Observing Fibrosis, Macular Atrophy and Sub retinal
Highly Reflective Material – Before and After
Intervention with Anti-VEGF Treatment:
An extension to the EDNA Study
FASBAT Study
Version 5.0
Protocol date 16th May 2016
Authorised by:
Name:
Mr Richard Gale
Signature:
Name:
Signature:
Role:
Chief Investigator
Date:
Dr Deborah Phillips
Role:
Date:
Sponsor Representative
FASBAT Study
GENERAL INFORMATION
This document describes the FASBAT Study and provides information about procedures for
entering patients into it. The protocol should not be used as an aide-memoire or guide for the
treatment of other patients; every care was taken in its drafting, but corrections or
amendments may be necessary. Clinical problems relating to this study should be referred to
the relevant Chief Investigator.
Compliance
The study will be conducted in compliance the protocol, data protection Act and NHS
research governance.
Sponsor
Dr Deborah Phillips
Research Advisor
York Teaching Hospital NHS Foundation Trust
Wigginton Road
York
YO31 8HE
Funder
Novartis Pharmaceuticals UK Limited
200 Frimley Business Park
GB- Frimley/Camberley, Surrey GU16 7SR
UNITED KINGDOM
Chief Investigators
Dr Richard Gale
York Teaching Hospital NHS Foundation Trust
Wigginton Road
York
YO31 8HE
[email protected]
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FASBAT Study
Study Management Group members
Professor Usha Chakravarthy, University of Belfast
Professor Tony Morland, University of York
Professor Sohba Sivaprasad, Moorfields Eye Hospital, London
Mr Martin Mckibbin, Leeds Teaching Hospitals
Research Fellow / Student TBC
Data Management
Centre for Healthcare Randomised Trials (CHaRT)
3rd Floor
Health Sciences Building
University of Aberdeen
Foresterhill
Aberdeen AB25 2ZD
Telephone: 01224 438196
Study Statistician(s)
Dr Victoria Allgar
Senior Lecturer in Medical Statistics
HYMS/Health Sciences
The University of York
Heslington
York.
YO10 5DD
Telephone: 07775907204
[email protected]
Clinical laboratories, medical and technical departments, institutions
Reading centre
Central Angiographic Resource Facility
Centre for Experimental Medicine
Queen's University Belfast
Grosvenor Road
Belfast BT12 6BA
Northern Ireland
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FASBAT Study
KEY IMPORTANT NOTIFICATIONS
SAE NOTIFICATION
Within 24 hours of becoming aware of an SAE fax a completed SAE
form to the R&D Unit on:
Fax: 01904 725700
Refer to R&D/S05
ADR NOTIFICATION
Within 24 hours of becoming aware of an ADR fax a completed
ADR form to the R&D Unit on:
Fax: 01904 725700
Refer to R&D/S05
SERIOUS BREACH
Within 24 hours of becoming aware of a Serious Breach, fax a
completed Notification of Breach to Sponsor form to the R&D Unit:
Fax: 01904 725700
Refer to R&D/S04
URGENT SAFETY MEASURE
(INCLUDING PARTICIPANT PREGNANCY)
Contact the CI and Sponsor immediately:
Fax: 01904 725700
Refer to R&D/S04
AMENDMENTS
Any amendment must first be assessed by and agreed with the Sponsor (unless an
Urgent Safety Measure). Any request should be made in writing to the R&D Unit:
[email protected]
Refer to R&D/S74
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FASBAT Study
CONTENTS TABLE
1
BACKGROUND........................................................................................................................................... 3
2
AIMS AND OBJECTIVES .......................................................................................................................... 8
2.1
2.2
2.3
2.4
3
SELECTION OF CENTRES/CLINICIANS ............................................................................................. 9
3.1
3.2
4
FLOW CHART/SCHEDULE FOR FOLLOW-UP ........................................................................................... 14
PROCEDURES FOR ASSESSING EFFICACY ............................................................................................... 15
PROCEDURES FOR ASSESSING SAFETY .................................................................................................. 15
LOSS TO FOLLOW-UP ............................................................................................................................ 15
STUDY CLOSURE................................................................................................................................... 15
ARCHIVING........................................................................................................................................... 16
WITHDRAWAL OF PATIENTS ............................................................................................................. 16
8.1
8.2
8.3
9
DATA SOURCE ...................................................................................................................................... 12
POPULATION......................................................................................................................................... 12
NUMBER OF CENTRES & PATIENTS ....................................................................................................... 12
SAMPLE SIZE ........................................................................................................................................ 12
ANALYSIS PLAN ................................................................................................................................... 12
EVALUATION CRITERIA ........................................................................................................................ 13
ASSESSMENTS AND FOLLOW-UP ...................................................................................................... 14
7.1
7.2
7.3
7.4
7.5
7.6
8
CO-ENROLMENT GUIDELINES ............................................................................................................... 10
OBTAINING INFORMED CONSENT .......................................................................................................... 10
METHODOLOGY ..................................................................................................................................... 11
6.1
6.2
6.3
6.4
6.5
6.6
7
PATIENT INCLUSION CRITERIA ................................................................................................................ 9
PATIENT EXCLUSION CRITERIA ............................................................................................................... 9
NUMBER AND SOURCE OF PATIENTS ..................................................................................................... 10
SCREENING PROCEDURES AND PRE-RANDOMISATION INVESTIGATIONS ................................................ 10
ENROLMENT PROCEDURE.................................................................................................................. 10
5.1
5.2
6
CENTRE/CLINICIAN INCLUSION CRITERIA ............................................................................................... 9
CENTRE/CLINICIAN EXCLUSION CRITERIA .............................................................................................. 9
SELECTION OF PATIENTS ..................................................................................................................... 9
4.1
4.2
4.3
4.4
5
AIM ........................................................................................................................................................ 8
PRIMARY OBJECTIVE .............................................................................................................................. 8
SECONDARY OBJECTIVES ....................................................................................................................... 8
EXPLORATORY OBJECTIVES ................................................................................................................... 8
WITHDRAWAL FROM STUDY ................................................................................................................. 16
PATIENT TRANSFERS ............................................................................................................................ 16
WITHDRAWAL FROM THE STUDY COMPLETELY .................................................................................... 16
STATISTICAL CONSIDERATIONS ...................................................................................................... 17
9.1
OUTCOMES ........................................................................................................................................... 17
9.1.1 Primary ........................................................................................................................................... 17
9.1.2 Secondary ........................................................................................................................................ 17
9.1.3 Interim analyses .............................................................................................................................. 18
10
STUDY MONITORING........................................................................................................................ 19
10.1
RISK ASSESSMENT ................................................................................................................................ 19
10.2
DATA MONITORING.............................................................................................................................. 19
10.3
CLINICAL SITE MONITORING ................................................................................................................. 19
10.3.1
Direct Access to Data ................................................................................................................. 19
10.3.2
Confidentiality ............................................................................................................................ 19
10.3.3
Quality Assurance and Quality Control of Data......................................................................... 19
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11
SAFETY REPORTING ......................................................................................................................... 20
11.1.1
Definitions................................................................................................................................... 20
11.1.2
Study Specific Exceptions to AE or Expedited SAE Notification and Reporting......................... 20
11.2
INSTITUTION/INVESTIGATOR RESPONSIBILITIES ................................................................................... 21
11.2.1
Urgent Safety Measures .............................................................................................................. 21
11.2.2
Pregnancy ................................................................................................................................... 22
11.2.3
Adverse Incidents ........................................................................................................................ 22
12
ETHICAL CONSIDERATIONS AND APPROVAL ......................................................................... 22
12.1
12.2
ETHICAL CONSIDERATIONS................................................................................................................... 22
ETHICAL APPROVAL ............................................................................................................................. 22
13
INDEMNITY .......................................................................................................................................... 23
14
FINANCE ............................................................................................................................................... 23
15
STUDY COMMITTEES ....................................................................................................................... 24
15.1
15.2
15.3
STUDY MANAGEMENT GROUP (TMG) ................................................................................................. 24
STUDY STEERING COMMITTEE (TSC) .................................................................................................. 24
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) .................................................................... 24
16
SOURCE DATA LIST .......................................................................................................................... 24
17
STANDARD OPERATING PROCEDURES (SOPS) ........................................................................ 25
18
PUBLICATION ..................................................................................................................................... 26
19
PROTOCOL AMENDMENTS ............................................................................................................ 27
20
REFERENCES ....................................................................................................................................... 28
21
APPENDICES ........................................................................................................................................ 29
Information required from sites for both eyes .............................................................................................. 29
Information from reading centre for both eyes ............................................................................................ 30
LIST OF TABLES
Table 1: EDNA and FASBAT patient observation time points
Table 2: Examples of FASBAT schedule of events for research staff
Table 3: Schedule of visits
APPENDICES
1. Tables summarising information required for FASBAT in addition to the EDNA study
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Abbreviations and Glossary
AE
Adverse event
AF
Autofluorescence
AMD
Age-related Macular Degeneration
AR
Adverse reaction
BCVA
Best Corrected Visual Acuity
CATT study
Comparison of AMD Treatments Trials
CF
Consent form
CI
Chief Investigator
CNV
Choroidal Neo-Vascularisation
CP
Colour Photography
CRF
Case Report Form
CTA
Clinical Trials Authorisation
DCF
Data Clarification Form
DMC
Data Monitoring Committee
DMO
Diabetic macular oedema
EDNA
Early Detection of Neovascular Age-related macular degeneration
ETDRS
Early Treatment Diabetic Retinopathy Study
FFA
Fundus Fluorescein Angiography
GA
Geographic Atrophy
GCP
Good Clinical Practice
ICG
Indo cyanine green
IDMC
Independent Data Monitoring Committee
MA
Macular Atrophy
NHS
National Health Service
NIHR
National Institute Health Research
nvAMD
Neovascular Age-related Macular Degeneration
OCT
Optical Coherence Tomography
PI
Principal Investigator
PIS
Patient information Sheet
R&D
Research and Development
SAE
Serious Adverse Event
SAR
Serious Adverse Reaction
SD OCT
Spectral Domain Optical Coherence Tomography
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SHRM
Sub retinal Highly Reflective Material
SOP
Standard Operating Procedures
SPC
Summary of Product Characteristics
SSA
Site Specific Assessment
SUSAR
Suspected Unexpected Serious Adverse Reaction
TMG
Trial Management Group
TSC
Trial Steering Committee
UAR
Unexpected adverse reaction
VA
Visual Acuity
VEGF
Vascular Endothelial Growth Factor
VFQ
Visual Function Questionnaire
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1 Background
Age-related macular degeneration (AMD) is the commonest cause of blindness in the
retired western world population. Anti-Vascular Endothelial Growth Factor (Anti-VEGF)
injectable treatment has had a significant impact on reducing the levels of blindness and
restoring part of the visual loss experienced by individuals who have the less common,
but more aggressive, (‘wet’) form of Age-related Macular Degeneration (AMD) or
neovascular AMD (nvAMD).
However, scarring, tissue loss and abnormal tissue formation (fibrosis and atrophy)
beneath the crucial light sensitive part of the eye, the macula, limits the visual
improvement that may be achieved for a patient. The late stage characteristics of fibrosis
and atrophy of the outer retina remain the key pathological element associated with
severe visual loss. New treatments are being developed that reduce this scar tissue
formation on the assumption that better visual outcome with treatment of wet AMD may
be possible. In particular there is a need to study whether it is possible to predict this
tissue formation and/or response.
At present there is no long term data on the
development and progression of these forms of abnormal tissue. Being able to identify
these features, develop new biomarkers, document their natural history and their
response to treatment will aid the development of new treatment strategies.
Literature
Sub-retinal fibrosis is a pathological process in the evolution of wet AMD. The formation
of fibrosis disrupts the retina and its architecture, which leads to irreversible visual loss. A
large (1059 patients) National Eye Institute funded Comparison of AMD Treatments
Trials (CATT) Research Group Study showed that evolution of sub-retinal fibrosis was
common in patients with wet AMD treated with monotherapy anti-VEGF therapy.
Approximately 32% of patients at one year and 45% of patients at two years developed
sub-retinal fibrosis in this CATT trial1.
Bloch et al retrospectively analysed 197 treatment naïve neovascular AMD (nvAMD)
patients over 2 years. She concluded the development of subfoveal fibrosis was more
likely in predominantly classic Choroidal Neo-Vascularisation (CNV), poorer visual acuity
at presentation and an interval of 15 days or more between diagnosis and treatment.
These participants lost 8.5 more Early Treatment Diabetic Retinopathy Study (ETDRS)
letters than those that did not develop fibrosis. Fibrosis was diagnosed with colour
photography (CP) and Spectral Domain Optical Coherence Tomography (SD OCT). No
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attempt was made to distinguish between fibrin and fibrosis on CP and it was noted that
CNV may have been indistinguishable from the Sub retinal Highly Reflective Material
(SHRM).
Daniel et al analysed 1059 eyes from the CATT study and at 2 years noted 45.3% had
developed fibrosis. Risk factors for development of fibrosis were predominantly classic
CNV, blocked fluorescence, thicker foveal depth, foveal subretinal fluid and SHRM at
baseline.
Willoughby et al evaluated the association of SHRM, Visual Acuity (VA) and fibrosis in an
analysis of 1185 CATT study patients. 77% had SHRM at baseline reducing to 54% at
104 weeks, fibrosis making the SHRM twice as likely to persist (64 vs 31%). At 54
weeks, mean VA was 73.5 when scar was absent and 63.9 when present at the fovea.
Post-hoc analyses of the CATT study revealed 7.3 % had Geographic Atrophy (GA) at
baseline 10.1% developed GA during year 1 and 3.0% during year 2. Growth rate was
0.13mm /year higher in those with GA in the fellow eye (Grunwald et al, 2014). Debate
continues as to whether the GA described in the CATT study is that of GA described in
AMD or a different form of Macular Atrophy (MA). These rates of development may be
different from that seen in the natural history of AMD and have been observed to be as
much as 2.6 mm/year (Sunness et al, 2007). The development of GA is not a common
finding in those receiving regular anti-VEGF therapy for treatment of Diabetic Macular
Oedema(DMO) (RIDE and RISE studies) leading to the conclusion that it is either the
development of the neovascularisation or the combination of the development of the
pathology with the treatment that produces the effect.
FASBAT Study
People with nvAMD in one eye have an increased probability of developing the condition
in their second (fellow) eye. It is therefore important to monitor patients and to detect the
development of nvAMD early on so that treatment can be initiated to prevent loss of
sight.
The Early Detection of Neovascular Age-related macular degeneration (EDNA) study (CI
Prof Chakravarthy, NIHR funded) aims to recruit 560-600 newly diagnosed nvAMD
patients over a 16 month period in 16-30 sites to determine the sensitivity and specificity
of two comparator tests on detecting nvAMD development in the fellow eye. The patient
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exit point of the EDNA study is when there is conversion to nvAMD in the fellow eye and
130 or more patients are anticipated to convert over the 3-year study period. The EDNA
study will therefore recruit and observe a large cohort of patients, monitor disease
progression in these patients and collect important and useful data about GA (using
Colour Photography (CP), Autofluorescence (AF), Optical Coherence Tomography
(OCT) and Fundus Fluorescein Angiography (FFA)).
The FASBAT study proposed here exploits the opportunity provided by the EDNA study
to observe patients both prior to and after the onset of nvAMD in their second eye.
Patients who are enrolled into EDNA will have already been diagnosed with nvAMD in
one eye, will have commenced anti-VEGF therapy and be regularly monitored for
disease activity in both eyes. This study aims to monitor the progression of abnormal
tissue formation based on (i) characteristics observed in an eye before (and after) the
development of wet AMD in that eye, and (ii) characteristics observed in an (as yet)
unaffected eye when a patient has wet AMD in their fellow eye.
The primary aim of the FASBAT study is to follow those patients who develop nvAMD in
their second eye, to look at the change in fibrosis and Sub retinal Highly Reflective
Material (SHRM) in the initial nvAMD eye following commencement of anti-VEGF therapy
and to compare this to the rate of change of fibrosis and SHRM in the fellow eye in
patients who convert in this eye. Observing patients before and after treatment for wet
AMD enables investigation of side effects of treatment. Loss of the light sensitive and
associated support cells of the retina, termed atrophy may be an important side effect.
Capturing vision data and quality of life data of patients will enable the investigation of
the disease burden associated with these tissues.
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FASBAT Study
Table 1: EDNA and FASBAT patient observation time points
Baseline
18 months post baseline
Patient enrolled into EDNA
EDNA
CONVERSION and/or 36
months post baseline
12 months post
conversion
Patient involvement in
EDNA concludes
Clinical Monitoring Visit:
Clinical Monitoring Visit:
Clinical Monitoring Visit:
Visual Acuity
OCT
Amsler Test
Fundus Evaluation
Colour Photograph
ICG (optional)
Visual Acuity
OCT
Amsler Test
Fundus Evaluation
Colour Photograph
ICG (optional)
Visual Acuity
OCT
Amsler Test
Fundus Evaluation
Colour Photograph
ICG (optional)
Patient enrolled into
FASBAT
FASBAT
24 months post
conversion
Patient involvement in
FASBAT concludes
Additional data collection:
Additional data collection:
Additional data collection:
Additional data collection:
Additional data collection:
NEI VFQ-25
Treatment agent
Treatment regime
Number of visits
Number of treatments
NEI VFQ-25
Treatment agent
Treatment regime
Number of visits
Number of treatments
NEI VFQ-25
Treatment agent
Treatment regime
Number of visits
Number of treatments
AF (optional)
OCT-A (optional)
AF (optional)
OCT-A (optional)
AF (optional)
OCT-A (optional)
Visual Acuity
OCT
Fundus Evaluation
Colour Photograph
NEI VFQ-25
Treatment agent
Treatment regime
Number of visits
Number of treatments
FFA
Visual Acuity
OCT
Fundus Evaluation
Colour Photograph
NEI VFQ-25
Treatment agent
Treatment regime
Number of visits
Number of treatments
ICG (optional)
AF (optional)
OCT-A (optional)
ICG (optional)
AF (optional)
OCT-A (optional)
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FASBAT Study
Table 2: Schedule of events for research staff
1.
Day 1
1 Month
PATIENT ENROLS INTO EDNA
14 Months
PATIENT ENROLS INTO
FASBAT
Patient completes EDNA consent form
PATIENT EXITS EDNA
Patient completes FASBAT consent
form
Complete EDNA baseline CRF from
closest clinic visit
12 M Post Conversion
Complete EDNA /FASBAT
Conversion/36 month CRFs
Complete FASBAT 12 month post
conversion CRF
Complete FASBAT 24 month post
conversion CRF
NEI VFQ-25
FFA (this will be additional to standard
care)
NEI VFQ-25
PATIENT EXITS FASBAT
NE1 VFQ-25
NEI VFQ-25
2.
24 M Post Conversion
PATIENT CONVERTS
Day 1
12 M Post Conversion
24 M Post Conversion
PATIENT HAS EXITED EDNA ON CONVERSION
Complete FASBAT 12 month post conversion CRF
Complete FASBAT 24 month post conversion CRF
NEI VFQ-25
FFA (this will be additional to standard care)
If ≤ 12months post conversion
PATIENT ENROLS INTO FASBAT
NEI VFQ-25
Patient completes FASBAT consent form
PATIENT EXITS FASBAT
NEI VFQ-25
3.
Day 1
6 Months
PATIENT ENROLS INTO
EDNA
PATIENT ENROLS INTO
FASBAT
Patient completes EDNA
consent form
Patient completes FASBAT
consent form
Complete EDNA baseline CRF
from closest clinic visit
NEI VFQ-25
18 Months
30 Months
12 M Post Conversion
24 M Post Conversion
PATIENT CONVERTS
Complete EDNA/ FASBAT 18
month CRFs
NEI VFQ-25
PATIENT EXITS EDNA
Complete EDNA /FASBAT
Conversion/36 month CRFs
Complete FASBAT 12 month
post conversion CRF
Complete FASBAT 24 month post
conversion CRF
NEI VFQ-25
FFA (this will be additional to
standard care)
NEI VFQ-25
NEI VFQ-25
PATIENT EXITS FASBAT
4.
Day 1
6 Months
PATIENT ENROLS INTO EDNA
PATIENT ENROLS INTO
FASBAT
18 Months
36 Months
NO CONVERSION
Complete EDNA/ FASBAT 18 month CRFs
Patient completes EDNA consent form
Patient completes FASBAT consent form
Complete EDNA baseline CRF from closest clinic
visit
Complete EDNA /FASBAT Conversion/36 month
CRFs
NEI VFQ-25
NEI VFQ-25
NEI VFQ-25
PATIENT EXITS EDNA AND FASBAT
1.
2.
Patient converts between enrolment and 18 months
Patient has already converted and exited EDNA
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3.
4.
Patient converts between 18 and 36 months
Patient does not convert
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FASBAT Study
2 Aims and Objectives
2.1
Aim
To assess fibrosis, atrophy and SHRM before and after the onset of nvAMD.
2.2
Primary Objective
The primary study objective is to determine the incidence/rate of change of fibrosis,
SHRM and atrophy development at/up to 12 months post development of nvAMD.
2.3
Secondary Objectives
i. To determine the incidence/rate of change of fibrosis, SHRM and atrophy
development at/up to 24 months post development of nvAMD.
ii. To determine the incidence/rate of change of fibrosis, SHRM and atrophy
development up to end of study in the initially nvAMD eye.
iii. To explore the association between Optical Coherence Tomography (OCT),
colour photo (CP), Autofluorescence(AF) and angiographic biomarkers, with
visual acuity (VA) at/up to24 months post development of nvAMD.
2.4
Exploratory Objectives
i. To explore the association between OCT, colour photo, AF, angiographic
biomarkers and VA with quality of life outcomes (NEI-VFQ-25) at/up to 24
months post development of nvAMD.
ii. To explore the association between OCT, colour photo, AF, angiographic
biomarkers with biomarkers obtained from the EDNA study at/up to 24 months
post development of nvAMD.
iii. To act as repository of data for future analysis and /or linkage studies.
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3 Selection of Centres/Clinicians
The centres invited to participate will have enrolled patients into the EDNA study.
3.1
Centre/Clinician inclusion criteria
To have patients enrolled in the EDNA study
3.2
Centre/Clinician exclusion criteria
Unable to collect data for 24 months post EDNA study
4 Selection of Patients
4.1
Patient inclusion criteria
Patients will be eligible to take part in this study if they have met the inclusion/exclusion
criteria specified for the EDNA study and are able to provide data for 2 years following
exit of EDNA. These criteria are listed here but are subject to change if the eligibility
criteria for the EDNA study are amended.
Individuals age 50 and over with newly diagnosed nAMD with one eye affected and
one eye unaffected who are about to commence or recently commenced anti VEGF
therapy in the affected eye.
In addition patients are eligible for inclusion if they have previously been enrolled in
EDNA and have not exited more than 12 months prior to consent for the FASBAT
study.
4.2
Patient exclusion criteria
1. nAMD in study eye detected at baseline for the EDNA study
2. Presenting worse than 68 letters at baseline in the EDNA study
3. Retinal or media pathology in either eye that will prevent sufficient quality of
imaging (in the view of the investigator).
4.
Not undergoing regular monitoring in standard of care
5. FFA contraindicated
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4.3
Number and source of patients
Potential FASBAT patients will already have been consented into the EDNA study, into
which 580-600 patients are expected to be enrolled. However, as there is a limited pool
of potential participants, recruitment numbers cannot be guaranteed and it is important
to be cognisant that substantially less than 580-600 may participate.
4.4
Screening procedures and pre-randomisation investigations
As potential participants come from the EDNA study then as long as they can commit
to a further two years of data collection, no further pre-screening procedures are
required. Any intervention required for their EDNA study eye, on conversion to nAMD
will be as a part of routine clinical practice.
Recruitment into the FASBAT study should not impede the decision of participants to
be recruited into the EDNA study. Participants are able to change their mind if they
initially decide not to. However, it is preferable for investigators to enrol patients as
soon as possible after they enter EDNA to maximise the data obtained for FASBAT.
5 Enrolment procedure
5.1
Co-enrolment guidelines
Participants will already have been enrolled in the EDNA observational study. The CI of
the EDNA study has given consent for this to happen and is a co-investigator of the
FASBAT study. Patients will not be co-enrolled into other interventional studies that
would alter the standard care or treatment of nvAMD.
5.2
Obtaining informed consent
Patients can be enrolled following enrolment onto the EDNA study, at a subsequent
date during EDNA participation, or following their involvement in EDNA. As this is an
observational study, and mirroring the EDNA study enrolment guidance, patients can
be enrolled on the same day they are approached about the study as long as they
have been given the Patient Information Sheet, understood it, and had an opportunity
to discuss it as necessary.
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FASBAT Study
Local Principle Investigators and research nurses will be responsible for all aspects of
local organisation such as identifying the patients, consenting data collection and entry
onto CRF and forwarding of anonymous data to the reading centre / clinical trials unit.
6 Methodology
FASBAT is an observational study. Patients entering the EDNA study will be
approached, and if they give informed consent they will be entered into this extension
study. The principle outcomes measurements would be acquired using colour fundus
photography, autofluorescence, fluorescein / ICG /OCT angiography and SD OCT, which
are acquired as a part of routine clinical practice. Images will be captured at the patient
visits that occur as close as possible to 18 and 36 months post baseline. These will be
the regular EDNA study visits. If a patient converts in their fellow eye during this period
then their involvement in EDNA will conclude but they will remain in the FASBAT study.
Approximately 130-180 patients would be expected to exit the EDNA study on
conversion and if 80% of these are willing to take part in the extension study, this would
result in a FASBAT study population of 104-144 eyes.
There will be two sources of data available:
i. Data collected as part of EDNA (at baseline, 18 months, 36 months and/or
conversion from both the nvAMD eye and the non nvAMD eye). This will last up
to 3 years (maximum duration of EDNA patient participation). The images
collected during EDNA will be analysed by the Reading Centre (Central
Angiographic Resource Facility) in Belfast with a protocol specific to the
FASBAT study.
ii. Data specific to the FASBAT study collected from patients who develop nvAMD
in their fellow eye (i.e. (i) additional data collected from the existing nvAMD eye
prior to conversion in the fellow eye, and (ii) data collected at 12 and 24 months
post conversion in the newly nvAMD fellow eye).
None of these data are
collected or analysed as part of EDNA
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FASBAT Study
6.1
Data source
This study will use a combination of both primary data collected for the purposes of the
EDNA study, primary data collected for the purposes of this study, and secondary data.
Refer to Table 2.
6.2
Population
Patients will be eligible to take part in this study if they meet the inclusion/exclusion
criteria specified for the EDNA study.
6.3
Number of centres & patients
The aim is to recruit from around 20 centres, each recruiting around 4 patients each
month.
6.4
Sample size
As the study is opportunistic in that the ongoing EDNA study provides a unique
opportunity to conduct this study. We aim to recruit as many patients as possible when
they enter the EDNA study. EDNA aims to recruit 560 patients in total. We expect
approximately 130-180 patients to exit this study after 3 years and if 80% of these are
enrolled in this study also then we estimate this to be a population of 104-144
participants in FASBAT. Based upon the CATT study, we anticipate 32% of
participants to develop fibrosis in the first 12 months, and SHRM to reduce from 77% to
54% at 24months, and GA to develop in 10% (Daniel et al. 2014, Willoughby et al,
2014, Grunwald et al, 2015). Based upon these estimates we anticipate that the events
can be quantified by calculating a 95% confidence interval (CI) with a width of 0.1 to .2
(i.e. 10% to 20%) depending upon the observed event rate and the actual number of
participants. Given the scarcity of data available regarding rate of change a
corresponding estimation of precision has not been carried out.
6.5
Analysis Plan
Descriptive and inferential statistical analyses. Incidence Occurrence of events will be
presented as proportions of eyes and 95% CIs generated. Rate of change will be
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FASBAT Study
calculated and other continuous measures with bootstrapped 95% CIs to account for
the anticipated non-normal distributions. Univariate associations will be quantified by
calculating correlations (Pearson or Spearman as appropriate with 95% CIs).
Regression models (linear or logistic) will be considered to further explore associations
between occurrence of events and patient characteristics prior to conversion.
6.6
Evaluation criteria
The principle outcomes measurements would be acquired using colour fundus
photography and autofluorescence, fluorescein angiography and SD OCT, which are
acquired as a part of routine clinical practice.
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7 Assessments and follow-up
7.1
Flow chart/Schedule for follow-up
Follow up will be as for routine clinical practice. The table below is the recommended
assessment schedule that most likely mirrors the patterns of routine clinical care of
most patients being treated with ranibizumab or aflibercept. Treatment may include
OAP030 if it is available at the time.
Milestone timings (1-5) will be approximated to the closest routine clinical visit to avoid
additional patient hospital visits. Shaded cells are those data that are specific to the
FASBAT study. White cells indicate data that is collected during the EDNA study.
Table 3: Schedule of visits
Visit number
1
2
3
4
5
Time of Visit
Baseline
18 months
Conversion
12 months
24 months
post
and/or 36
post
post
baseline
months
conversion
conversion
x
x
x
x
x
x
x
x
x
x
optional
optional
optional
optional
optional
Fundus Evaluation
x
x
x
x
x
Colour photograph
x
x
x
x
x
AF
optional
optional
optional
optional
optional
ICG
optional
optional
optional
optional
optional
Treatment agent
x
x
x
x
x
Treatment regime
x
x
x
x
x
Number of visits for
x
x
x
x
x
Number of treatments
x
x
x
x
x
FFA
x
x
x
Adverse events
x
x
x
x
x
ADRs
x
x
x
x
x
NEI-VFQ-25
x
x
x
x
x
Inclusion/Exclusion
x
criteria
Information & Informed
x
consent
Best corrected Visual
acuity
OCT
OCT-A
AMD
assessment/treatment
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FASBAT Study
Patients will be attending clinic regularly during this time for their routine care. In the
first year patients are likely to attend clinic every 4 to 8 weeks and every 8 to 12 weeks
thereafter. Table 2 details the study assessments which will be performed as a part of
routine clinical care, some of which are optional depending upon availability or clinical
need. The NEI VFQ-25 QoL questionnaire, however, is not part of routine clinical care.
The data collected will be recorded on the EDNA/FASBAT CRF. Patients will already
be enrolled in the EDNA study and will therefore have clinic visits at Baseline, 18
months, 36 months and/or conversion.
Patients enrolled into FASBAT and who convert in the fellow eye will also have
additional data collected at 12 and 24 months post conversion in that eye.
7.2
Procedures for assessing efficacy
No independent efficacy endpoint committee is required as this is a study of routine
clinical practice. Clinical evaluations will be as per the EDNA study protocol.
7.3
Procedures for assessing safety
All AEs will be recorded in the medical notes as per standard care. All AEs/SAEs that
result from a patient’s direct involvement in FASBAT or any suspected Adverse Drug
Reaction (ADR) will be reported to the Sponsor in an expedited fashion.
Safety
Reporting is covered in more detail in Section 11.
7.4
Loss to follow-up
Local routine clinical procedures for contacting patients lost to follow up will be
implemented.
7.5
Study closure
The formal end of the study will be defined as the last visit of the last patient enrolled
into FASBAT. The end of the study will be reported to the REC within 90 days, or 15
days if the study is terminated prematurely.
A summary of the study will be provided to the REC within a year of the end of the
study. A full end of study report will be prepared for publication.
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FASBAT Study
7.6
Archiving
Study documents will be archived at the participating sites. Where Sites would prefer
the Sponsor to archive documentation then this may be agreed on the condition that
participating sites retain a core set of study documents.
8 Withdrawal of patients
8.1
Withdrawal from study
All patients consented into the study will be followed up for clinical outcome unless they
choose to withdraw consent (see section 8.3). Patients who are unable to continue for
clinical reasons or who lose capacity during the study will continue to be followed up
clinically. Patients who are deemed to have lost capacity during the course of the
study will not be asked to complete the study questionnaire.
8.2
Patient transfers
For patients moving from the area, every effort should be made for the patient to be
followed-up at another participating study centre and for this study centre to take over
responsibility for the patient. A copy of the patient CRFs will need to be provided to the
new site. The patient may have to sign a new consent form at the new site, and until
this occurs, the patient remains the responsibility of the original centre.
8.3
Withdrawal from the study completely
If the patient withdraws consent then no further data collection will take place for this
patient.
Previously collected data will be retained for analysis unless the patient
explicitly requests otherwise in which case those data will be excluded.
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FASBAT Study
9 Statistical Considerations
9.1
Outcomes
‘Baseline’ refers to the point at which the participants were enrolled into the EDNA study.
‘Conversion’ refers to the point at which the initially dry eye converts to neovascular
disease. The eyes will be referred to at the ‘initially dry eye’ or the ‘initially nAMD’ eye’.
9.1.1

Primary
Incidence of fibrosis and SHRM over 12 months post-conversion in the initially dry
eye

Presence of fibrosis and SHRM over 12 months post-conversion in the initially
nAMD eye

Rate of change of atrophy from baseline to conversion initially dry eye (based on
Colour photography)

Rate of change of atrophy (total and area distinct from CNV) from baseline to
conversion in the initially nAMD eye (based on Colour photography)
9.1.2
Secondary

Mean VA and change from baseline to conversion in both eyes

Mean VA and change from conversion to 12 and 24 months post conversion with
15 letters gained/lost in both eyes

The quantity of SHRM at baseline in the initially treated eye and at conversion in
the initially dry eye (correlation)

The change in the quantity of SHRM from baseline in the initially nAMD eye and
from conversion in the initially dry eye over the study period (correlation)

Rate of change of SHRM stratified with baseline quantity (small and large
depending upon baseline mean area), treatment type, number of treatments,
visits and regimen

The rate of change of SHRM in those of different angiographic subgroups
leakage, presence of haemorrhage, RPE changes, IRF, SRF, ORTs, drusen or
pseudo drusen

The quantity of fibrosis at baseline in the initially treated eye and at conversion in
the initially dry eye (correlation)

The change in the quantity of fibrosis from baseline in the initially nAMD eye and
from conversion in the initially dry eye over the study period (correlation)
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FASBAT Study

Rate of change of fibrosis stratified with baseline quantity (small and large
depending upon baseline mean area), treatment type, number of treatments,
visits and regimen

The rate of change of fibrosis in those of different angiographic subgroups
leakage, presence of haemorrhage, RPE changes, IRF, SRF, ORTs, drusen or
pseudo drusen

Correlation between identification (rates) of fibrosis on Colour and OCT

The background rate of atrophy (total and CNV distinct) in both the initially dry
and nAMD eyes

Rate of change of atrophy (total and area distinct from CNV) in both the dry and
nAMD eyes over the course of the study (correlation)

Rate of change of atrophy stratified with baseline area (small and large depending
upon 50% baseline mean area), hyper reflective AF categories, treatment type

Rate of change of atrophy in those of different angiographic subgroups, leakage,
presence of haemorrhage, RPE changes, drusen or pseudo drusen

Correlation between the rates of atrophy during the study based upon Colour, AF
and OCT

Rate of change of atrophy stratified with baseline area (small and large depending
upon baseline mean area), treatment type

Correlation between the rate of change of atrophy and SHRM

Mean change in VA correlated with baseline presence of type and location of GA,
SHRM, RPE changes, IRF, SRF, ORT’s, PED, drusen, reticular pseudo drusen,
haemorrhage

9.1.3
Change in QoL score correlated with change in VA, atrophy, fibrosis and SHRM
Interim analyses
An interim analysis will incorporate the total number of patients who have 12 months post
conversion data at a date to be identified around June to December 2017, depending upon
recruitment. We will also include all patients that have been recruited into the study who
have baseline and 18 month follow-up data in their initially nAMD eye. Incidence of SHRM
and Fibrosis will be presented. Rate of change of GA and VA may also be analysed, together
with QoL data. The interim analysis data will be provided to Novartis but it will be made clear
that this is interim data. A full dataset will be analysed on completion of the study.
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FASBAT Study
10 Study Monitoring
10.1 Risk assessment
As this is a non-interventional study there is a low risk to patients. The main risk to the
study is that there are a limited number of potential participants. (A Risk assessment
will be undertaken in collaboration with the Sponsor following the procedure in
R&D/S18 Risk Assessment).
10.2 Data Monitoring
Data will be entered onto a CRF which will be assessed by a Study Data Monitor. Data
management will adhere to R&D/S29 (Data Management).
10.3 Clinical site monitoring
10.3.1 Direct Access to Data
Participating investigators will agree to allow study-related monitoring,
including audits, ethics committee review and regulatory inspections by
providing direct access to source data/documents as required. Patients’
consent for this is obtained as part of the consent process.
10.3.2 Confidentiality
The study should comply with the principles of the Data Protection Act. All data
leaving the local sites will be anonymised using a specific study number.
Participants will not be able to be identified in resulting presentations or
publications.
10.3.3 Quality Assurance and Quality Control of Data
This is not an investigational medicinal product study, however the study will
be performed in accordance with the principles of GCP and local regulatory
authorities. A study monitor will be appointed to oversee quality control of the
data.
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11 Safety Reporting
GCP requires that both investigators and sponsors follow specific procedures when
notifying and reporting adverse events/reactions in clinical studies. These procedures
are described in this section of the protocol.
Whilst this is not a clinical trial of a
medicinal product the study will be run in accordance with the principles of GCP.
11.1.1 Definitions
An adverse event (AE)isany unfavourable and unintended sign, symptom or disease
temporally associated with participation in the research project.
A serious adverse event (SAE) is defined as an untoward occurrence that:
(a) results in death;
(b) is life-threatening;
(c) requires hospitalisation or prolongation of existing hospitalisation;
(d) results in persistent or significant disability or incapacity;
(e) consists of a congenital anomaly or birth defect; or
(f) is otherwise considered medically significant by the investigator
11.1.2 Study Specific Exceptions to AE or Expedited SAE Notification and Reporting
During FASBAT all AEs will be recorded as per standard care practice in the medical
notes at clinic visits. However, only AEs resulting from a patient’s direct involvement
in the study or suspected to be possibly related to Novartis drug product will be
reported for the purposes of FASBAT. See 11.2 below.
Most participants will be elderly and therefore deaths unrelated to the study
procedures or drug product will be recorded but not reported to the Sponsor as SAEs.
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FASBAT Study
11.2 Institution/Investigator Responsibilities
All AEs/SAEs
All AEs/SAEs must be recorded at clinic visits in the medical notes for the duration that
a participant is enrolled in the FASBAT study.
AEs considered possibly, probably or definitely related to study processes
As this is an observational non-interventional study the only AEs that are expected to
be recorded/reported that are related to FASBAT study processes (but not EDNA
where they will be collected separately) will relate to the FFA undertaken at 24 months
post conversion. Any such AEs should be recorded on the FASBAT AE record form.
ADRs
AEs suspected to possibly, probably or definitely be related to a drug product (IMP) will
be defined as Adverse Drug Reactions (ADRs). All ADRs (serious and non-serious)
should be recorded by the study team and reported to the Sponsor within 24 hours of
becoming aware. ADR’s should be reported on a faxed ADR form. Trusts’ standard
local reporting processes will also apply (e.g. yellow card scheme).
SAE/SADRs
If an AE or ADR is assessed as Serious by an investigator (or delegate) then this must
be reported to the study Sponsor on a SAE report form within 24 hours of becoming
aware. Note the SAE reporting exclusion listed in Section 11.1.2.
The Sponsor will immediately liaise with the CI/PI (or delegate) to assess the
seriousness, causality and expectedness of the event. Related and unexpected SAEs
will be reported to the REC 15 days of becoming aware of the event. SADRs will also
be onward reported.
11.2.1 Urgent Safety Measures
An urgent safety measure must be communicated to the CI and Sponsor immediately
and discussed with the REC by telephone. Refer to R&D/S06 and R&D/F20.
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11.2.2 Pregnancy
The mean age of participants is expected to be 80 years. It is highly unlikely that
pregnancy will occur but in the case of this event the sponsor and CI will be informed
by fax within 24 hours.
11.2.3 Adverse Incidents
In the same way that adverse incidents, including clinical, non-clinical and near
misses can involve patients, staff and visitors during routine care, adverse incidents
can also occur during research related activities. It is important that research related
adverse incidents are treated in the same way as non-research related adverse
incidents.
accordance
Research related Adverse Incidents must therefore be reported in
with
the
local
NHS
Trusts
own
Adverse
Incident
Reporting
Procedure/System.
12 Ethical Considerations and Approval
12.1 Ethical considerations
As this is a non-interventional observational study, it is low risk for the participants.
However, study risks may include:

Allergic reaction to FFA /ICG

Additional time required to complete the QoL survey
The right of the patient to refuse to participate in the study without giving reasons will
be respected. After the patient has entered the study, the patient will remain free to
withdraw at any time from the protocol treatment and study follow-up without giving
reasons and without prejudicing his/her further treatment.
12.2 Ethical approval
Ethical approval will be obtained from an NHS Research Ethics Committee.
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13 Indemnity
York Teaching Hospitals NHS Foundation Trust is the Sponsor of the study. The NHS is
a publicly funded body and is not allowed to purchase advance insurance to cover
indemnity because it is backed by the resources of the Treasury. NHS employees will
be covered by the NHS indemnity scheme for claims for negligent harm. The NHS does
not provide cover for non-negligent harm.
14 Finance
The study has been fully costed with input from the R&D Unit and will be funded by
Novartis as an Investigator Initiated Trial.
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FASBAT Study
15 Study Committees
15.1 Study Management Group (TMG)
A Study Management Group (TMG) will be formed comprising the Chief Investigator,
the other lead investigators (clinical and non-clinical) and other members (e.g. FASBAT
Study Manager) as appropriate.
The TMG will be responsible for the day-to-day
running and management of the study and will meet/ TC approximately 2 times a year
or more often if need arises.
15.2 Study Steering Committee (TSC)
The York Teaching Hospital NHS Foundation Trust R&D Group will take on the
function of the TSC. The ultimate decision for the continuation of the study lies with the
TSC.
15.3 Independent Data Monitoring Committee (IDMC)
It is not proposed to establish an IDMC for the study. The R&D Unit will receive regular
updates on the study on behalf of the Sponsor and will escalate any issues to the R&D
Group as necessary.
16 Source Data List
Patient notes
CPD
Patient images
Questionnaires
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FASBAT Study
17 Standard Operating Procedures (SOPs)
The Standard Operating Procedures of York Teaching Hospital NHS Foundation Trust will
apply for this study.
The most relevant SOPs are listed below (although this list is not exclusive). Refer to
http://www.northyorksresearch.nhs.uk/sops_and_guidance_/ for a full list and to view
documents.
Title
Number
Delegation of Tasks for Trust Sponsored Research Studies
R&D/S03
Serious Breach of GCP or the Study Protocol
R&D/S04
Research Related Adverse Event Reporting Procedure for CTIMP Studies R&D/S05
Safety Reporting
R&D/S06
Monitoring of Trust Sponsored Research Studies
R&D/S08
Set-Up and Management of Research Studies
R&D/S09
Archiving of Research Study Documents
R&D/S11
Research Misconduct and Fraud
R&D/S16
Study Close-Out: CTIMPs and other research studies
R&D/S21
Identifying Research Participants in the Medical Records and on CPD
R&D/S24
Providing and Documenting Training for Researchers
R&D/S25
End of Study Reports and Publications
R&D/S27
Quality Assurance
R&D/S28
Data Management
R&D/S29
Making Amendments to Trust Sponsored Research Studies
R&D/S74
Case Report Form (CRF) Design and Completion
R&D/S81
Preparing a Statistical Analysis Plan
R&D/S85
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18 Publication
We have a commitment to publish the findings of the research. At a minimum this study
will have a results paper published in a peer-reviewed medical/scientific journal. If all
grant holders and researcher staff fulfil authorship rules, group authorship will be used
under the collective title of ‘the FASBAT study Group’. If one or more individuals have
made a significant contribution above and beyond other group members but where all
group members fulfil authorship rules, authorship will be attributed to the named
individual(s) and the FASBAT Study Group.
For reports which specifically arise from the study but where all members do not fulfil
authorship rules (for example, specialist sub-study publications), authorship should be
attributed to the named individual(s) for the FASBAT Study Group.
To safeguard the integrity of the main study, reports of explanatory or satellite studies
will not be submitted for publication without prior arrangement from the Study
Management Group and the Study Steering Committee.
Once the main report has been published, a lay summary of the findings will be sent in a
final FASBAT Newsletter to all involved in the study.
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19 Protocol Amendments
Version number
Version date
Reason for
Implemented
amendment
1.0
19th November 2015
2.0
3rd December 2015
Sponsorship
agreed
3.0
11th December 2015
Incorporation
Novartis
of
comments
on safety reporting
Contract signed
4.0
17th February 2016
Final
changes
to
include patients who
have completed in
EDNA study
Submitted to HRA
5.0
16th May 2016
Minor
amendment;
Change of Sponsor
Representative/Study
Statistician/changes
to
wording
&
additional paragraph
in
sections
1/4.1/4.2/4.4/5.2/7.4
Amendment
to
format of Table 1 and
3 and the addition of
Table 2: Schedule of
events for research
staff
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20 References
Sunness et al. The long term Natural History of Geographic Atrophy from Age related
Macular Degeneration. Ophthalmology. 2007, 114(2), 271-277
Grunwald et al Risk of geographic atrophy in the Comparison of Age-related Macular
Degeneration Treatment Trials.Ophthalmology 2014; 121(1), 150-161.
Bloch et al. Subretinal fibrosis in Eye with Neovascular age related Macular
degeneration Am JOphthalmol , 2013
Daniel et al Risk of scar in the Comparison of age-related Macular degeneration
Treatment trials. Am J Ophthalmol, 2014
Willoughby et al SubretinalHyperrefelctive Material in the Comparison of Age-related
Macular Degeneration Treatment Trials. Ophthalmology 2015
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21 Appendices
Appendix 1
Information required from sites for both eyes
Baseline
18 months
conversion
12 months
24 months
post
post
post
EDNA
conversion
conversion
Additional costs
baseline
BCVA
x
x
x
x
x
Colour photograph
x
x
x
x
x
AF
x
x
x
x
x
OCT
x
x
x
x
x
FFA
x
x
x
Yes 12 months post baseline and
post conversion
Yes 12 months post baseline and
post conversion
All visits (may already be routinely
collected, pre conversion)
Yes 12 months post baseline and
post conversion
NEI VFQ-25
x
x
24 months post conversion
x
Yes all visits
x
x
x
ICG
optional
optional
optional
optional
OCT-A
optional
optional
optional
optional
x
x
x
Yes 12 months post baseline and 24
post conversion and
Treatment agent. (initially
x
x
treated, eye, second eye)
All visits
All visits (may already be routinely
collected, pre conversion)
(ranibizumab, aflibercept)
Treatment regime (prn, T
x
x
x
x
x
and E, Fixed, other)
(initially
treated,
All visits (may already be routinely
collected, pre conversion)
eye,
second eye)
Number of visits for AMD
x
x
x
x
x
assessment / treatment.
All visits (may already be routinely
collected, pre conversion)
Specifically for
1.initially treated eye only
2. Second eye only
3 for both eyes same day
Number of treatments
x
x
x
Specifically for
x
x
All visits (may already be routinely
collected, pre conversion)
1.initially treated eye only
2. Second eye only
3 for both eyes same day
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Information from reading centre for both eyes
Baseline
18 months
post
baseline
conversion
12 months
post
conversion
24 months
post
conversion
Additional
cost for CARF
BCVA
x
x
x
x
x
NO
Colour photograph to quantify:
1.Haem- Yes/no
2. Pigment- Yes/ No
3. Fibrosis- Yes / no (subfoveal or not)
4. Atrophy (Total macular (within arcades),
area distinct from CNV (may have to
defined retrospectively), non foveal, outside
macular)
x
x
x
x
x
Expanded
colour grading
time
+ post
conversion full
grading
AF to quantify:
1. Atrophy (Total macular within arcades),
area distinct from CNV (may have to
defined retrospectively), non foveal, outside
macular)
2. Hyper reflective banding (nil, broken,
linear)
x
x
x
x
x
Collation and
storage of AF
and grading at
all visits (not
part of EDNA
grading)
OCT to quantify:
1. Atrophy
(Total macular ( within
arcades), area distinct from CNV ( may
have to defined retrospectively), non
foveal, outside macular)
2. SHRM (investigators will need to define,
but divided into CNV complex and fibrosis if
possible), foveal, non foveal)
3. IRF (yes / no)
4.IRC (yes/ no)
5. SRF (yes / no)
6. PED (any, drusenoid, serous)
7. RPE RIP (yes / no)
8. Drusen (yes. no)
9. Reticular psuedodrusen (yes/no)
10. PVD (yes / no)
10. Central (1mm2) retinal thickness
11. Maximal retinal thickness
12 ORT (yes/ no)
x
x
x
x
x
Expanded
OCT grading
time plus post
conversion full
grading
FFA to qualify:
1. CNV (yes/ no)
2.Classification (classic,
minimally, occult)
3. leakage (yes /no)
4 Size (mm2)
x
x
x
x
Expanded
FFA grading
ICG to quantify:
1 Type CNV (hot spot/ plaque / mixed
pattern)
2.polyps (yes / no)
If
supplied
If supplied
If supplied
If supplied
ICG grading
as not part of
EDNA
OCT- A (may be no sites)
1 CNV (yes/ no)
2 Retinal layer of CNV
If
supplied
If supplied
If supplied
If supplied
OCT A
grading as not
part of EDNA
predominantly,
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