain tests show that you are not right for this study or for the
study drug
You cannot follow instructions for treatment or follow-up visits
You get any new health problems during the study
You get pregnant or decide that you want to become pregnant
The study doctor thinks it is in your best interest to stop
GSK (the study sponsor), the regulatory authority, or the study doctor may choose to
stop the study at any time. We will give you the reason at that time.
What happens if I leave the study?
There may be problems after stopping the study drug.
Suddenly withdrawing
medications that treat your COPD can cause your symptoms to worsen. Be sure you
talk to your physician about alternative treatment for your lung disease if you decide
to stop treatment in the study. We will contact you approximately 2 weeks after you
have stopped taking study drug to ask about any medical problems you have
experienced since leaving the study. We will ask you to return any leftover study
drug.
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If you leave the study, no more information about you will be collected for the study.
But all the information you gave us before you left the study will still be used for the
study.
What side effects or risks can I expect from this study?
You may have side effects while on this study. We will watch everyone in the study
for any side effects.
Side effects may be mild or serious. We may give you medicines to help lessen side
effects. Some side effects will go away as soon as you stop taking the drug. In some
cases, side effects can be serious, lasting or may never go away.
Risks Associated with Study Procedures
The lung function tests using a spirometer are accepted diagnostic procedures
commonly performed in hospitals and medical clinics. These procedures are not
painful, but it is important that you are comfortable using the lung function testing
equipment. Some people may find the lung function testing quite tiring and
repetitive. During the lung function tests you may experience shortness of breath,
coughing, light-headedness or fainting, and/or chest tightness. If any of these things
should happen to you, you will receive medical treatment. There are no likely longterm side effects and no serious risks are expected.
A chest x-ray uses a small amount of radiation to produce an image (picture) of your
lungs.
There may be unknown risks and inconveniences to the subject associated with any of
the study tests/procedures.
Risks Associated with Study Medicines
Albuterol inhalation aerosol
Albuterol is available by prescription.
Call your study doctor right away if you have any of these side effects:
There have been very rare reports of serious allergic reactions manifesting as
hives swelling of the face, mouth, and tongue, and breathing problems. Call
your healthcare provider or get emergency medical care immediately if you
get any symptoms of a severe allergic reaction.
The following side effects may be likely:
Headache
Increased pulse rate
Tremor (shakiness of the hands)
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The following side effects are less likely:
Awareness of heart pounding or racing
Mouth/throat irritation
Muscle cramps
The following side effects are rare:
Skin flushing
Low blood potassium
Irregular heart beat/heart rhythm problems
Hyperactivity
An immediate increase in wheeze after dosing
Fluticasone propionate/salmeterol (ADVAIR DISKUS):
Call your study doctor right away if you have any of these side effects:
There have been rare reports of serious allergic reactions manifesting as hives
swelling of the face, mouth, and tongue, and breathing problems and very
rarely more severe allergic (anaphylactic) reactions have been reported. Call
your healthcare provider or get emergency medical care immediately if you
get any symptoms of a severe allergic reaction.
The following side effects may be likely:
Fungal infections of the mouth and throat
Hoarseness
Irritated throat
Viral respiratory infections
Headache
Tremor (shakiness of the hands)
Musculoskeletal pain
Pneumonia
Awareness of heart pounding or racing
The following side effects are less likely:
Rash
Bruising
Increased pulse rate
The following side effects are rare:
Muscle cramps
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The following side effects are very rare:
Hyperactivity/irritability
Sleep disorders
Increase in blood sugar levels
Feeling anxious
Rounded face
Immediate increase in wheeze after dosing
Lower bone mineral density
Eye problems (cataracts, glaucoma)
Joint pains
Irregular heart beat/heart rhythm problems
Low blood potassium and increased blood pressure can also occur with the class of
drugs salmeterol (a component of ADVAIR®) belongs to.
ADVAIR® contains two medicines. One of the medicines is fluticasone propionate
(FLOVENT®). Fluticasone propionate is an inhaled corticosteroid, a medicine that
reduces inflammation in the airways of the lungs. The other medicine is salmeterol
(SEREVENT®), a long-acting beta2-agonist medicine that gradually opens up
narrowed airways of the lungs.
There is the possibility that the fluticasone propionate component of ADVAIR®
could reduce the normal production of cortisol by your adrenal glands (HPA
suppression). Cortisol is a natural hormone needed to maintain regular body
functions, and if it is decreased, you may suffer symptoms of fatigue, dizziness, and
low blood pressure.
Salmeterol is one of the drugs in the combination drug of fluticasone
propionate/salmeterol, and data from a large placebo-controlled US study that
compared the safety of salmeterol (SEREVENT® Inhalation Aerosol) or placebo
added to usual asthma therapy showed a small but significant increase in asthmarelated deaths in patients receiving salmeterol (13 deaths out of 13,176 patients
treated for 28 weeks) versus those on placebo (3 out of 13,179). Subgroup analyses
suggest the risk may be greater in African American patients compared to Caucasians.
This study was stopped early because of the findings in African Americans and
difficulties in enrollment. This study was not designed to show whether the use of an
inhaled steroid like fluticasone propionate, the other component of the combination
drug, protects from the risk. Therefore, it is not known whether the findings of this
study apply to the combination drug of fluticasone propionate/salmeterol.
ADVAIR should be used with caution in patients with thyrotoxicosis.
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Tiotropium Bromide (SPIRIVA®)
Call your study doctor right away if you have any of these side effects:
Immediate hypersensitivity reactions may occur after administration of
tiotropium bromide inhalation powder. Call your healthcare provider or get
emergency medical care immediately if you get any symptoms of a severe
allergic reaction.
The following side effects may be likely:
Accidents
Chest pain
Swelling
Abdominal pain
Constipation
Dry mouth
Indigestion
Vomiting
Muscle pain
Infection
Mouth/throat infection
Nosebleed
Inflammation of the pharynx
Inflammation of the nose
Inflammation of the sinuses
Upper respiratory tract infection
Rash
Urinary tract infection
Arthritis
Coughing
Flu-like symptoms
The following side effects are less likely:
Allergic reaction
Leg pain
Difficulty speaking
Tingling/numbing sensation of the skin
Gastrointestinal disorder
Inflammation of the stomach
Inflammation of the lining of the mouth
High cholesterol
Low blood sugar
Skeletal pain
Acute heart pain
Depression
Herpes zoster
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Laryngitis
Cataracts
The following side effects are rare:
Abnormal heart rhythm
Rapid heartbeat
Rapid swelling of the skin or mucous membranes
Urinary retention
In common with all inhaled medications, tiotropium may cause inhalation-induced
bronchospasm. Local upper airway irritant phenomena have also been observed in
patients receiving tiotropium bromide.
Tiotropium bromide should be used with caution in patients with narrow-angle
glaucoma, prostatic hyperplasia or bladder-neck obstruction.
There may be other side effects that may happen that are not known now. For
example, all drugs can cause an allergic reaction in some patients. Certain problems
can be dangerous if not treated quickly; call your doctor right away if you:
Feel very tired or faint
Feel pain or sick in your stomach and not want to eat
Bruise easily or develop itching
Have yellow eyes or skin, or dark urine
Become confused.
If you experience certain serious problems (such as an allergic reaction, swelling,
difficulty breathing, a bad skin rash, liver or kidney damage, or changes in your heart
rhythm), you may be asked to return to the clinic for more assessments, which may
include more blood tests. Your doctor will explain these tests to you if they are
needed. You may also need to stop taking the study drug after talking with your
study doctor.
You should not take part in this study if you are pregnant. Mothers should not
breastfeed a baby while on this study.
You should not become pregnant while you are in this study because the drugs in this
study may affect an unborn baby.
If you get pregnant during this study, call the study doctor right away. You may be
asked questions later about the pregnancy and the baby.
Ask the study doctor if you have any questions about side effects.
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What benefits can I expect from this study?
Taking part in this study may or may not make your health/condition better.
Information from this study will help doctors learn more about COPD and treatment
for COPD. This information will help future COPD patients.
Will I be compensated for being part of this study?
You may receive $
per study visit that you complete to reimburse you for the
cost of study participation. If you withdraw from the study early, you will only be
compensated for the visits that you complete.
Will I have to pay anything to be part of this study?
As part of the study, you will receive the study drug and all the study tests and
procedures at no cost to you.
You and your insurance company will continue to pay for your regular health care.
What happens if I get hurt taking part in this study?
GSK will pay your out-of-pocket costs (not covered by insurance) for reasonable and
necessary care if you are hurt by the study drug or a procedure that is done to you
only because you are part of this study.
Signing this consent form does not change any legal rights you may have.
Who is GlaxoSmithKline and what does it do?
GlaxoSmithKline is a company that creates and makes medicines and other health
products. It is also called “GSK.”
GSK pays the study doctor to run this study.
Information about this study is confidential. This information belongs to GSK. We
ask that you keep it private. You can discuss this information in private with your
doctor or family to talk about your healthcare or to decide about taking part in this
study.
What is the “pharmacogenetics” part of this study and why is it being done?
The purpose of the pharmacogenetics part of this study is to see why different people
may react differently to medicines. This research is called “pharmacogenetics.”
Scientists will look for differences in people’s genes that might explain this. We get
our genes from our parents, and different genes may affect how a body reacts to a
drug.
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Joining this part of the study is optional. This means that you may:
Choose not to join the pharmacogenetics part of the study but still take part in
the main study.
Choose to join and then change your mind before your sample is taken or at
any time in the study.
Choose to not join at this time, but decide to join later. If so, please talk to
your study doctor.
If you choose to stop the pharmacogenetics part of the study after giving a sample, we
will destroy it within 30 days. If you stop the main part of the study after giving a
sample, you can ask us to destroy it. If your sample is being processed we will have
to wait until all steps are done before we can destroy it. This might be longer than 30
days. GSK will not use your data for analysis.
If you choose to take part in the pharmacogenetics study, we will collect about 1
teaspoon of saliva. If there is a problem looking at your saliva sample, we may ask to
take the sample again.
What benefits can I expect from the pharmacogenetics part of the study?
If you take part in the pharmacogenetics part of the study and agree to give a sample,
you may help scientists understand why people react to or handle COPD differently.
This may help identify who is more likely to benefit from COPD and who may have
side effects.
What happens to my samples?
As mentioned earlier, if you take part in the study, you will be asked to give saliva
samples for pharmacogenetic research. Similar to information, samples may be used
by GSK or shared by GSK with other companies or universities to better understand
COPD, other diseases or conditions, or to further develop the study drug or other
drugs.
Your samples will be given the same code as your other study information and kept in
locked storage. Anyone who works with your samples will hold the information and
results in confidence.
GSK may store your tissue samples for 15 years after the end of the study.
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CONSENT for [ADVAIR DISKUS plus SPIRIVA® compared with SPIRIVA®
alone in patients with COPD] Study
By signing below, I show that:
1. I have read this form, and the study has been explained to me.
2. I have discussed the study and asked questions. I am satisfied with the
answers.
3. I have had time to make my decision.
4. I freely agree to take part in the study described in this form.
5. I have been given names of study staff whom I can call.
6. I agree that GSK, study staff, and others may have access to my medical and
personal information, as described in this form.
Signature
Date
Printed name
Signature of legal representative [if any]
Date
Printed name of legal representative
Signature of witness [if any]
Date
Printed name of witness
Signature of study staff conducting consent
Date
Printed name of study staff
IRB Version Control
Version: 4-0
Sponsor Version: 06 Jan 2009
Approved by
IRB, LLC
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Date: 06 Jan 2009
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CONSENT for the Pharmacogenetics Part of the [ADVAIR DISKUS plus
SPIRIVA® compared with SPIRIVA® alone in patients with COPD] Study
By signing below, I show that:
1. I have read this form, and the pharmacogenetics part of the study has been
explained to me.
2. I have discussed the study and asked questions. I am satisfied with the
answers.
3. I have had time to make my decision.
4. I freely agree to give a pharmacogenetics saliva sample, as described in this
form.
5. I agree that GSK, study staff, and others may have access to my medical and
personal information, as described in this form.
Signature
Date
Printed name
Signature of legal representative [if any]
Date
Printed name of legal representative
________________________________________________________________________
Signature of witness [if any]
Date
Printed name of witness
Signature of study staff conducting consent
Date
Printed name of study staff
IRB Version Control
Version: 4-0
Sponsor Version: 06 Jan 2009
Approved by
IRB, LLC
TEMPLATE ONLY
Date: 06 Jan 2009
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Will my information be kept private?
If you decide to take part in the study, you give us permission to use
information about you and share it with GSK and others. This permission
continues until the study is over, including the length of time that we must
keep records about the study.
Personal and medical information about you will be kept confidential. It
will be kept in a secured file. At any time, you may ask to see your personal
information (such as name and address) and correct it if necessary.
Your study information will be used in two ways.
1. Study management
Information collected in the study about you will be checked to make sure
that the study is being run properly. People who work for or with GSK, and
others (like the ethics board or government officials who approve new
drugs) will check how the study is run. They will keep all information
confidential.
2. Study findings
Medical information about you will be combined with information about
other people in the study. This study information will be used to learn about
the study drug. Information will be labeled with a code number, and will not
include your name or other information that directly identifies you.
During the study, we may find new medical information about you. We will
share this with you right away if it is important to your health. We may
advise you to get other tests to check this new information. Once the study
is over, you can see any medical information about yourself.
Study information about you that is not helpful to your health care (like most
genetic research information) will not be given to you or others (unless it is
required by a government agency or other legal authority). This means that
no one (not you, your family, your doctor, your insurance company, or your
employer) will have access to this information during the study.
If you do get genetic research information and share it with others, there is a
chance it may affect your insurance or employment.
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Once your personal or medical information is shared with someone who is
not a health care provider, it is not protected by the US federal privacy rules
(called HIPAA).
When you sign this consent form, you agree to have your personal and
medical information used as described here.
What does GSK do with the study information?
We will send coded information to GSK. GSK may:
Keep it and analyze it by computer to find out what this study is
telling us
Share it with officials who approve new drugs, or with groups that
check that studies are done properly
Write up the study results for medical journals
Share it with other companies or universities to better understand
COPD or to further develop the study drug or other drugs
Use it to plan new studies to further develop the study drug or learn
more about COPD and/or other diseases or conditions.
Share parts of the study with other GSK offices here and in other
countries. If the information is sent to another country anywhere in
the world, GSK will apply the same level of protection to your
information, to the extent permitted by local law.
Your name will not appear in any of these reports.
GSK will be the owner of the study results. GSK plans to use the results, and
may get patents, or sell the drug in the future, or make profits other ways.
You will not be paid any part of this.
You may decide not to sign this authorization (by choosing not to sign this
consent form), or you may revoke (cancel) this authorization in writing at
any time. However, you can only participate in the study if you authorize
the use and disclosure of the information as described above. If you decide
not to sign this consent form, you will not be enrolled in the study. If you
sign this consent form and decide later to revoke this authorization, you will
be dropped from the study at that time. Information collected up to the time
you revoke this authorization will continue to be used as study information if
it is necessary to maintain the integrity of the study.
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This authorization does not expire, unless you live in California, in which
case this authorization expires 50 years from the date of your signature.
By signing below, I show that:
1. I have read this form, and the study has been explained to me.
2. I have discussed the study and asked questions. I am satisfied with the
answers.
3. I have had time to make my decision.
4. I freely agree to take part in the study described in this form.
5. I have been given names of study staff whom I can call.
6. I agree that GSK, study staff, and others may have access to my
medical and personal information, as described in this form.
7. I agree that my information may be shared with people who are not
healthcare providers and that the information would no longer be
protected by HIPAA.
8. I agree that the study doctor may tell my doctor that I am taking part
in this study
Signature
Date
Printed name
Signature of legal representative [if any]
Date
Printed name of legal representative
________________________________________________________________
Signature of witness [if any]
Date
Printed name of witness
Signature of study staff conducting consent
Date
Printed name of study staff
IRB Version Control
Version: 4-0
Sponsor Version: 06 Jan 2009
Approved by
IRB, LLC
TEMPLATE ONLY
Date: 06 Jan 2009
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Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
1. Sequence and Treatment Definitions
Treatments
Sequence
FSC250/50+Tio
Tiotropium
Report generated by:
Code
Description
1
2
FSC250/50+Tio
Tiotropium
on: 29-MAR-2010
1
Period
1
1
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StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
2. Randomisation Schedule - Treatment or Sequence Assignments
Schedule: 1
Stratum
Reversible
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
2
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StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
3
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Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
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Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
5
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Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
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Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
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ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
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Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
9
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ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
10
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ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
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Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
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Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
13
Page 13 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
14
Page 14 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
15
Page 15 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
16
Page 16 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
17
Page 17 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
18
Page 18 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
19
Page 19 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
20
Page 20 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
21
Page 21 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
22
Page 22 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
23
Page 23 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
24
Page 24 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
25
Page 25 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
26
Page 26 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
27
Page 27 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
28
Page 28 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
29
Page 29 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
30
Page 30 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
31
Page 31 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
32
Page 32 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
33
Page 33 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
34
Page 34 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
35
Page 35 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
36
Page 36 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
37
Page 37 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
38
Page 38 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
39
Page 39 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
40
Page 40 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
41
Page 41 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
42
Page 42 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
43
Page 43 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
44
Page 44 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
45
Page 45 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
46
Page 46 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
47
Page 47 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
48
Page 48 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
49
Page 49 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
50
Page 50 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
51
Page 51 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
52
Page 52 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
53
Page 53 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
54
Page 54 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
55
Page 55 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
56
Page 56 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
57
Page 57 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
58
Page 58 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
59
Page 59 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
60
Page 60 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
61
Page 61 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
62
Page 62 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
63
Page 63 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
64
Page 64 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
65
Page 65 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
66
Page 66 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
67
Page 67 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
68
Page 68 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
69
Page 69 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
70
Page 70 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
71
Page 71 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
72
Page 72 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
73
Page 73 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
74
Page 74 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
75
Page 75 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
76
Page 76 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
77
Page 77 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
78
Page 78 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
79
Page 79 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
80
Page 80 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
81
Page 81 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
82
Page 82 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
83
Page 83 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
84
Page 84 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
85
Page 85 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
Schedule: 1
Stratum
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Non-Reversible
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
86
Page 86 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
87
Page 87 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
88
Page 88 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
89
Page 89 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
90
Page 90 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
91
Page 91 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
92
Page 92 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
93
Page 93 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
94
Page 94 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
95
Page 95 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
96
Page 96 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
97
Page 97 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
98
Page 98 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
99
Page 99 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
100
Page 100 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
101
Page 101 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
102
Page 102 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
103
Page 103 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
104
Page 104 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
105
Page 105 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
106
Page 106 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
107
Page 107 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
108
Page 108 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
109
Page 109 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
110
Page 110 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
111
Page 111 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
112
Page 112 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
113
Page 113 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
114
Page 114 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
115
Page 115 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
116
Page 116 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
117
Page 117 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
118
Page 118 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
119
Page 119 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
120
Page 120 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
121
Page 121 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
122
Page 122 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
123
Page 123 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
124
Page 124 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
125
Page 125 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
126
Page 126 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
127
Page 127 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
128
Page 128 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
129
Page 129 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
130
Page 130 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
131
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
132
Page 132 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
133
Page 133 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
134
Page 134 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
135
Page 135 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
136
Page 136 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
137
Page 137 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
138
Page 138 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
139
Page 139 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
140
Page 140 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
141
Page 141 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
142
Page 142 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
143
Page 143 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
144
Page 144 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
145
Page 145 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
146
Page 146 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
147
Page 147 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
148
Page 148 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
149
Page 149 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
150
Page 150 of 169
CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
151
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
152
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
153
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
154
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
155
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
156
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
157
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
158
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
159
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
160
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
161
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
162
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
163
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
164
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
165
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Report generated by:
on: 29-MAR-2010
166
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
Report generated by:
on: 29-MAR-2010
167
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
168
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CONFIDENTIAL
RM2010/00132/00
ADC111114
Master Schedule Report
StudyID:
Description:
ADC111114
A Randomized, D-B, P-G, 24-Wk Study to Evaluate the Efficacy & Safety of
ADVAIR DISKUS (Fluticasone Propionate/Salmeterol 250/50mcg) BID Plus
Spiriva HandiHaler (Tiotropium Bromide 18mcg) QD vs. Spiriva QD Plus Placebo
DISKUS BID in Subjects with COPD
Main Schedule
Randomisation Treatment / Sequence
Number
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
FSC250/50+Tio
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Tiotropium
Tiotropium
FSC250/50+Tio
Report generated by:
on: 29-MAR-2010
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ADC111114
ICH Listing
Page
Listing - ICH 1 Listing of Randomized and Actual Treatments (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
2
This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clincal Study Register.
Table 1: Protocol Level Administration
Study Number: ADC111114
Study Title: A Randomized, Double-Blind, Parallel-Group, 24-Week Study to Evaluate the Efficacy and Safety of ADVAIR
DISKUS (Fluticasone Propionate/Salmeterol Combination Product 250/50mcg Inhalation Powder) BID Plus Spiriva HandiHaler
(Tiotropium Bromide Inhalation Powder 18mcg) QD Versus Spiriva QD Plus Placebo DISKUS BID in Subjects with Chronic
Obstructive Pulmonary Disease (COPD)
Statistics Group
Study Sponsor
Address
Data Management
Group
Randomisation
Company and
Address
Address
;
;
GlaxoSmithKline 5
Moore Drive,
Research Triangle
Park, NC 277093398, USA.
GlaxoSmithKline
5 Moore Drive,
Research Triangle
Park, NC 277093398, USA.
GlaxoSmithKline
GlaxoSmithKline Registration and
5 Moore Drive, Medication
Ordering System
Research
(RAMOS)
Triangle Park,
NC 27709-3398, New Frontiers
Science Park
USA.
Third Avenue
Harlow
Essex
CM19 5AW,
United Kingdom.
Site of
Manufacture &
Assembly
Address
GlaxoSmithKline
Ware, Stockley
Park West,
Uxbridge,
Middlesex, UB11
1BT, United
kingdom.
Medical Writing:
Clinical Report
Authorship
Names of authors
and their Address
;
;
GlaxoSmithKlin
e 5 Moore
Drive, Research
Triangle Park,
NC 277093398, USA.
Site of EU
release
Location of Study
Master File
Address
Address
NA
GlaxoSmithKline
New Frontiers
Science Park,
Third Avenue,
Harlow, Essex,
CM19 5AW,
United kingdom.
GCP
Regulatory
inspection
Name of
Agency
NA
CONFIDENTIAL
1
GlaxoSmithKline
Five Moore
Drive, P.O.
13398,
Research
Triangle Park,
NC 27709-3398,
USA.
Medical Writing:
Protocol Authorship
Names of authors
and their Address
Address
RM2010/00132/00
ADC111114
Table 2
Country Level Administration
Study Number: ADC111114
Study Title: A Randomized, Double-Blind, Parallel-Group, 24-Week Study to Evaluate the Efficacy and Safety of ADVAIR
DISKUS (Fluticasone Propionate/Salmeterol Combination Product 250/50mcg Inhalation Powder) BID Plus Spiriva HandiHaler
(Tiotropium Bromide Inhalation Powder 18mcg) QD Versus Spiriva QD Plus Placebo DISKUS BID in Subjects with Chronic
Obstructive Pulmonary Disease (COPD)
Participating
Countries
Responsible for
which sites
Address of resource
Centre Numbers
Laboratory
Assessments
Laboratory name and
address
Sites of distribution
in Europe
Address
Audits
Were Audits done?
Centre Number of
Site(s)
yes/no
Centre numbers
Conducted by:
Name and address of
audit group
NA
NA
United States
2
GlaxoSmithKline,
5 Moore Drive,
PO Box 13398,
Research Triangle
Park,
NC27709.
United States.
NA
NO
CONFIDENTIAL
Country Name
Monitoring
RM2010/00132/00
ADC111114
Study Number: ADC111114
Study Title: A Randomized, Double-Blind, Parallel-Group, 24-Week Study to Evaluate the Efficacy and Safety of ADVAIR
DISKUS (Fluticasone Propionate/Salmeterol Combination Product 250/50mcg Inhalation Powder) BID Plus Spiriva HandiHaler
(Tiotropium Bromide Inhalation Powder 18mcg) QD Versus Spiriva QD Plus Placebo DISKUS BID in Subjects with Chronic
Obstructive Pulmonary Disease (COPD)
Participating
Countries
Responsible for
which sites
Country Name
Monitoring
Address of resource
Centre Numbers
Laboratory
Assessments
Laboratory name and
address
Sites of distribution
in Europe
Address
Audits
Were Audits done?
Centre Number of
Site(s)
yes/no
Centre numbers
Conducted by:
Name and address of
audit group
CONFIDENTIAL
3
RM2010/00132/00
ADC111114
1
1