The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in
any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product
mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their
country.
Study No.: SMS40016
Title: A double-blind, double dummy, placebo controlled, randomised, cross-over, single dose study comparing the
bronchodilator effects of salmeterol 50mcg with a combination bronchodilator Combivent® (ipratropium bromide and
salbutamol) in subjects with chronic obstructive pulmonary disease (COPD)
Rationale: The aim of this study was to compare the bronchodilator properties of salmeterol (SAL) with ipratropium
bromide/salbutamol (IPRA+SB) aerosol combination in a single dose design. In addition, the study examined the effects of
the two drugs on work of breathing.
Phase: IV
Study Period: November 20, 1998 – June 25, 1999
Study Design: A double-blind, double dummy, placebo controlled, randomised, cross-over, single-dose clinical trial.
Centres: Single centre in the United Kingdom
Indication: COPD
Treatment: Subjects were screened and invited to return for three treatment visits at 3 – 7 day intervals over a 2 - 3 week
period. At the treatment visits subjects were randomised to receive two inhalations (via Volumatic® spacer device) of either
SAL 25mcg and placebo aerosol combination, or IPRA+SB (20mcg/100mcg) and placebo SAL, or placebo SAL and placebo
aerosol combination according to the cross-over design. Subjects that required rescue medication were given 100-200mcg of
salbutamol immediately after the lung function assessment (a minimum of 6 hours after inhaling study medication).
Objectives: To compare the bronchodilating effects and the effects on breathlessness and static lung volumes of single
doses of SAL 50mcg with IPRA+SB (40mcg/200mcg) in a single dose design in subjects with COPD.
Primary Outcome/Efficacy Variable: The primary endpoint was forced expiratory volume in one second (FEV1) area under
curve (AUC) over 12 hours for each dosing period of the study.
Secondary Outcome/Efficacy Variable(s): Secondary endpoints included rescue medication use, increase in forced vital
capacity (FVC), duration of action, maximum change in FEV1, total lung capacity (TLC), functional residual capacity (FRC),
residual volume (RV) and vital capacity (VC), exercise capacity as defined by shuttle walk test (SWT) and perception of
breathlessness as defined by Borg scores.
Statistical Methods: The sample size was based upon the FEV1 AUC as determined over a 12 hour period. It was
anticipated that a total of 48 subjects would be recruited to ensure 30 evaluable subjects were available for analysis. This
number was sufficient to ensure that 80% power was achieved assuming a significance level of 0.016 and a difference in
FEV1 AUC0-12h of 1.61 litres. It was estimated that using a 0.05 significance level with 30 evaluable subjects in the study
would have 90% power to detect the treatment difference stated above. For tests of first-order carry-over, the 10%
significance level has been used. The intention-to-treat (ITT) sample was defined as those subjects who were randomised
and received at least one dose of study medication. The efficacy evaluable (EF) sample consisted of those subjects who
were randomised and received each of the three medications in this study and had data for each period for the primary
endpoint. The run-in-sample was those subjects who withdrew prior to randomisation. Unless otherwise stated, the ITT
sample was used for all summaries and analyses.
Study Population: Male and female subjects, current or ex-smokers, ≥40 years of age, with a documented clinical history of
COPD were eligible. In addition, subjects were required to have a FEV1/FVC ratio of ≤70% and a FEV1 of 25 -70% of their
predicted value, a limited reversibility to salbutamol in their FEV1 of at least 7% and not more than 10% of their baseline
FEV1, and an absolute increase of no more than 300 ml, 30 minutes after the inhalation of 200mcg of salbutamol. Subjects
with any permanent or temporary physical disabilities preventing them from taking part in the shuttle walk exercise capacity
test were excluded.
IPRA+SB IPRA+SB Placebo/ Placebo/
Number of Subjects:
SAL/
SAL/
IPRA+SB Placebo/ /SAL/
/Placebo/ SAL/
IPRA+SB
/Placebo IPRA+SB Placebo
SAL
IPRA+SB /SAL
(ISP)
(SIP)
(IPS)
(SPI)
(PSI)
(PIS)
N=4
N=6
N=5
N=6
N=5
N=6
Planned, N
Randomised, N
Completed, N (%)
Total Number Subjects Withdrawn, N (%)
Withdrawn due to Adverse Events n (%)
5
6
6 (100)
0
0
5
6
6 (100)
0
0
1
5
4
3 (75)
1 (25)
1 (25)
5
5
5 (100)
0
0
5
5
5 (100)
0
0
5
6
5 (83)
1 (17)
1 (17)
Withdrawn due to Lack of Efficacy n (%)
Withdrawn for other reasons n (%)
Demographics
N (ITT)
Females: Males
Mean Age, years (SD)
0
0
SIP
6
3:3
70.5 (4.0)
0
0
SPI
6
1:5
64.8 (8.8)
0
0
ISP
4
1:3
72.3 (4.8)
0
0
IPS
5
1:4
61.8 (7.2)
White, N (%)
Current smoker, Yes:No
Primary Efficacy Results: EF population
FEV1 AUC over 12 hours (L/min)
Overall mean (L/min) (SD)
Adjusted mean (L/min) (SE)
Change from pre-dose FEV1 AUC over 12
hours (L/min)
Adjusted mean (L/min) (SE)
Pairwise comparisons
6 (100)
0:6
6 (100)
4:2
4 (100)
1:3
5 (100)
1:4
0
0
PSI
5
1:4
63.6
(10.8)
5 (100)
2:3
0
0
PIS
6
0:6
67.8 (6.6)
6 (100)
0:6
SAL (N=30)
882.5 (265.4)
866.5 (8.5)
SAL (N=30)
IPRA+SB (N=32)
810.5 (243.4)
813.6 (8.3)
IPRA+SB (N=32)
Placebo (N=31)
759.2 (232.6)
746.6 (8.3)
Placebo (N=31)
100.7 (8.5)
S-I (SAL-IPRA+SB)
47.8 (8.3)
S-P (SAL-Placebo)
-19.2 (8.3)
I-P (IPRA+SBPlacebo)
67.0
(43.7, 90.3)
<0.0001
Estimate of true treatment difference (L/min) 52.9
95% confidence interval (L/min)
(28.8, 77.0)
p-value
<0.0001
Secondary Outcome Variable(s): EF Population
Rescue medication use
SAL (N=30)
N: yes (%)
3 (10)
N: no (%)
27 (90)
Change from pre-dose FVC AUC over 12
S-I (SAL-IPRA+SB)
hours (L/min), pairwise comparisons
Estimate of true treatment difference (L/min) 86.6
95% confidence interval (L/min)
(35.1, 138.1)
Duration of action (minutes)
SAL (N=30)
Median time to return to pre-dose
Not Available (NA)
(minutes=mins)
Maximum change in FEV1 from pre-dose, S-I (SAL-IPRA+SB)
pairwise comparisons (L)
119.9
(96.3, 143.4)
<0.0001
IPRA+SB (N=32)
8 (25)
24 (75)
S-P (SAL-Placebo)
233.6
(181.8, 285.3)
IPRA+SB (N=32)
423
TLC (L), pairwise comparisons
S-I (SAL-IPRA+SB)
0.18 (0.13, 0.23)
S-P (SAL-Placebo)
120 mins after study medication was taken,
estimate of true treatment difference, L
(95% confidence interval)
330 mins after study medication was taken,
estimate of true treatment difference, L
(95% confidence interval)
720 mins after study medication was taken,
estimate of true treatment difference, L
(95% confidence interval)
FRC (L), pairwise comparisons
0.07 (-0.20, 0.34)
0.03 (-0.24, 0.30)
I-P (IPRA+SBPlacebo)
0.18 (0.13, 0.22)
I-P (IPRA+SBPlacebo)
-0.04 (-0.30, 0.23)
-0.09 (-0.37, 0.18)
-0.21 (-0.48, 0.06)
-0.11 (-0.38, 0.16)
0.08 (-0.36, 0.51)
-0.03 (-0.47, 0.40)
-0.11 (-0.55, 0.32)
S-I (SAL-IPRA+SB)
S-P (SAL-Placebo)
0.15 (-0.09, 0.39)
-0.27 (-0.51, -0.03)
I-P (IPRA+SBPlacebo)
-0.42 (-0.65, -0.18)
-0.38 (-0.62, -0.14)
-0.51 (-0.74, -0.27)
-0.12 (-0.36, 0.11)
-0.34 (-0.64, -0.04)
-0.35 (-0.65, -0.04)
-0.01 (-0.31, 0.29)
120 mins after study medication was taken,
estimate of true treatment difference, L
(95% confidence interval)
330 mins after study medication was taken,
estimate of true treatment difference, L
(95% confidence interval)
720 mins after study medication was taken,
estimate of true treatment difference, L
2
S-P (SAL-Placebo)
Placebo (N=31)
9 (29)
22 (71)
I-P (IPRA+SBPlacebo)
147.0
(95.7, 198.3)
Placebo (N=31)
20
(95% confidence interval)
RV (L)
Overall mean, pre-dose, L (SD)
Overall mean, 120 mins after study
medication was taken, L (SD)
Overall mean, 330 mins after study
medication was taken, L (SD)
Overall mean, 720 mins after study
medication was taken, L (SD)
VC (L)
Overall mean, pre-dose, L (SD)
Overall mean, 120 mins after study
medication was taken, L (SD)
Overall mean, 330 mins after study
medication was taken, L (SD)
Overall mean, 720 mins after study
medication was taken, L (SD)
Perception of breathlessness (Borg
score)
Overall change in breathlessness between
the assessment prior to the 120 minute
SWT and that prior to the pre-dose SWT,
change in score (%)
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
2
SAL (N=30)
4.97 (1.45)
4.54 (1.27)
IPRA+SB (N=32)
5.01 (1.31)
4.47 (1.22)
Placebo (N=31)
5.03 (1.27)
4.85 (1.24)
4.38 (1.31)
4.74 (1.29)
4.97 (1.23)
4.67 (1.28)
4.97 (1.26)
4.99 (1.38)
SAL (N=30)
2.95 (1.08)
3.26 (0.77)
IPRA+SB (N=32)
2.79 (0.90)
3.37 (0.81)
Placebo (N=31)
2.90 (0.71)
2.92 (0.67)
3.12 (0.76)
2.89 (0.78)
2.75 (0.68)
3.11 (0.79)
2.80 (0.75)
2.85 (0.76)
SAL (N=30)
IPRA+SB (N=32)
Placebo (N=31)
0
0
2 (7)
1 (3)
2 (7)
2 (7)
15 (52)
4 (14)
0
1 (3)
2 (7)
2 (6)
1 (3)
2 (6)
1 (3)
6 (19)
4 (13)
15 (47)
1 (3)
0
0
0
0
0
0
0
3 (10)
6 (19)
16 (52)
5 (16)
1 (3)
0
0
IPRA+SB Placebo
(N=32) (N=31) Placebo (N=31)
ween
SALOverall
(N=30)change in breathlessness betIPRA+SB
(N=32)
the assessment after the 120 minute SWT
and that after the pre-dose SWT, change in
score (%)
-3
0
-2
2 (7)
-1
6 (20)
0
16 (53)
1
5 (17)
2
0
3
1 (3)
Overall change in breathlessness between
the assessment prior to the 345 minute
SWT and that prior to the pre-dose SWT,
change in score (%)
-3
1 (3)
-2.5
1 (3)
-2
0
-1.5
0
-1
3 (10)
-0.5
1 (3)
3
1(3)
4 (13)
9 (28)
10 (31)
5 (16)
2 (6)
1 (3)
0
0
4 (13)
17 (55)
9 (29)
0
1 (3)
0
1 (3)
3 (9)
1 (3)
1 (3)
8 (25)
0
0
0
1 (3)
1 (3)
4 (13)
0
0.5
1
1.5
2
Overall change in breathlessness between
the assessment after the 345 minute SWT
and that after the pre-dose SWT, change in
score (%)
-2
-1
0
1
2
3
Overall change in breathlessness between
the assessment prior to the 720 minute
SWT and that prior to the pre-dose SWT,
change in score (%)
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
2
2.5
3
SWT (metres), pairwise comparisons
15 (50)
7 (23)
2 (7)
0
0
15 (47)
0
3 (9)
0
0
18 (58)
2 (6)
3 (10)
1 (3)
1 (3)
2 (7)
1 (3)
17 (57)
8 (27)
1 (3)
1 (3)
2 (6)
5 (16)
16 (50)
7 (22)
1 (3)
1 (3)
0
1 (3)
13 (42)
16 (52)
1 (3)
0
1 (3)
1 (3)
0
2 (7)
4 (13)
1 (3)
11 (37)
5 (17)
0
1 (3)
0
4 (13)
0
S-I (SAL-IPRA+SB)
1 (3)
1 (3)
1 (3)
0
5 (16)
6 (19)
11 (34)
1 (3)
3 (9)
1 (3)
0
1 (3)
1 (3)
S-P (SAL-Placebo)
0
0
0
0
2 (6)
1 (3)
12 (39)
5 (16)
2 (6)
2 (6)
4 (13)
2 (6)
1 (3)
I-P (IPRA+SBPlacebo)
22.4 (-7.4, 52.1)
At 120 minutes, estimate of true treatment
-33.3 (-63.8, -2.91)
-11.0 (-41.1, 19.1)
difference, m (95% confidence interval)
At 345 minutes, estimate of true treatment
-9.6 (-42.5, 23.2)
7.7 (-24.8, 40.2)
17.3 (-14.8, 49.5)
difference, m (95% confidence interval)
Safety results (ITT): Adverse events (AE) and serious adverse events (SAEs) were recorded during the run-in period and
the treatment period. AEs on therapy were defined as those occurring from the start of the treatment period.
Most Frequent
Compound:
Compound:
Compound:
Washout:
Adverse Events
S
P
I
– On-Therapy
(n=32)
(n=32)
(n=32)
(n=32)
Subjects with any 1 (3)
3 (9)
3 (9)
10 (31)
AE(s), n (%)
Chest infection
0
2 (6)
0
3 (9)
Cold symptoms
0
0
1 (3)
3 (9)
Cough
0
0
0
3 (9)
Headache
1 (3)
1 (3)
1 (3)
0
Discomfort in
0
0
0
2 (6)
chest
Conjunctivitis left
0
0
0
1 (3)
eye
Mild cold
0
0
0
1 (3)
Runny nose
0
0
1 (3)
0
Swollen right
0
0
0
1 (3)
4
ankle
Tooth pain
0
0
0
following
extraction
Serious Adverse Events - On-Therapy
n (%) [n considered by the investigator to be related to study medication]
Compound:
Compound:
Compound:
S
P
I
(n=32)
(n=32)
(n=32)
Subjects with
0
0
0
non-fatal SAEs, n
(%)
Subjects with fatal 0
0
0
SAEs, n (%)
1 (3)
Washout:
(n=32)
0
0
Conclusions:
See publication below
Publications:
Langley S, Woodcock A, Jones SW, Rice L A placebo controlled comparison of the effect of single doses of salmeterol and
the combination bronchodilator Combivent on lung function over 12 hours in patients with chronic obstructive pulmonary
disease (COPD). Thorax 1999; 54; supp 3; A65
Date Updated: 13-Mar-2006
5