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 I (NCT NCT01172808)

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

1071 participants

Primary outcome timeframe

24 weeks

Results posted on

2014-06-09

Participant Flow

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

Participant milestones

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	269	262	264	275
Overall Study COMPLETED	248	249	241	260
Overall Study NOT COMPLETED	21	13	23	15

Reasons for withdrawal

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	8	4	8	3
Overall Study Lack of Efficacy	1	0	0	0
Overall Study Protocol Violation	2	2	2	0
Overall Study Lost to Follow-up	0	1	1	3
Overall Study Withdrawal by Subject	4	1	3	2
Overall Study Other	6	5	9	7

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 I

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=269 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=262 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=264 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=275 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Total n=1070 Participants Total of all reporting groups
Age, Continuous	42.5 years STANDARD_DEVIATION 13.1 • n=5 Participants	43.7 years STANDARD_DEVIATION 13.1 • n=7 Participants	44.4 years STANDARD_DEVIATION 12.6 • n=5 Participants	42.6 years STANDARD_DEVIATION 12.6 • n=4 Participants	43.3 years STANDARD_DEVIATION 12.9 • n=21 Participants
Sex: Female, Male Female	166 Participants n=5 Participants	156 Participants n=7 Participants	154 Participants n=5 Participants	159 Participants n=4 Participants	635 Participants n=21 Participants
Sex: Female, Male Male	103 Participants n=5 Participants	106 Participants n=7 Participants	110 Participants n=5 Participants	116 Participants n=4 Participants	435 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 excluding patients from one centre due to non-compliance with good clinical practice.

Outcome measures

Outcome measures
Measure	Placebo n=250 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=247 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=241 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=259 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	0.053 Litre Standard Error 0.021	0.289 Litre Standard Error 0.021	0.250 Litre Standard Error 0.021	0.266 Litre Standard Error 0.020

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

Outcome measures
Measure	Placebo n=250 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=247 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=241 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=259 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Trough FEV1 Response	-0.036 Litre Standard Error 0.022	0.148 Litre Standard Error 0.022	0.115 Litre Standard Error 0.022	0.086 Litre Standard Error 0.022

PRIMARY outcome

Timeframe: 24 weeks

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

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. The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment).

Outcome measures

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 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)	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

Outcome measures
Measure	Placebo n=250 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=247 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=241 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=259 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	0.045 Litre Standard Error 0.022	0.219 Litre Standard Error 0.022	0.148 Litre Standard Error 0.023	0.168 Litre Standard Error 0.022

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

Outcome measures
Measure	Placebo n=250 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=247 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=241 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=259 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Trough FVC Response	-0.039 Litre Standard Error 0.025	0.086 Litre Standard Error 0.026	0.036 Litre Standard Error 0.026	0.028 Litre Standard Error 0.025

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

Outcome measures
Measure	Placebo n=250 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=247 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=241 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=259 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	-0.033 Litre Standard Error 0.020	0.192 Litre Standard Error 0.020	0.163 Litre Standard Error 0.020	0.182 Litre Standard Error 0.020

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

Outcome measures
Measure	Placebo n=250 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=247 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=241 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=259 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	-0.066 Litre Standard Error 0.023	0.092 Litre Standard Error 0.023	0.041 Litre Standard Error 0.024	0.062 Litre Standard Error 0.023

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

Outcome measures
Measure	Placebo n=250 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=247 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=241 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=259 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Trough PEF Response	2.913 Litre/min Standard Error 3.641	40.819 Litre/min Standard Error 3.664	36.590 Litre/min Standard Error 3.712	31.317 Litre/min Standard Error 3.596

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. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

Outcome measures

Outcome measures
Measure	Placebo n=247 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=246 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=242 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=260 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	5.449 units on a scale Standard Error 0.049	5.522 units on a scale Standard Error 0.049	5.519 units on a scale Standard Error 0.049	5.654 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. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

Outcome measures

Outcome measures
Measure	Placebo n=247 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=247 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=242 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=259 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Total Asthma Control Questionnaire (ACQ) Score at the End of the 24-week Treatment Period	1.563 units on a scale Standard Error 0.043	1.362 units on a scale Standard Error 0.043	1.431 units on a scale Standard Error 0.044	1.302 units on a scale Standard Error 0.043

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 ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment).

Outcome measures

Outcome measures
Measure	Placebo n=265 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=259 Participants Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=261 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=271 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	53.2 Percentage of Participants	62.5 Percentage of Participants	66.7 Percentage of Participants	68.6 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

Outcome measures
Measure	Placebo n=238 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=247 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=254 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	-10.159 Litre/min Standard Error 3.537	20.432 Litre/min Standard Error 3.547	13.501 Litre/min Standard Error 3.587	22.467 Litre/min Standard Error 3.491

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: FAS

Outcome measures

Outcome measures
Measure	Placebo n=239 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=236 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=252 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	-9.181 Litre/min Standard Error 3.245	18.978 Litre/min Standard Error 3.245	15.188 Litre/min Standard Error 3.273	19.727 Litre/min Standard Error 3.190

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, centre, week, baseline, treatment by week, and baseline by week.

Outcome measures

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=244 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=252 Participants Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
PEF Variability	-1.400 Percentage of mean PEF Standard Error 0.437	-1.958 Percentage of mean PEF Standard Error 0.434	0.180 Percentage of mean PEF Standard Error 0.441	-2.300 Percentage of mean PEF Standard Error 0.427

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: FAS

Outcome measures

Outcome measures
Measure	Placebo n=238 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=247 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=254 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	0.021 Litre Standard Error 0.022	0.101 Litre Standard Error 0.022	0.073 Litre Standard Error 0.022	0.117 Litre Standard Error 0.021

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: FAS

Outcome measures

Outcome measures
Measure	Placebo n=239 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=236 Participants Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=252 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	-0.000 Litre Standard Error 0.022	0.065 Litre Standard Error 0.022	0.039 Litre Standard Error 0.022	0.072 Litre Standard Error 0.022

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

Outcome measures
Measure	Placebo n=239 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=247 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=254 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	-0.962 Number of Puffs Standard Error 0.102	-1.124 Number of Puffs Standard Error 0.102	-0.818 Number of Puffs Standard Error 0.103	-1.416 Number of Puffs Standard Error 0.100

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: FAS

Outcome measures

Outcome measures
Measure	Placebo n=239 Participants Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=247 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=254 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	0.162 Days Standard Error 0.021	0.207 Days Standard Error 0.021	0.157 Days Standard Error 0.021	0.266 Days Standard Error 0.021

SECONDARY outcome

Timeframe: 24 weeks

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

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

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 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)	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 205.419 (NCT01172821) and 205.418 (NCT01172808)

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

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 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)	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: 10 serious events

Other events: 115 other events

Deaths: 0 deaths

Tio R2.5

Serious events: 5 serious events

Other events: 79 other events

Deaths: 0 deaths

Tio R5

Serious events: 4 serious events

Other events: 96 other events

Deaths: 0 deaths

Salmeterol

Serious events: 7 serious events

Other events: 95 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=269 participants at risk Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=262 participants at risk Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=264 participants at risk Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=275 participants at risk Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Cardiac disorders Acute myocardial infarction	0.37% 1/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Cardiac disorders Atrial fibrillation	0.00% 0/269 • 24 weeks	0.38% 1/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Cardiac disorders Coronary artery disease	0.37% 1/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Cardiac disorders Myocardial infarction	0.00% 0/269 • 24 weeks	0.38% 1/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Eye disorders Vitreous haemorrhage	0.37% 1/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Gastrointestinal disorders Duodenal obstruction	0.37% 1/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Hepatobiliary disorders Cholelithiasis	0.00% 0/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.38% 1/264 • 24 weeks	0.00% 0/275 • 24 weeks
Infections and infestations Appendicitis	0.37% 1/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Infections and infestations Chikungunya virus infection	0.37% 1/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Infections and infestations Gastroenteritis	0.00% 0/269 • 24 weeks	0.38% 1/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.36% 1/275 • 24 weeks
Infections and infestations Peritonsillar abscess	0.37% 1/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Infections and infestations Pneumonia	0.00% 0/269 • 24 weeks	0.38% 1/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Infections and infestations Pyelonephritis	0.00% 0/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.36% 1/275 • 24 weeks
Infections and infestations Urinary tract infection	0.00% 0/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.36% 1/275 • 24 weeks
Injury, poisoning and procedural complications Post procedural bile leak	0.37% 1/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Metabolism and nutrition disorders Dehydration	0.37% 1/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Musculoskeletal and connective tissue disorders Osteoarthritis	0.37% 1/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign salivary gland neoplasm	0.00% 0/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.38% 1/264 • 24 weeks	0.00% 0/275 • 24 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastrointestinal tract adenoma	0.37% 1/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Nervous system disorders Cerebrovascular accident	0.74% 2/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.36% 1/275 • 24 weeks
Nervous system disorders Intracranial haematoma	0.00% 0/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.36% 1/275 • 24 weeks
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.37% 1/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Pregnancy, puerperium and perinatal conditions Abortion spontaneous complete	0.00% 0/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.36% 1/275 • 24 weeks
Reproductive system and breast disorders Cervical dysplasia	0.00% 0/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.38% 1/264 • 24 weeks	0.00% 0/275 • 24 weeks
Respiratory, thoracic and mediastinal disorders Asthma	0.37% 1/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.36% 1/275 • 24 weeks
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/269 • 24 weeks	0.38% 1/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.36% 1/275 • 24 weeks
Surgical and medical procedures Abortion induced	0.00% 0/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.38% 1/264 • 24 weeks	0.00% 0/275 • 24 weeks
Vascular disorders Deep vein thrombosis	0.00% 0/269 • 24 weeks	0.00% 0/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.36% 1/275 • 24 weeks
Vascular disorders Hypertension	0.00% 0/269 • 24 weeks	0.38% 1/262 • 24 weeks	0.00% 0/264 • 24 weeks	0.00% 0/275 • 24 weeks

Other adverse events

Other adverse events
Measure	Placebo n=269 participants at risk Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tio R2.5 n=262 participants at risk Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tio R5 n=264 participants at risk Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol n=275 participants at risk Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Infections and infestations Nasopharyngitis	8.2% 22/269 • 24 weeks	6.9% 18/262 • 24 weeks	8.3% 22/264 • 24 weeks	5.8% 16/275 • 24 weeks
Infections and infestations Upper respiratory tract infection	7.1% 19/269 • 24 weeks	6.1% 16/262 • 24 weeks	2.7% 7/264 • 24 weeks	9.1% 25/275 • 24 weeks
Investigations Peak expiratory flow rate decreased	19.0% 51/269 • 24 weeks	10.7% 28/262 • 24 weeks	12.9% 34/264 • 24 weeks	10.5% 29/275 • 24 weeks
Respiratory, thoracic and mediastinal disorders Asthma	21.6% 58/269 • 24 weeks	13.7% 36/262 • 24 weeks	22.7% 60/264 • 24 weeks	18.5% 51/275 • 24 weeks

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: [email protected]

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