Trial Outcomes & Findings for Evaluation of Tiotropium 2.5 and 5 mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo and Salmeterol HydroFluoroAlkane (HFA) Metered Dose Inhaler (MDI) (50 mcg Twice Daily) in Patient With Moderate Persistent Asthma II (NCT NCT01172821)

NCT ID: NCT01172821

Last Updated: 2014-06-09

Results Overview

Peak forced expiratory volume in one second (FEV1) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1032 participants
• Primary outcome timeframe: 24 weeks
• Results posted on: 2014-06-09

Participant Flow

There was 1 patient in the TIO R2.5 and 1 patient in the TIO R5 group randomized but not treated.

Participant milestones

Measure	Placebo Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Overall Study STARTED	254	257	253	266
Overall Study COMPLETED	240	245	240	249
Overall Study NOT COMPLETED	14	12	13	17

Reasons for withdrawal

Measure	Placebo Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Overall Study Adverse Event	5	2	2	7
Overall Study Protocol Violation	0	2	1	2
Overall Study Lost to Follow-up	4	1	2	2
Overall Study Withdrawal by Subject	2	3	3	3
Overall Study Other	3	4	5	3

Baseline Characteristics

Evaluation of Tiotropium 2.5 and 5 mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo and Salmeterol HydroFluoroAlkane (HFA) Metered Dose Inhaler (MDI) (50 mcg Twice Daily) in Patient With Moderate Persistent Asthma II

Baseline characteristics by cohort

Measure	Placebo n=254 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=257 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=253 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=266 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Total n=1030 Participants Total of all reporting groups
Age, Continuous	43.0 years STANDARD_DEVIATION 13.0 • n=5 Participants	43.0 years STANDARD_DEVIATION 12.6 • n=7 Participants	44.3 years STANDARD_DEVIATION 12.7 • n=5 Participants	41.5 years STANDARD_DEVIATION 13.1 • n=4 Participants	42.9 years STANDARD_DEVIATION 12.9 • n=21 Participants
Sex: Female, Male Female	145 Participants n=5 Participants	160 Participants n=7 Participants	146 Participants n=5 Participants	153 Participants n=4 Participants	604 Participants n=21 Participants
Sex: Female, Male Male	109 Participants n=5 Participants	97 Participants n=7 Participants	107 Participants n=5 Participants	113 Participants n=4 Participants	426 Participants n=21 Participants

PRIMARY outcome

Timeframe: 24 weeks

Population: Full Analysis Set (FAS) - all treated patients who had baseline data and at least 1 on-treatment efficacy measurement.

Peak forced expiratory volume in one second (FEV1) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

Outcome measures

Measure	Placebo n=242 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=245 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=240 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=251 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Peak FEV1 Within 3 Hours Post-dose Response	0.075 Litre Standard Error 0.020	0.287 Litre Standard Error 0.020	0.244 Litre Standard Error 0.020	0.252 Litre Standard Error 0.019

PRIMARY outcome

Timeframe: 24 weeks

Population: FAS

Trough FEV1 response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

Outcome measures

Measure	Placebo n=242 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=245 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=240 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=251 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Trough FEV1 Response	-0.012 Litre Standard Error 0.021	0.164 Litre Standard Error 0.021	0.121 Litre Standard Error 0.021	0.094 Litre Standard Error 0.021

PRIMARY outcome

Timeframe: 24 weeks

Population: FAS of combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821).

The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period (on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points.

Outcome measures

Measure	Placebo n=518 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=515 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=513 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=535 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)	57.7 Percentage of participants	64.5 Percentage of participants	64.3 Percentage of participants	66.5 Percentage of participants

SECONDARY outcome

Timeframe: 24 weeks

Population: FAS

Peak forced vital capacity (FVC) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

Outcome measures

Measure	Placebo n=242 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=245 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=240 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=251 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Peak FVC Within 3 Hours Post-dose Response	0.071 Litre Standard Error 0.022	0.181 Litre Standard Error 0.022	0.160 Litre Standard Error 0.022	0.188 Litre Standard Error 0.021

SECONDARY outcome

Timeframe: 24 weeks

Population: FAS

Trough FVC response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

Outcome measures

Measure	Placebo n=242 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=245 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=240 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=251 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Trough FVC Response	-0.048 Litre Standard Error 0.027	0.039 Litre Standard Error 0.027	0.035 Litre Standard Error 0.027	0.020 Litre Standard Error 0.027

SECONDARY outcome

Timeframe: 24 weeks

Population: FAS

Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24- week treatment. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

Outcome measures

Measure	Placebo n=242 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=245 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=240 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=251 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response	-0.005 Litre Standard Error 0.019	0.196 Litre Standard Error 0.019	0.158 Litre Standard Error 0.019	0.173 Litre Standard Error 0.019

SECONDARY outcome

Timeframe: 24 weeks

Population: FAS

Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24- week treatment. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

Outcome measures

Measure	Placebo n=242 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=245 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=240 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=251 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
FVC Area Under Curve 0-3 Hours (AUC0-3h) Response	-0.065 Litre Standard Error 0.024	0.043 Litre Standard Error 0.024	0.024 Litre Standard Error 0.025	0.066 Litre Standard Error 0.024

SECONDARY outcome

Timeframe: 24 weeks

Population: FAS

Trough peak expiratory flow (PEF) response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

Outcome measures

Measure	Placebo n=242 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=245 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=240 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=251 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Trough PEF Response	7.938 Litre/min Standard Error 3.659	36.698 Litre/min Standard Error 3.614	36.117 Litre/min Standard Error 3.646	29.352 Litre/min Standard Error 3.572

SECONDARY outcome

Timeframe: 24 weeks

Population: FAS

Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ(s)) determined at the end of 24-week treatment.

The AQLQ(s) contains 32 questions, each question has a 7 point scale from 1 (highest intensity) till 7 (no symptoms). Total score was defined as the sum of all items divided by the number of items and ranges from from 1 (highest intensity) till 7 (no symptoms). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

Outcome measures

Measure	Placebo n=240 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=245 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=240 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=250 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Total Asthma Quality of Life Questionnaire (AQLQs)) Score	5.551 units on a scale Standard Error 0.050	5.562 units on a scale Standard Error 0.049	5.548 units on a scale Standard Error 0.050	5.634 units on a scale Standard Error 0.048

SECONDARY outcome

Timeframe: 24 weeks

Population: FAS

Control of asthma as assessed by the ACQ determined at the end of 24-week treatment. The ACQ contains 7 questions, each question has a 7 point scale from 0 (no symptoms) till 6 (highest intensity). Total score was defined as the sum of all items divided by the number of items and ranges from from 0 (no symptoms) till 6 (highest intensity). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

Outcome measures

Measure	Placebo n=240 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=245 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=240 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=250 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Total Asthma Control Questionnaire (ACQ) Score	1.442 units on a scale Standard Error 0.043	1.315 units on a scale Standard Error 0.042	1.359 units on a scale Standard Error 0.043	1.318 units on a scale Standard Error 0.042

SECONDARY outcome

Timeframe: 24 weeks

Population: FAS

The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period. A patient was considered to be a responder if he or she was reported with an improvement (decrease) in ACQ total score of at least 0.5 points.The score ranges from 0 (no impairment) to 6 (maximum impairment).

Outcome measures

Measure	Placebo n=253 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=256 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=252 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=264 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
The Responder Rate as Assessed by the ACQ	62.5 Percentage of participants	66.4 Percentage of participants	61.9 Percentage of participants	64.4 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: FAS

Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week

Outcome measures

Measure	Placebo n=235 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=238 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=236 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=247 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24	2.764 Litre/min Standard Error 3.292	23.377 Litre/min Standard Error 3.267	27.521 Litre/min Standard Error 3.294	19.779 Litre/min Standard Error 3.219

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: FAS

Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

Outcome measures

Measure	Placebo n=236 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=238 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=236 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=247 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24	-0.072 Litre/min Standard Error 3.328	15.919 Litre/min Standard Error 3.303	21.175 Litre/min Standard Error 3.330	11.617 Litre/min Standard Error 3.256

SECONDARY outcome

Timeframe: Last 7 days before week 24 visit

Population: FAS

PEF daily variability was assesed by patients at home using the AM3 device. PEF variability is the absolute difference between morning and evening PEF value divided by their mean, based on the weekly mean response at week 24. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

Outcome measures

Measure	Placebo n=232 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=237 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=234 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=244 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
PEF Variability	-0.448 Percentage of Mean PEF Standard Error 0.484	-1.401 Percentage of Mean PEF Standard Error 0.480	-0.627 Percentage of Mean PEF Standard Error 0.487	-1.518 Percentage of Mean PEF Standard Error 0.472

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: FAS

Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

Outcome measures

Measure	Placebo n=235 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=238 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=236 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=247 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24	0.020 Litre Standard Error 0.023	0.099 Litre Standard Error 0.023	0.084 Litre Standard Error 0.023	0.103 Litre Standard Error 0.022

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: FAS

Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

Outcome measures

Measure	Placebo n=236 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=238 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=236 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=247 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24	-0.002 Litre Standard Error 0.024	0.066 Litre Standard Error 0.023	0.064 Litre Standard Error 0.024	0.048 Litre Standard Error 0.023

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: FAS

Daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

Outcome measures

Measure	Placebo n=237 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=238 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=236 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=247 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24	-0.952 Number of Puffs Standard Error 0.093	-1.123 Number of Puffs Standard Error 0.092	-0.843 Number of Puffs Standard Error 0.093	-1.078 Number of Puffs Standard Error 0.091

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: FAS

Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. An asthma symptom-free day was defined as a day with no reported symptoms and no use of rescue medication.

Outcome measures

Measure	Placebo n=237 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=238 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=236 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=247 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24	0.189 Days Standard Error 0.023	0.164 Days Standard Error 0.023	0.196 Days Standard Error 0.023	0.195 Days Standard Error 0.022

SECONDARY outcome

Timeframe: 24 weeks

Population: FAS of combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)

Time to first severe asthma exacerbation during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)

Outcome measures

Measure	Placebo n=518 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=515 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=513 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=535 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)	NA weeks The median time to first severe asthma exacerbation could not be calculated as less than 50% of patients in each treatment group experienced an asthma exacerbation.	NA weeks The median time to first severe asthma exacerbation could not be calculated as less than 50% of patients in each treatment group experienced an asthma exacerbation.	NA weeks The median time to first severe asthma exacerbation could not be calculated as less than 50% of patients in each treatment group experienced an asthma exacerbation.	NA weeks The median time to first severe asthma exacerbation could not be calculated as less than 50% of patients in each treatment group experienced an asthma exacerbation.

SECONDARY outcome

Timeframe: 24 weeks

Population: FAS of combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)

Time to first asthma exacerbation (including severe, non-severe; symptomatic, asymptomatic; i.e. any exacerbation) during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)

Outcome measures

Measure	Placebo n=518 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=515 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=513 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=535 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Time to First Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)	NA weeks The median time to first asthma exacerbation could not be calculated as less than 50% of patients in each treatment group experienced an asthma exacerbation.	NA weeks The median time to first asthma exacerbation could not be calculated as less than 50% of patients in each treatment group experienced an asthma exacerbation.	NA weeks The median time to first asthma exacerbation could not be calculated as less than 50% of patients in each treatment group experienced an asthma exacerbation.	NA weeks The median time to first asthma exacerbation could not be calculated as less than 50% of patients in each treatment group experienced an asthma exacerbation.

Adverse Events

Placebo

Serious events: 4 serious events

Other events: 102 other events

Deaths: 0 deaths

Tio R2.5

Serious events: 7 serious events

Other events: 89 other events

Deaths: 0 deaths

Tio R5

Serious events: 7 serious events

Other events: 87 other events

Deaths: 0 deaths

Salmeterol

Serious events: 4 serious events

Other events: 90 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=254 participants at risk Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=257 participants at risk Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=253 participants at risk Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=266 participants at risk Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Gastrointestinal disorders Anal fistula	0.00% 0/254 • 24 weeks	0.39% 1/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.00% 0/266 • 24 weeks
Gastrointestinal disorders Colitis	0.00% 0/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.40% 1/253 • 24 weeks	0.00% 0/266 • 24 weeks
Gastrointestinal disorders Ileus paralytic	0.00% 0/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.38% 1/266 • 24 weeks
General disorders Suprapubic pain	0.00% 0/254 • 24 weeks	0.39% 1/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.00% 0/266 • 24 weeks
Immune system disorders Anaphylactic reaction	0.00% 0/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.40% 1/253 • 24 weeks	0.00% 0/266 • 24 weeks
Infections and infestations Pneumonia	0.00% 0/254 • 24 weeks	0.39% 1/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.00% 0/266 • 24 weeks
Infections and infestations Pyelonephritis	0.39% 1/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.00% 0/266 • 24 weeks
Injury, poisoning and procedural complications Chemical poisoning	0.00% 0/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.40% 1/253 • 24 weeks	0.00% 0/266 • 24 weeks
Injury, poisoning and procedural complications Intestinal anastomosis complication	0.00% 0/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.38% 1/266 • 24 weeks
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.38% 1/266 • 24 weeks
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.00% 0/254 • 24 weeks	0.39% 1/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.00% 0/266 • 24 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian adenoma	0.00% 0/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.40% 1/253 • 24 weeks	0.00% 0/266 • 24 weeks
Nervous system disorders Cerebral haemorrhage	0.39% 1/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.00% 0/266 • 24 weeks
Nervous system disorders Cervicobrachial syndrome	0.00% 0/254 • 24 weeks	0.39% 1/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.00% 0/266 • 24 weeks
Pregnancy, puerperium and perinatal conditions Ectopic pregnancy	0.00% 0/254 • 24 weeks	0.39% 1/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.00% 0/266 • 24 weeks
Reproductive system and breast disorders Benign prostatic hyperplasia	0.00% 0/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.38% 1/266 • 24 weeks
Reproductive system and breast disorders Parovarian cyst	0.00% 0/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.40% 1/253 • 24 weeks	0.00% 0/266 • 24 weeks
Respiratory, thoracic and mediastinal disorders Asthma	0.79% 2/254 • 24 weeks	0.78% 2/257 • 24 weeks	0.40% 1/253 • 24 weeks	0.38% 1/266 • 24 weeks
Respiratory, thoracic and mediastinal disorders Eosinophilic pneumonia	0.00% 0/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.38% 1/266 • 24 weeks
Respiratory, thoracic and mediastinal disorders Nasal polyps	0.00% 0/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.40% 1/253 • 24 weeks	0.00% 0/266 • 24 weeks
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	0.00% 0/254 • 24 weeks	0.39% 1/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.00% 0/266 • 24 weeks
Vascular disorders Hypertension	0.00% 0/254 • 24 weeks	0.39% 1/257 • 24 weeks	0.00% 0/253 • 24 weeks	0.00% 0/266 • 24 weeks
Vascular disorders Hypertensive crisis	0.00% 0/254 • 24 weeks	0.00% 0/257 • 24 weeks	0.40% 1/253 • 24 weeks	0.00% 0/266 • 24 weeks

Other adverse events

Measure	Placebo n=254 participants at risk Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=257 participants at risk Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=253 participants at risk Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=266 participants at risk Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Infections and infestations Nasopharyngitis	10.2% 26/254 • 24 weeks	12.1% 31/257 • 24 weeks	7.5% 19/253 • 24 weeks	9.4% 25/266 • 24 weeks
Infections and infestations Upper respiratory tract infection	8.7% 22/254 • 24 weeks	4.3% 11/257 • 24 weeks	4.7% 12/253 • 24 weeks	6.0% 16/266 • 24 weeks
Investigations Peak expiratory flow rate decreased	11.0% 28/254 • 24 weeks	8.2% 21/257 • 24 weeks	9.9% 25/253 • 24 weeks	6.8% 18/266 • 24 weeks
Respiratory, thoracic and mediastinal disorders Asthma	21.3% 54/254 • 24 weeks	17.1% 44/257 • 24 weeks	19.8% 50/253 • 24 weeks	19.5% 52/266 • 24 weeks

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

Results disclosure agreements

• Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
• Publication restrictions are in place

Restriction type: OTHER