Trial Outcomes & Findings for Efficacy and Safety Comparison of Tiotropium Daily + Salmeterol Daily or Twice Daily Versus Tiotropium Daily in Patients With COPD (NCT NCT00662792)
NCT ID: NCT00662792
Last Updated: 2022-06-28
Results Overview
FEV1 AUC was defined as the area under the FEV1 curve normalized for time. It was calculated from time 0 to 12 h (FEV1 AUC0-12), using the trapezoidal rule divided by the corresponding duration (12 h) to give the results in liter (L). FEV1 AUC0-12h response is defined as the change from baseline: FEV1 AUC0-12h response = FEV1 AUC0-12h - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
147 participants
Primary outcome timeframe
At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose after 6 weeks of treatment.
Results posted on
2022-06-28
Participant Flow
Randomised, double-blind, 4-way crossover efficacy and safety comparison of Tiotropium/Salmeterol, Tiotropium Salmeterol and the free combination Tiotropium plus Salmeterol (50 μg) following chronic Administration in patients with COPD. Patients received each of the 4 treatments for 6 weeks in a randomised sequence.
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participant milestones
| Measure |
T+S_PE/ Tio18GEL / Salm50DPI / T18GEL+S_DPI
Period 1: Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening.
Period 2: 18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening.
Period 3: One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID), in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning.
Period 4: 18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning.
Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
Tio18GEL/ T18GEL+S_DPI/ T+S_PE/ Salm50DPI
Period 1: 18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening.
Period 2:
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning.
Period 3: Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening.
Period 4: One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID), in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
Salm50DPI/ T+S_PE/ T18GEL+S_DPI/ Tio18GEL
Period 1: One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID), in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning.
Period 2: Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening.
Period 3: 18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning.
Period 4: 18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
T18GEL+S_DPI/ Salm50DPI/ Tio18GEL/ T+S_PE
Period 1: 18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Period 2: One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID), in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Period 3: 18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Period 4: Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Period 1
STARTED
|
34
|
38
|
36
|
39
|
|
Period 1
Treated
|
34
|
37
|
36
|
39
|
|
Period 1
COMPLETED
|
32
|
31
|
32
|
39
|
|
Period 1
NOT COMPLETED
|
2
|
7
|
4
|
0
|
|
Period 2
STARTED
|
32
|
31
|
32
|
39
|
|
Period 2
Treated
|
32
|
31
|
32
|
39
|
|
Period 2
COMPLETED
|
31
|
31
|
32
|
36
|
|
Period 2
NOT COMPLETED
|
1
|
0
|
0
|
3
|
|
Period 3
STARTED
|
31
|
31
|
32
|
36
|
|
Period 3
Treated
|
31
|
31
|
32
|
36
|
|
Period 3
COMPLETED
|
30
|
31
|
30
|
35
|
|
Period 3
NOT COMPLETED
|
1
|
0
|
2
|
1
|
|
Period 4
STARTED
|
30
|
31
|
30
|
35
|
|
Period 4
Treated
|
30
|
31
|
30
|
35
|
|
Period 4
COMPLETED
|
29
|
30
|
30
|
34
|
|
Period 4
NOT COMPLETED
|
1
|
1
|
0
|
1
|
Reasons for withdrawal
| Measure |
T+S_PE/ Tio18GEL / Salm50DPI / T18GEL+S_DPI
Period 1: Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening.
Period 2: 18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening.
Period 3: One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID), in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning.
Period 4: 18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning.
Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
Tio18GEL/ T18GEL+S_DPI/ T+S_PE/ Salm50DPI
Period 1: 18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening.
Period 2:
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning.
Period 3: Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening.
Period 4: One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID), in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
Salm50DPI/ T+S_PE/ T18GEL+S_DPI/ Tio18GEL
Period 1: One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID), in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning.
Period 2: Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening.
Period 3: 18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning.
Period 4: 18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
T18GEL+S_DPI/ Salm50DPI/ Tio18GEL/ T+S_PE
Period 1: 18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Period 2: One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID), in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Period 3: 18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Period 4: Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Period 1
Personal Reasons
|
0
|
0
|
1
|
0
|
|
Period 1
Refused continuing medication
|
0
|
1
|
1
|
0
|
|
Period 1
Lost to Follow-up
|
1
|
0
|
0
|
0
|
|
Period 1
Other adverse event (AE)
|
0
|
2
|
0
|
0
|
|
Period 1
Worsening of disease under study (AE)
|
1
|
3
|
2
|
0
|
|
Period 1
Not treated
|
0
|
1
|
0
|
0
|
|
Period 2
Worsening of disease under study
|
1
|
0
|
0
|
3
|
|
Period 3
Refused continuing medication
|
1
|
0
|
1
|
0
|
|
Period 3
Other adverse event (AE)
|
0
|
0
|
1
|
1
|
|
Period 4
Refused continuing medication
|
0
|
1
|
0
|
0
|
|
Period 4
Other adverse event (AE)
|
1
|
0
|
0
|
0
|
|
Period 4
Worsening of disease under study (AE)
|
0
|
0
|
0
|
1
|
Baseline Characteristics
Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available.
Baseline characteristics by cohort
| Measure |
Study Total
n=146 Participants
Total number of patients treated in the study. This was a randomized, double-blind 4-way cross over study. Patients were assigned randomly to one of 4 treatment sequences in which they received each of the 4 treatments (7.5 µg/25 µg Tio/Salmeterol, 18 µg Tiotropium, 50 µg Salmeterol MDPI and 18 µg Tiotropium Free combination). The duration of each treatment period was 6 weeks on average with no washout period between treatments.
|
|---|---|
|
Age, Continuous
|
61.4 Years
STANDARD_DEVIATION 7.6 • n=146 Participants
|
|
Sex: Female, Male
Female
|
53 Participants
n=146 Participants
|
|
Sex: Female, Male
Male
|
93 Participants
n=146 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
3 Participants
n=146 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=146 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=146 Participants
|
|
Race (NIH/OMB)
Black or African American
|
0 Participants
n=146 Participants
|
|
Race (NIH/OMB)
White
|
143 Participants
n=146 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=146 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=146 Participants
|
|
FEV1 AUC0-12 at baseline
|
1.55 Liter (L)
STANDARD_DEVIATION 0.51 • n=135 Participants • Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available.
|
PRIMARY outcome
Timeframe: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
FEV1 AUC was defined as the area under the FEV1 curve normalized for time. It was calculated from time 0 to 12 h (FEV1 AUC0-12), using the trapezoidal rule divided by the corresponding duration (12 h) to give the results in liter (L). FEV1 AUC0-12h response is defined as the change from baseline: FEV1 AUC0-12h response = FEV1 AUC0-12h - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0 - 12 Hours (AUC0-12)
|
0.187 Liter (L)
Standard Error 0.026
|
0.117 Liter (L)
Standard Error 0.026
|
0.057 Liter (L)
Standard Error 0.026
|
0.211 Liter (L)
Standard Error 0.026
|
PRIMARY outcome
Timeframe: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
The FEV1 AUC was defined as the area under the FEV1 curve (AUC) normalised for time. It was calculated from time 12 to 24 h (FEV1 AUC12-24), using the trapezoidal rule divided by the corresponding duration (i.e. 12 h) to give the results in L. AUC12-24h response is defined as the change from baseline: FEV1 AUC12-24h response = FEV1 AUC12-24h - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit (Visit 2) just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Forced Expiratory Volume in Second (FEV1) Area Under the Curve From 12 - 24 Hours (AUC12 -24)
|
0.068 Liter (L)
Standard Error 0.025
|
0.003 Liter (L)
Standard Error 0.025
|
0.003 Liter (L)
Standard Error 0.025
|
0.124 Liter (L)
Standard Error 0.025
|
PRIMARY outcome
Timeframe: At baseline and within 3 hours post-morning dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Peak FEV1 was defined as the highest FEV1 reading observed within 3 hours after inhalation of the last morning dose of each randomized treatment. Peak FEV1 response is defined as change from baseline: Peak FEV1 response = Peak FEV1 - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Peak Forced Expiratory Volume in 1 Second (FEV1)
|
0.296 Liter
Standard Error 0.026
|
0.229 Liter
Standard Error 0.026
|
0.161 Liter
Standard Error 0.026
|
0.320 Liter
Standard Error 0.026
|
PRIMARY outcome
Timeframe: At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Trough FEV1 is determined at the end of each treatment period and is defined as the pre-dose FEV1 measured just prior to the last administration of the morning dose of randomized treatment. Trough FEV1 response is defined as the change from baseline: Trough FEV1 response = Trough FEV1 - FEV1 (Baseline) The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Trough Forced Expiratory Volume in 1 Second (FEV1)
|
0.062 Liter
Standard Error 0.024
|
0.032 Liter
Standard Error 0.024
|
0.003 Liter
Standard Error 0.024
|
0.097 Liter
Standard Error 0.024
|
SECONDARY outcome
Timeframe: At baseline and 10 minutes (min) prior and 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
FEV1 AUC was defined as the area under the FEV1 curve normalized for time. It was calculated from time 0 to 24 h (FEV1 AUC0-24), using the trapezoidal rule divided by the corresponding duration (24 h) to give the results in liter (L). FEV1 AUC0-24h response is defined as the change from baseline: FEV1 AUC0-24h response = FEV1 AUC0-24h - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0-24 Hours (AUC0-24)
|
0.128 Liter
Standard Error 0.025
|
0.060 Liter
Standard Error 0.025
|
0.030 Liter
Standard Error 0.025
|
0.167 Liter
Standard Error 0.025
|
SECONDARY outcome
Timeframe: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
FVC AUC was defined as the area under the FVC curve normalized for time. It was calculated from time 0 to 12 h (FVC AUC0-12), using the trapezoidal rule divided by the corresponding duration (12 h) to give the results in liter (L). FVC AUC0-12h response is defined as the change from baseline: FVC AUC0-12h response = FVC AUC0-12h - FVC (Baseline). The baseline value for FVC based parameters is defined as the pre-dose FVC measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Forced Vital Capacity (FVC) Area Under the Curve From 0 to 12 Hours (AUC0-12)
|
0.337 Liter
Standard Error 0.047
|
0.253 Liter
Standard Error 0.047
|
0.160 Liter
Standard Error 0.048
|
0.381 Liter
Standard Error 0.047
|
SECONDARY outcome
Timeframe: At baseline and 10 minutes (min) prior to inhalation and 30 min, 60 min, 2, 10, 11 and 12 hours after inhalation of the evening dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
The FVC AUC was defined as the area under the FVC curve (AUC) normalised for time. It was calculated from time 12 to 24 h (FVC AUC12-24), using the trapezoidal rule divided by the corresponding duration (i.e. 12 h) to give the results in L. AUC12-24h response is defined as the change from baseline: FVC AUC12-24h response = FVC AUC12-24h - FVC (Baseline). The FVC baseline value is defined as the pre-dose FVC measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Forced Vital Capacity (FVC) Area Under the Curve From 12 to 24 Hours (AUC12-24)
|
0.163 Liter
Standard Error 0.048
|
0.076 Liter
Standard Error 0.048
|
0.043 Liter
Standard Error 0.048
|
0.245 Liter
Standard Error 0.048
|
SECONDARY outcome
Timeframe: At baseline and 10 minutes (min) prior and 60 min, 2, 3, 4, 6, 8, 10 and 12 hour after inhalation the morning dose and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
The FVC AUC was defined as the area under the FVC curve (AUC) normalised for time. It was calculated from time 0 to 24 h (FVC AUC0-24), using the trapezoidal rule divided by the corresponding duration (i.e. 24 h) to give the results in L. AUC response was defined as the change from the baseline FVC; baseline was defined as the FVC measured on randomisation visit. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Forced Vital Capacity (FVC) Area Under the Curve From 0 - 24 Hours (AUC0-24)
|
0.250 Liter
Standard Error 0.046
|
0.165 Liter
Standard Error 0.046
|
0.102 Liter
Standard Error 0.046
|
0.313 Liter
Standard Error 0.046
|
SECONDARY outcome
Timeframe: At baseline and within 3 hours post-morning dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analyzed may vary across endpoints.
Peak FEV1 was defined as the highest FEV1 reading observed within 3 hours after inhalation of the last morning dose of each randomized treatment. Peak FEV1 response is defined as change from baseline: Peak FEV1 response = Peak FEV1 - FEV1 (Baseline). The FEV1 baseline value is defined as the pre-dose FEV1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Peak Forced Vital Capacity (FVC)
|
0.502 Liter
Standard Error 0.049
|
0.449 Liter
Standard Error 0.049
|
0.359 Liter
Standard Error 0.050
|
0.556 Liter
Standard Error 0.049
|
SECONDARY outcome
Timeframe: At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Trough FVC1 is determined at the end of each 6-week treatment period and is defined as the pre-dose FVC1 measured just prior to the last administration of the morning dose of randomized treatment. Trough FVC1 response is defined as the change from baseline: Trough FVC1 response = Trough FVC1 - FVC1 (Baseline) The FVC1 baseline value is defined as the pre-dose FVC1 measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Trough Forced Vital Capacity (FVC)
|
0.139 Liter
Standard Deviation 0.047
|
0.165 Liter
Standard Deviation 0.047
|
0.095 Liter
Standard Deviation 0.048
|
0.229 Liter
Standard Deviation 0.047
|
SECONDARY outcome
Timeframe: At baseline and 10 minutes (min) prior and 30 min, 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
PEF(L/min) AUC0-12(h) response is defined as the change from baseline. AUC0-12(h) was calculated as the area under the curve from 0 to 12 hours using the trapezoidal rule, divided by the full duration (12 hours) to report in liter/minutes. PEF AUC0-12h response = PEF AUC0-12h - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Peak Expiratory Flow Rate (PEF) Area Under the Curve Form 0 to 12 Hours (AUC0-12)
|
34.5 Liter/minutes (L/min)
Standard Error 5.2
|
22.5 Liter/minutes (L/min)
Standard Error 5.2
|
10.2 Liter/minutes (L/min)
Standard Error 5.2
|
37.8 Liter/minutes (L/min)
Standard Error 5.1
|
SECONDARY outcome
Timeframe: At baseline and 10 minutes (min) prior and 30 min, 60 min, 2, 10, 11 and 12 hours after inhalation of the evening dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
PEF(L/min) AUC12-24(h) response is defined as the change from baseline. AUC12-24(h) was calculated as the area under the curve from 12 to 24 hours using the trapezoidal rule, divided by the full duration (12 hours) to report in liter/minutes. PEF AUC12-24h response = PEF AUC12-24h - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Peak Expiratory Flow Rate (PEF) Area Under the Curve From 12 to 24 Hours (AUC12-24)
|
7.3 Liter/minutes (L/min)
Standard Error 5.1
|
-1.3 Liter/minutes (L/min)
Standard Error 5.1
|
-3.4 Liter/minutes (L/min)
Standard Error 5.1
|
20.0 Liter/minutes (L/min)
Standard Error 5.1
|
SECONDARY outcome
Timeframe: At baseline and 10 minutes (min) prior and 60 min, 2, 3, 4, 6, 8, 10 and 12 hours after inhalation of the morning dose and 30 min, 60 min, 2, 10, 11, and 12 hours after inhalation of the evening dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
PEF(L/min) AUC0-24(h) response is defined as the change from baseline. AUC0-24(h) was calculated as the area under the curve from 0 to 24 hours using the trapezoidal rule, divided by the full duration (24 hours) to report in liter/minutes. PEF AUC0-24h response = PEF AUC0-24h - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Peak Expiratory Flow Rate (PEF) Area Under the Curve From 0 to 24 Hours (AUC0-24)
|
20.8 Liter/minutes (L/min)
Standard Error 5.0
|
10.6 Liter/minutes (L/min)
Standard Error 5.0
|
3.4 Liter/minutes (L/min)
Standard Error 5.0
|
28.9 Liter/minutes (L/min)
Standard Error 5.0
|
SECONDARY outcome
Timeframe: At baseline and within 3 hours post-morning dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Peak PEF was defined as the highest PEF reading observed within 3 hours after inhalation of the last morning dose of randomized treatment. Peak PEF response is defined as change from baseline: Peak PEF response = Peak PEF - PEF (Baseline). The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Peak PEF (Peak Expiratory Flow Rate)
|
53.9 Liter/minutes (L/min)
Standard Error 5.2
|
40.6 Liter/minutes (L/min)
Standard Error 5.2
|
30.8 Liter/minutes (L/min)
Standard Error 5.3
|
59.0 Liter/minutes (L/min)
Standard Error 5.2
|
SECONDARY outcome
Timeframe: At baseline and 5 minutes prior to the last administration of the morning dose after 6 weeks of treatment.Population: Full Analysis Set: All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Trough PEF is determined at the end of each treatment period and is defined as the pre-dose PEF measured just prior to the last administration of the morning dose of randomized treatment. Trough PEF response is defined as the change from baseline: Trough PEF response = Trough PEF - PEF (Baseline) The PEF baseline value is defined as the pre-dose PEF measurement in the morning at the randomization visit just prior to administration of the first dose of randomized treatment. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Trough Peak Expiratory Flow Rate (PEF)
|
14.4 Liter/minutes (L/min)
Standard Error 4.9
|
11.3 Liter/minutes (L/min)
Standard Error 4.9
|
7.1 Liter/minutes (L/min)
Standard Error 4.9
|
22.9 Liter/minutes (L/min)
Standard Error 4.9
|
SECONDARY outcome
Timeframe: At baseline, pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 14, 22, 23, and 24 hours post morning dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Response in individual forced expiratory volume in 1 second (FEV1) over a 24 hour observation period. Response is defined as change from baseline. Means are adjusted for treatment, centre, treatment period and patient within centre.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
0 hour
|
0.062 Liter (L)
Standard Error 0.024
|
0.032 Liter (L)
Standard Error 0.024
|
0.003 Liter (L)
Standard Error 0.024
|
0.097 Liter (L)
Standard Error 0.024
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
0.5 hour
|
0.180 Liter (L)
Standard Error 0.024
|
0.129 Liter (L)
Standard Error 0.024
|
0.068 Liter (L)
Standard Error 0.025
|
0.204 Liter (L)
Standard Error 0.024
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
1 hour
|
0.211 Liter (L)
Standard Error 0.025
|
0.139 Liter (L)
Standard Error 0.025
|
0.084 Liter (L)
Standard Error 0.025
|
0.236 Liter (L)
Standard Error 0.025
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
2 hour
|
0.242 Liter (L)
Standard Error 0.026
|
0.163 Liter (L)
Standard Error 0.026
|
0.108 Liter (L)
Standard Error 0.026
|
0.277 Liter (L)
Standard Error 0.026
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
3 hour
|
0.257 Liter (L)
Standard Error 0.027
|
0.167 Liter (L)
Standard Error 0.027
|
0.111 Liter (L)
Standard Error 0.027
|
0.277 Liter (L)
Standard Error 0.027
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
4 hour
|
0.231 Liter (L)
Standard Error 0.027
|
0.162 Liter (L)
Standard Error 0.027
|
0.102 Liter (L)
Standard Error 0.027
|
0.262 Liter (L)
Standard Error 0.027
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
6 hour
|
0.209 Liter (L)
Standard Error 0.028
|
0.121 Liter (L)
Standard Error 0.028
|
0.064 Liter (L)
Standard Error 0.028
|
0.218 Liter (L)
Standard Error 0.028
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
8 hour
|
0.167 Liter (L)
Standard Error 0.028
|
0.098 Liter (L)
Standard Error 0.028
|
0.044 Liter (L)
Standard Error 0.028
|
0.185 Liter (L)
Standard Error 0.028
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
10 hour
|
0.138 Liter (L)
Standard Error 0.028
|
0.080 Liter (L)
Standard Error 0.028
|
0.006 Liter (L)
Standard Error 0.028
|
0.166 Liter (L)
Standard Error 0.028
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
12.5 hour
|
0.101 Liter (L)
Standard Error 0.028
|
0.048 Liter (L)
Standard Error 0.028
|
0.021 Liter (L)
Standard Error 0.028
|
0.147 Liter (L)
Standard Error 0.028
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
13 hour
|
0.105 Liter (L)
Standard Error 0.028
|
0.043 Liter (L)
Standard Error 0.028
|
0.035 Liter (L)
Standard Error 0.028
|
0.153 Liter (L)
Standard Error 0.028
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
22 hour
|
0.005 Liter (L)
Standard Error 0.025
|
-0.057 Liter (L)
Standard Error 0.025
|
-0.034 Liter (L)
Standard Error 0.025
|
0.068 Liter (L)
Standard Error 0.025
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
23 hour
|
0.071 Liter (L)
Standard Error 0.025
|
0.018 Liter (L)
Standard Error 0.025
|
0.008 Liter (L)
Standard Error 0.026
|
0.116 Liter (L)
Standard Error 0.025
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
24 hour
|
0.112 Liter (L)
Standard Error 0.025
|
0.058 Liter (L)
Standard Error 0.025
|
0.024 Liter (L)
Standard Error 0.026
|
0.147 Liter (L)
Standard Error 0.025
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
12 hour
|
0.117 Liter (L)
Standard Error 0.027
|
0.060 Liter (L)
Standard Error 0.027
|
-0.007 Liter (L)
Standard Error 0.027
|
0.137 Liter (L)
Standard Error 0.027
|
|
Response in Individual Forced Expiratory Volume in 1 Second (FEV1) Over a 24 Hour Observation Period
14 hour
|
0.115 Liter (L)
Standard Error 0.029
|
0.040 Liter (L)
Standard Error 0.029
|
0.031 Liter (L)
Standard Error 0.029
|
0.172 Liter (L)
Standard Error 0.028
|
SECONDARY outcome
Timeframe: At baseline, pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 14, 22, 23 and 24 hours post morning dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Response in forced vital capacity (FVC) over a 24 hour observation period. Response is defined as change from baseline.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
0 hour
|
0.139 Liter
Standard Error 0.047
|
0.165 Liter
Standard Error 0.047
|
0.095 Liter
Standard Error 0.048
|
0.229 Liter
Standard Error 0.047
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
0.5 hour
|
0.354 Liter
Standard Error 0.049
|
0.302 Liter
Standard Error 0.049
|
0.200 Liter
Standard Error 0.049
|
0.395 Liter
Standard Error 0.048
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
3 hours
|
0.425 Liter
Standard Error 0.051
|
0.319 Liter
Standard Error 0.051
|
0.252 Liter
Standard Error 0.051
|
0.457 Liter
Standard Error 0.051
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
4 hours
|
0.396 Liter
Standard Error 0.050
|
0.312 Liter
Standard Error 0.050
|
0.223 Liter
Standard Error 0.050
|
0.463 Liter
Standard Error 0.050
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
6 hours
|
0.368 Liter
Standard Error 0.050
|
0.254 Liter
Standard Error 0.051
|
0.179 Liter
Standard Error 0.051
|
0.399 Liter
Standard Error 0.050
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
8 hours
|
0.309 Liter
Standard Error 0.051
|
0.225 Liter
Standard Error 0.051
|
0.141 Liter
Standard Error 0.051
|
0.355 Liter
Standard Error 0.051
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
10 hours
|
0.264 Liter
Standard Error 0.051
|
0.185 Liter
Standard Error 0.051
|
0.051 Liter
Standard Error 0.051
|
0.306 Liter
Standard Error 0.051
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
12 hours
|
0.229 Liter
Standard Error 0.050
|
0.142 Liter
Standard Error 0.050
|
0.051 Liter
Standard Error 0.051
|
0.258 Liter
Standard Error 0.050
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
12.5 hours
|
0.206 Liter
Standard Error 0.052
|
0.131 Liter
Standard Error 0.053
|
0.066 Liter
Standard Error 0.053
|
0.273 Liter
Standard Error 0.052
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
13 hours
|
0.194 Liter
Standard Error 0.052
|
0.116 Liter
Standard Error 0.052
|
0.106 Liter
Standard Error 0.052
|
0.266 Liter
Standard Error 0.052
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
14 hours
|
0.225 Liter
Standard Error 0.052
|
0.122 Liter
Standard Error 0.052
|
0.082 Liter
Standard Error 0.052
|
0.287 Liter
Standard Error 0.052
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
22 hours
|
0.081 Liter
Standard Error 0.049
|
0.001 Liter
Standard Error 0.049
|
-0.014 Liter
Standard Error 0.049
|
0.191 Liter
Standard Error 0.049
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
23 hours
|
0.176 Liter
Standard Error 0.050
|
0.098 Liter
Standard Error 0.050
|
0.043 Liter
Standard Error 0.050
|
0.243 Liter
Standard Error 0.050
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
24 hours
|
0.208 Liter
Standard Error 0.050
|
0.153 Liter
Standard Error 0.050
|
0.089 Liter
Standard Error 0.050
|
0.280 Liter
Standard Error 0.050
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
1 hour
|
0.386 Liter
Standard Error 0.050
|
0.332 Liter
Standard Error 0.050
|
0.220 Liter
Standard Error 0.050
|
0.411 Liter
Standard Error 0.050
|
|
Response in Individual Forced Vital Capacity (FVC) Over a 24 Hour Observation Period
2 hours
|
0.409 Liter
Standard Error 0.049
|
0.330 Liter
Standard Error 0.049
|
0.243 Liter
Standard Error 0.050
|
0.464 Liter
Standard Error 0.049
|
SECONDARY outcome
Timeframe: At baseline, pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 14, 22, 23, and 24 hours post morning dose after 6 weeks of treatment.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Response in individual peak expiratory flow (PEF) over a 24 hour observation period. Response is defined as change from baseline. Means are adjusted for treatment, centre, treatment period and patient within centre.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
12 hours
|
23.4 Liter/minutes (L/min)
Standard Error 5.6
|
11.8 Liter/minutes (L/min)
Standard Error 5.6
|
-0.6 Liter/minutes (L/min)
Standard Error 5.6
|
26.8 Liter/minutes (L/min)
Standard Error 5.6
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
12.5 hours
|
13.6 Liter/minutes (L/min)
Standard Error 5.7
|
5.5 Liter/minutes (L/min)
Standard Error 5.7
|
-0.7 Liter/minutes (L/min)
Standard Error 5.8
|
26.6 Liter/minutes (L/min)
Standard Error 5.7
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
0 hour
|
14.4 Liter/minutes (L/min)
Standard Error 4.9
|
11.3 Liter/minutes (L/min)
Standard Error 4.9
|
7.1 Liter/minutes (L/min)
Standard Error 4.9
|
22.9 Liter/minutes (L/min)
Standard Error 4.9
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
0.5 hour
|
30.8 Liter/minutes (L/min)
Standard Error 5.1
|
20.1 Liter/minutes (L/min)
Standard Error 5.2
|
13.7 Liter/minutes (L/min)
Standard Error 5.2
|
34.3 Liter/minutes (L/min)
Standard Error 5.1
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
2 hours
|
42.2 Liter/minutes (L/min)
Standard Error 5.3
|
27.6 Liter/minutes (L/min)
Standard Error 5.3
|
18.5 Liter/minutes (L/min)
Standard Error 5.3
|
47.0 Liter/minutes (L/min)
Standard Error 5.2
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
3 hours
|
45.0 Liter/minutes (L/min)
Standard Error 5.4
|
27.9 Liter/minutes (L/min)
Standard Error 5.4
|
17.1 Liter/minutes (L/min)
Standard Error 5.4
|
49.9 Liter/minutes (L/min)
Standard Error 5.4
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
4 hours
|
41.9 Liter/minutes (L/min)
Standard Error 5.6
|
26.4 Liter/minutes (L/min)
Standard Error 5.6
|
17.2 Liter/minutes (L/min)
Standard Error 5.6
|
46.5 Liter/minutes (L/min)
Standard Error 5.5
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
6 hours
|
37.8 Liter/minutes (L/min)
Standard Error 5.5
|
25.0 Liter/minutes (L/min)
Standard Error 5.5
|
11.1 Liter/minutes (L/min)
Standard Error 5.5
|
38.9 Liter/minutes (L/min)
Standard Error 5.5
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
13 hours
|
12.0 Liter/minutes (L/min)
Standard Error 5.7
|
5.8 Liter/minutes (L/min)
Standard Error 5.7
|
2.6 Liter/minutes (L/min)
Standard Error 5.7
|
25.3 Liter/minutes (L/min)
Standard Error 5.6
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
14 hours
|
15.6 Liter/minutes (L/min)
Standard Error 5.7
|
4.5 Liter/minutes (L/min)
Standard Error 5.7
|
1.4 Liter/minutes (L/min)
Standard Error 5.8
|
27.9 Liter/minutes (L/min)
Standard Error 5.7
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
23 hours
|
9.1 Liter/minutes (L/min)
Standard Error 5.3
|
2.3 Liter/minutes (L/min)
Standard Error 5.3
|
-5.7 Liter/minutes (L/min)
Standard Error 5.3
|
18.1 Liter/minutes (L/min)
Standard Error 5.3
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
24 hours
|
14.0 Liter/minutes (L/min)
Standard Error 5.3
|
9.6 Liter/minutes (L/min)
Standard Error 5.3
|
2.0 Liter/minutes (L/min)
Standard Error 5.3
|
24.0 Liter/minutes (L/min)
Standard Error 5.3
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
1 hour
|
35.5 Liter/minutes (L/min)
Standard Error 5.1
|
22.2 Liter/minutes (L/min)
Standard Error 5.1
|
14.6 Liter/minutes (L/min)
Standard Error 5.1
|
41.0 Liter/minutes (L/min)
Standard Error 5.1
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
8 hours
|
33.9 Liter/minutes (L/min)
Standard Error 5.6
|
23.3 Liter/minutes (L/min)
Standard Error 5.6
|
8.6 Liter/minutes (L/min)
Standard Error 5.6
|
35.5 Liter/minutes (L/min)
Standard Error 5.6
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
10 hours
|
26.9 Liter/minutes (L/min)
Standard Error 5.7
|
19.0 Liter/minutes (L/min)
Standard Error 5.7
|
1.9 Liter/minutes (L/min)
Standard Error 5.7
|
28.8 Liter/minutes (L/min)
Standard Error 5.7
|
|
Response in Individual Peak Expiratory Flow (PEF) Over a 24 Hour Observation Period
22 hours
|
-4.2 Liter/minutes (L/min)
Standard Error 5.1
|
-11.7 Liter/minutes (L/min)
Standard Error 5.1
|
-9.7 Liter/minutes (L/min)
Standard Error 5.1
|
10.1 Liter/minutes (L/min)
Standard Error 5.1
|
SECONDARY outcome
Timeframe: At baseline and last 3 weeks of 6-week treatment period.Population: Full Analysis Set (FAS): All patients where baseline data and any on-Treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints
The mean PEF is defined as the mean of the values obtained during the weeks after the first three weeks of treatment. Morning and evening mean PEF were calculated and analyzed separately. PEF was measured twice daily (in the morning prior to inhalation of study medication and in the evening prior to inhalation of study medication). Morning and evening mean PEF response are defined as the change from morning and evening baseline, respectively. Morning and evening mean PEF baseline are defined as the mean of the morning and evening values, respectively obtained from the last week preceding the randomization visit. Mean is adjusted for treatment, center, treatment period and patient within center.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=127 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=124 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=125 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Morning and Evening Peak Expiratory Flow Rate (PEF), Recorded by Patients at Home
PEF, morning
|
6.8 Liter / minute (L/min)
Standard Error 4.0
|
1.2 Liter / minute (L/min)
Standard Error 4.0
|
0.6 Liter / minute (L/min)
Standard Error 4.0
|
14.8 Liter / minute (L/min)
Standard Error 4.0
|
|
Response in Morning and Evening Peak Expiratory Flow Rate (PEF), Recorded by Patients at Home
PEF, evening
|
16.7 Liter / minute (L/min)
Standard Error 4.9
|
5.8 Liter / minute (L/min)
Standard Error 4.9
|
-6.4 Liter / minute (L/min)
Standard Error 4.9
|
15.2 Liter / minute (L/min)
Standard Error 4.9
|
SECONDARY outcome
Timeframe: At baseline and last 3 weeks of 6-week treatment period.Population: Full Analysis Set (FAS): All patients where baseline data and any on-Treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Per treatment period, the morning mean FEV1 (mean of the pre-dose morning FEV1 measurements) and evening mean FEV1 (mean of the pre-dose evening FEV1 measurement) were calculated. Per treatment period the data obtained after the first 3 weeks were used for calculating these means. Morning and evening mean FEV1 responses are defined as the change from morning and evening baseline, respectively. The baseline values, morning and evening mean FEV1(Baseline), are defined as the mean of the morning and evening values, respectively obtained from the last week preceding the randomization visit . Mean is adjusted for treatment, centre, treatment period and patient within centre.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=127 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=124 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=125 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Morning and Evening Forced Expiratory Volume in 1 Second (FEV1) Recorded by Participants at Home
FEV1, evening
|
0.094 Liter (L)
Standard Error 0.036
|
0.038 Liter (L)
Standard Error 0.036
|
-0.010 Liter (L)
Standard Error 0.036
|
0.075 Liter (L)
Standard Error 0.036
|
|
Response in Morning and Evening Forced Expiratory Volume in 1 Second (FEV1) Recorded by Participants at Home
FEV1, morning
|
0.052 Liter (L)
Standard Error 0.035
|
0.013 Liter (L)
Standard Error 0.035
|
0.026 Liter (L)
Standard Error 0.035
|
0.075 Liter (L)
Standard Error 0.035
|
SECONDARY outcome
Timeframe: At baseline and last 3 weeks of 6-week treatment period.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Response (change from baseline) in mean number of days with rescue medication use in day-time, night-time and 24-hours. Per treatment period, the response in mean number of days using rescue medication was calculated for day-time (from inhalation of morning dose until 12 hours thereafter), night-time (from inhalation of evening dose until 12 hours thereafter) and 24h-total (from inhalation of morning dose until 24 hours thereafter) separately. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating means. Mean is adjusted mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=127 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=124 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=125 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Mean Number of Days With Rescue Medication Use
24 hours
|
-0.13 Days
Standard Error 0.04
|
-0.04 Days
Standard Error 0.04
|
-0.06 Days
Standard Error 0.04
|
-0.14 Days
Standard Error 0.04
|
|
Response in Mean Number of Days With Rescue Medication Use
Daytime
|
-0.08 Days
Standard Error 0.03
|
-0.01 Days
Standard Error 0.03
|
-0.06 Days
Standard Error 0.03
|
-0.11 Days
Standard Error 0.03
|
|
Response in Mean Number of Days With Rescue Medication Use
Night-time
|
-0.15 Days
Standard Error 0.04
|
-0.06 Days
Standard Error 0.04
|
-0.07 Days
Standard Error 0.04
|
-0.14 Days
Standard Error 0.04
|
SECONDARY outcome
Timeframe: At baseline and last 3 weeks of 6-week treatment period.Population: Full Analysis Set (FAS): All patients where baseline data any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Response in mean number of puffs of rescue medication. Per treatment period, the response in mean number of puffs rescue medication used was calculated, for day-time (from inhalation of morning dose until 12 hours thereafter), night-time (from inhalation of evening dose until 12 hours thereafter) and 24h-total (from inhalation of morning dose until 24 hours thereafter) separately. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating means. Night-time, day-time and 24h-total mean number of puffs rescue medication used responses are defined as the change from night-time, day-time and 24h-total baseline, respectively. The baseline values, night-time, day-time and 24h-total mean mean number of puffs rescue medication used (Baseline), are defined as the mean of the night-time, day-time and 24h-total values, respectively obtained from the last week preceding the randomisation visit.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Mean Number of Puffs of Rescue Medication
Daytime
|
-0.61 Puffs
Standard Error 0.18
|
-0.27 Puffs
Standard Error 0.18
|
-0.25 Puffs
Standard Error 0.18
|
-0.65 Puffs
Standard Error 0.18
|
|
Response in Mean Number of Puffs of Rescue Medication
Night-time
|
-0.16 Puffs
Standard Error 0.12
|
0.01 Puffs
Standard Error 0.12
|
-0.07 Puffs
Standard Error 0.12
|
-0.28 Puffs
Standard Error 0.12
|
|
Response in Mean Number of Puffs of Rescue Medication
Over 24 hours
|
-0.76 Puffs
Standard Error 0.28
|
-0.23 Puffs
Standard Error 0.28
|
-0.30 Puffs
Standard Error 0.28
|
-0.92 Puffs
Standard Error 0.28
|
SECONDARY outcome
Timeframe: At baseline and last 3 weeks of 6-week treatment period.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Response in mean number of days with night-time awakenings. Per treatment period, the mean number days with awakening during the night was calculated. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating this mean. Mean number of days with night-time awakenings response is defined as the change from baseline. The baseline value, mean number of days with night-time awakenings (Baseline), is defined as the mean of the number of days with night-time awakenings obtained from the last week preceding the randomization visit.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=127 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=124 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=125 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Mean Number of Days With Night-time Awakenings
|
-0.06 Days
Standard Error 0.03
|
-0.06 Days
Standard Error 0.03
|
-0.05 Days
Standard Error 0.03
|
0.07 Days
Standard Error 0.03
|
SECONDARY outcome
Timeframe: At baseline and last 3 weeks of 6-week treatment period.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Per treatment period, the mean number days with awakening (only chronic obstructive pulmonary disease (COPD) related awakenings) during the night was calculated. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating the mean. Mean number of days with COPD related awakenings response is defined as the change from baseline. The baseline value, mean number of days with COPD related awakenings (Baseline), is defined as the mean of the number of days with COPD related awakenings obtained from the last week preceding the randomization visit.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=127 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=124 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=125 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Mean Number of Days With Night-time Awakenings Due to Shortness of Breath (SOB)
|
-0.05 Days
Standard Error 0.02
|
-0.04 Days
Standard Error 0.02
|
-0.04 Days
Standard Error 0.02
|
-0.07 Days
Standard Error 0.02
|
SECONDARY outcome
Timeframe: At baseline and last 3 weeks of 6-week treatment period.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Per treatment period, the mean number of awakening (only chronic obstructive pulmonary disease (COPD) related awakenings) during the night was calculated. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating this mean. Mean number of COPD related awakenings response is defined as the change from baseline. The baseline value, mean number of COPD related awakenings (Baseline), is defined as the mean of the number of days with COPD related awakenings obtained from the last week preceding the randomization visit.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=127 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=124 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=125 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Means Number of Awakenings Due to Shortness of Breath (SOB)
|
-0.02 Awakenings
Standard Error 0.04
|
-0.02 Awakenings
Standard Error 0.04
|
-0.04 Awakenings
Standard Error 0.04
|
-0.08 Awakenings
Standard Error 0.04
|
SECONDARY outcome
Timeframe: At baseline and last 3 weeks of 6-week treatment period.Population: Full Analysis Set (FAS): All patients where baseline data and any on-treatment efficacy data are available. This definition was applied separately for each endpoint, so that the number of patients analysed may vary across endpoints.
Response in average shortness of breath (SOB) score at night. The SOB measured the shortness of breath, ranging from 1 to 5, where 1 = not at all, 2 = a little bit, 3 = somewhat, 4 = quite a bit and 5 = very much. A higher score indicates a worse outcome. Per 6-week treatment period the data obtained after the first 3 weeks was used for calculating the mean.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=127 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=124 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=125 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Response in Average Shortness of Breath (SOB) Score at Night
|
-0.06 Score on a scale
Standard Error 0.05
|
-0.04 Score on a scale
Standard Error 0.05
|
-0.06 Score on a scale
Standard Error 0.05
|
-0.11 Score on a scale
Standard Error 0.05
|
SECONDARY outcome
Timeframe: From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.Population: Treated Set (TS): All randomised patients who took at least one dose of study medication.
Number of participants with drug related adverse events.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=132 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=135 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=137 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=132 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Number of Participants With Drug Related Adverse Events
|
0 Participants
|
2 Participants
|
2 Participants
|
2 Participants
|
SECONDARY outcome
Timeframe: At baseline and 6 hours following the morning dose of study medication after 6 weeks of treatment.Population: Treated Set (TS): All randomised patients who took at least one dose of study medication and who had available data.
Marked changes from baseline in vital signs were defined as followed: Systolic blood pressure * Increase of ≥25 millimetre of mercury (mmHg) above baseline * Decrease below 100 mmHg if not at that level at baseline and a decrease of \>10 mmHg below baseline Diastolic blood pressure * Increase above 90 mmHg and an increase of \>10 mmHg above baseline * Decrease below 60 mmHg if not at that level at baseline and a decrease of \>10 mmHg below baseline Pulse * Increase above 100 bpm if not at that level at baseline and an increase of \>10 bpm above baseline * Decrease below 60 bpm if not at that level at baseline and a decrease of \>10 bpm below baseline Baseline is defined as the pre-dose measurement at randomisation visit.
Outcome measures
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=127 Participants
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=128 Participants
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=125 Participants
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=127 Participants
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
|---|---|---|---|---|
|
Number of Patients With Marked Changes in Vital Signs
Increase in systolic blood pressure
|
18 Participants
|
18 Participants
|
16 Participants
|
15 Participants
|
|
Number of Patients With Marked Changes in Vital Signs
Increase in diastolic blood pressure
|
16 Participants
|
16 Participants
|
11 Participants
|
14 Participants
|
|
Number of Patients With Marked Changes in Vital Signs
Increase in pulse rate
|
6 Participants
|
10 Participants
|
9 Participants
|
13 Participants
|
|
Number of Patients With Marked Changes in Vital Signs
Decrease in systolic blood pressure
|
3 Participants
|
4 Participants
|
3 Participants
|
4 Participants
|
|
Number of Patients With Marked Changes in Vital Signs
Decrease in diastolic blood pressure
|
5 Participants
|
7 Participants
|
3 Participants
|
5 Participants
|
|
Number of Patients With Marked Changes in Vital Signs
Decrease in pulse rate
|
6 Participants
|
7 Participants
|
7 Participants
|
2 Participants
|
Adverse Events
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
Serious events: 1 serious events
Other events: 14 other events
Deaths: 0 deaths
18 µg Tiotropium (Tio18GEL)
Serious events: 7 serious events
Other events: 15 other events
Deaths: 1 deaths
50 µg Salmeterol MDPI (Salm50DPI)
Serious events: 4 serious events
Other events: 14 other events
Deaths: 0 deaths
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
Serious events: 2 serious events
Other events: 11 other events
Deaths: 0 deaths
Total Treated
Serious events: 13 serious events
Other events: 47 other events
Deaths: 1 deaths
Serious adverse events
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=132 participants at risk
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=135 participants at risk
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=137 participants at risk
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=132 participants at risk
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
Total Treated
n=146 participants at risk
All patients who received at least one dose of study medication.
|
|---|---|---|---|---|---|
|
Infections and infestations
Pneumonia
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
1.5%
2/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.73%
1/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
2.1%
3/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Infections and infestations
Mastoiditis
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.74%
1/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Infections and infestations
Meningitis pneumococcal
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.74%
1/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Infections and infestations
Pneumococcal infection
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.74%
1/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.74%
1/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic neoplasm malignant
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.74%
1/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.73%
1/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Blood and lymphatic system disorders
Haemorrhagic anaemia
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.74%
1/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Nervous system disorders
Intracranial aneurysm
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.74%
1/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Nervous system disorders
Subarachnoid haemorrhage
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.74%
1/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Cardiac disorders
Cardiac failure
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.76%
1/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Cardiac disorders
Congestive cardiomyopathy
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.76%
1/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Cardiac disorders
Right ventricular failure
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.74%
1/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
|
0.76%
1/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
1.5%
2/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.73%
1/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
2.7%
4/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.73%
1/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Gastrointestinal disorders
Diarrhoea haemorrhagic
|
0.76%
1/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Gastrointestinal disorders
Diverticulum intestinal haemorrhagic
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.74%
1/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Gastrointestinal disorders
Gastrointestinal haemorrhage
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.74%
1/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Gastrointestinal disorders
Intestinal haemorrhage
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.74%
1/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Hepatobiliary disorders
Cholecystitis
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.76%
1/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Hepatobiliary disorders
Cholelithiasis
|
0.00%
0/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.00%
0/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.76%
1/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.68%
1/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
Other adverse events
| Measure |
7.5 µg /25 µg Tio /Salmeterol (T+S_PE)
n=132 participants at risk
Fixed-dose combination of 7.5 µg/ 25 µg Tiotropium/Salmeterol (T+S\_PE) inhalation powder from one capsule via the blue HandiHaler® once daily (QD) in the morning, one capsule of matching placebo via the grey HandiHaler® and one actuation from the placebo Multi-Dose Powder Inhaler (MDPI) in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium (Tio18GEL)
n=135 participants at risk
18 µg Tiotropium (Tio18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® QD in the morning, one capsule of matching placebo via the blue HandiHaler® and one actuation from the placebo MDPI in the morning and one actuation from the placebo MDPI in the evening. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
50 µg Salmeterol MDPI (Salm50DPI)
n=137 participants at risk
One actuation of 50 µg Salmeterol MDPI (Salm50DPI) twice daily (BID) in the morning and in the evening, one capsule of matching placebo from grey HandiHaler® and one capsule of matching placebo from the blue HandiHaler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
18 µg Tiotropium Free Combination (T18GEL+S_DPI)
n=132 participants at risk
18 µg Tiotropium (T18GEL) inhalation powder from one capsule via the grey Spiriva HandyHaler® in the morning plus one actuation of 50 µg Salmeterol MDPI (S\_DPI) BID, in the morning and in the evening, and one placebo capsule from blue Handi Haler® in the morning. Each dose of study medication had to be taken approximately at the same time, with 12 hours between the evening and morning dose. Each treatment period was 6 weeks on average with no wash-out between the treatment periods.
|
Total Treated
n=146 participants at risk
All patients who received at least one dose of study medication.
|
|---|---|---|---|---|---|
|
Infections and infestations
Nasopharyngitis
|
6.8%
9/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
6.7%
9/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
5.1%
7/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
4.5%
6/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
18.5%
27/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
|
3.0%
4/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
3.7%
5/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
5.1%
7/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
2.3%
3/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
12.3%
18/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
1.5%
2/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
2.2%
3/135 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
0.73%
1/137 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
1.5%
2/132 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
5.5%
8/146 • From first drug administration until last drug administration (average duration of 42 days) + 30 days, up to 91 days for T+S_PE, up to 98 days for Tio18GEL, up 89 days for Salm50DPI and up to 113 days for T18GEL+S_DPI.
Treated Set (TS): All randomised patients who took at least one dose of study medication.
|
Additional Information
Boehringer Ingelheim, Call Center
Boehringer Ingelheim
Phone: 1-800-243-0127
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
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Restriction type: OTHER