Trial Outcomes & Findings for Efficacy and Safety of 2 Doses of Tiotropium Respimat® Compared to Placebo in Children With Severe Persistent Asthma (NCT NCT01634152)

NCT ID: NCT01634152

Last Updated: 2016-01-29

Results Overview

Change from baseline in peak forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak(0-3h)) measured at week 12. Measured values presented are actually adjusted means.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 401 participants
• Primary outcome timeframe: Baseline and 12 weeks
• Results posted on: 2016-01-29

Participant Flow

Participant milestones

Measure	Placebo Respimat Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Study STARTED	134	137	130
Overall Study COMPLETED	130	136	126
Overall Study NOT COMPLETED	4	1	4

Reasons for withdrawal

Measure	Placebo Respimat Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Overall Study Adverse Event	2	0	2
Overall Study Consent withdrawn not due to AE	1	0	1
Overall Study Not treated	0	1	0
Overall Study Other reason not defined above	1	0	1

Baseline Characteristics

Efficacy and Safety of 2 Doses of Tiotropium Respimat® Compared to Placebo in Children With Severe Persistent Asthma

Baseline characteristics by cohort

Measure	Placebo Respimat n=134 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=130 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Total n=400 Participants Total of all reporting groups
Age, Continuous	9.1 Years STANDARD_DEVIATION 1.6 • n=5 Participants	8.8 Years STANDARD_DEVIATION 1.7 • n=7 Participants	9.2 Years STANDARD_DEVIATION 1.6 • n=5 Participants	9.0 Years STANDARD_DEVIATION 1.6 • n=4 Participants
Sex: Female, Male Female	41 Participants n=5 Participants	40 Participants n=7 Participants	40 Participants n=5 Participants	121 Participants n=4 Participants
Sex: Female, Male Male	93 Participants n=5 Participants	96 Participants n=7 Participants	90 Participants n=5 Participants	279 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and 12 weeks

Population: Full Analysis Set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in peak forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak(0-3h)) measured at week 12.

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=130 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=135 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=128 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
FEV1 Peak(0-3h) Change From Baseline	0.252 Litres Standard Error 0.025	0.287 Litres Standard Error 0.025	0.391 Litres Standard Error 0.026

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 12.

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=130 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=135 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=128 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Trough FEV1 Change From Baseline	0.136 Litres Standard Error 0.027	0.154 Litres Standard Error 0.026	0.223 Litres Standard Error 0.027

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak(0-3h)) after 12 weeks of treatment.

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=130 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=135 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=128 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
FVC Peak(0-3h) Change From Baseline	0.244 Litres Standard Error 0.028	0.201 Litres Standard Error 0.027	0.275 Litres Standard Error 0.028

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in Trough (pre-dose) FVC measured at week 12.

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=130 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=135 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=128 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Trough FVC Change From Baseline	0.141 Litres Standard Error 0.029	0.094 Litres Standard Error 0.029	0.150 Litres Standard Error 0.030

SECONDARY outcome

Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline of area under the curve (AUC) from 0 to 3 hours for FEV1 (FEV1 AUC (0-3h)) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=130 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=135 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=128 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
FEV1 AUC (0-3h) Change From Baseline	0.175 Litres Standard Error 0.023	0.206 Litres Standard Error 0.022	0.301 Litres Standard Error 0.023

SECONDARY outcome

Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline of area under the curve (AUC) from 0 to 3 hours for FVC (Forced vital capacity) (FVC AUC (0-3h)) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=130 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=135 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=128 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
FVC AUC (0-3h) Change From Baseline	0.145 Litres Standard Error 0.025	0.105 Litres Standard Error 0.024	0.182 Litres Standard Error 0.025

SECONDARY outcome

Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Forced expiratory volume in one second (FEV1) change from baseline at each individual timepoint.

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=130 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=135 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=128 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
FEV1 Change From Baseline at Each Individual Timepoint 1 hour post-dose	0.177 Litres Standard Error 0.025	0.203 Litres Standard Error 0.024	0.300 Litres Standard Error 0.025
FEV1 Change From Baseline at Each Individual Timepoint 2 hours post-dose	0.191 Litres Standard Error 0.025	0.216 Litres Standard Error 0.025	0.324 Litres Standard Error 0.026
FEV1 Change From Baseline at Each Individual Timepoint 3 hours post-dose	0.168 Litres Standard Error 0.026	0.215 Litres Standard Error 0.026	0.308 Litres Standard Error 0.026
FEV1 Change From Baseline at Each Individual Timepoint 10 minutes pre-dose	0.136 Litres Standard Error 0.027	0.154 Litres Standard Error 0.026	0.223 Litres Standard Error 0.027
FEV1 Change From Baseline at Each Individual Timepoint 30 minutes post-dose	0.166 Litres Standard Error 0.024	0.202 Litres Standard Error 0.023	0.285 Litres Standard Error 0.024

SECONDARY outcome

Timeframe: Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

FVC change from baseline at each individual timepoint.

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=130 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=135 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=128 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
FVC Change From Baseline at Each Individual Timepoint 30 minutes post-dose	0.130 Litres Standard Error 0.026	0.096 Litres Standard Error 0.026	0.164 Litres Standard Error 0.027
FVC Change From Baseline at Each Individual Timepoint 1 hour post-dose	0.146 Litres Standard Error 0.027	0.097 Litres Standard Error 0.026	0.181 Litres Standard Error 0.027
FVC Change From Baseline at Each Individual Timepoint 2 hours post-dose	0.159 Litres Standard Error 0.028	0.113 Litres Standard Error 0.027	0.199 Litres Standard Error 0.028
FVC Change From Baseline at Each Individual Timepoint 3 hours post-dose	0.132 Litres Standard Error 0.028	0.110 Litres Standard Error 0.028	0.176 Litres Standard Error 0.029
FVC Change From Baseline at Each Individual Timepoint 10 minutes pre-dose	0.141 Litres Standard Error 0.029	0.094 Litres Standard Error 0.029	0.150 Litres Standard Error 0.030

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) total score measured at week 12.

The ACQ-IA is a scale containing 7 questions. Each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ-IA total score is calculated as the mean of the responses to all 7 questions.

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=130 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=126 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Control of Asthma as Assessed by ACQ-IA Total Score	1.026 Units on a scale Standard Error 0.060	1.046 Units on a scale Standard Error 0.059	0.948 Units on a scale Standard Error 0.061

SECONDARY outcome

Timeframe: 12 weeks

Population: FAS, missing data for patients not withdrawn from the study were either categorised as no change or based on available data, withdrawn patients were imputed based upon discontinuation reason.

Responder categories based on the ACQ-IA total score after 12 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5 <change from trial baseline <0.5) and worsening (change from trial baseline ≥0.5) No statistical testing was performed for ACQ-IA total score responders.

The ACQ-IA is a scale containing 7 questions, each question has a 7-point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment.

Outcome measures

Measure	Placebo Respimat n=134 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=130 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
ACQ-IA Total Score Responders Responder	76.9 Percentage of participants	79.4 Percentage of participants	80.8 Percentage of participants
ACQ-IA Total Score Responders No change	20.9 Percentage of participants	18.4 Percentage of participants	16.2 Percentage of participants
ACQ-IA Total Score Responders Worsening	2.2 Percentage of participants	2.2 Percentage of participants	3.1 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used per day (24 hour period) based on the weekly mean at week 12.

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=128 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=127 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Use of PRN Rescue Medication Per Day	-0.570 Number of puffs of rescue medication Standard Error 0.096	-0.553 Number of puffs of rescue medication Standard Error 0.094	-0.660 Number of puffs of rescue medication Standard Error 0.097

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the daytime based on the weekly mean at week 12.

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=127 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=126 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Use of PRN Rescue Medication During the Daytime	-0.279 Number of puffs of rescue medication Standard Error 0.057	-0.294 Number of puffs of rescue medication Standard Error 0.055	-0.365 Number of puffs of rescue medication Standard Error 0.057

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the night-time based on the weekly mean at week 12.

Measured values presented are actually adjusted means

Outcome measures

Measure	Placebo Respimat n=128 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=126 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Use of PRN Rescue Medication During the Night-time	-0.285 Number of puffs of rescue medication Standard Error 0.051	-0.250 Number of puffs of rescue medication Standard Error 0.050	-0.310 Number of puffs of rescue medication Standard Error 0.052

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in the morning (a.m.) peak expiratory flow based on the weekly mean at week 12.

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=128 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=126 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Peak Expiratory Flow (PEF) a.m. Change From Baseline	8.343 L/min Standard Error 3.613	13.119 L/min Standard Error 3.500	13.086 L/min Standard Error 3.630

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in the evening (p.m.) peak expiratory flow based on the weekly mean at week 12.

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=127 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=126 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Peak Expiratory Flow (PEF) p.m. Change From Baseline	7.892 L/min Standard Error 3.717	8.459 L/min Standard Error 3.599	3.785 L/min Standard Error 3.731

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in the peak expiratory flow variability based on the weekly mean at week 12.

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=127 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=125 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Peak Expiratory Flow (PEF) Variability Change From Baseline	0.150 Percentage of PEF Standard Error 0.777	-0.800 Percentage of PEF Standard Error 0.749	-0.352 Percentage of PEF Standard Error 0.780

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in morning (a.m.) FEV1 based on the weekly mean at week 12.

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=128 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=126 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
FEV1 a.m. Change From Baseline	0.174 Litres Standard Error 0.030	0.142 Litres Standard Error 0.029	0.125 Litres Standard Error 0.030

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in evening (p.m.) FEV1 based on the weekly mean at week 12.

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=127 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=126 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
FEV1 p.m. Change From Baseline	0.155 Litres Standard Error 0.031	0.104 Litres Standard Error 0.030	0.094 Litres Standard Error 0.032

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in nighttime awakenings based on the weekly mean at week 12.

Nighttime awakenings was assessed by the question "Did you wake up during the night due to your asthma?" from the e-diary. Scores range from 1 (did not wake up) to 5 (was awake all night).

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=128 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=126 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Change From Baseline in Nighttime Awakenings	-0.165 Units on a scale Standard Error 0.032	-0.166 Units on a scale Standard Error 0.031	-0.159 Units on a scale Standard Error 0.033

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in morning asthma symptoms based on the weekly mean at week 12.

Morning asthma symptoms was assessed by the question "how were your asthma symptoms this morning?" from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms).

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=128 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=126 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Change From Baseline in Morning Asthma Symptoms	-0.207 Units on a scale Standard Error 0.038	-0.213 Units on a scale Standard Error 0.037	-0.221 Units on a scale Standard Error 0.038

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in daytime asthma symptoms based on the weekly mean at week 12.

Daytime asthma symptoms was assessed by the question "how were your asthma symptoms during the day?" from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms).

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=127 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=126 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Change From Baseline in Daytime Asthma Symptoms	-0.226 Units on a scale Standard Error 0.040	-0.262 Units on a scale Standard Error 0.039	-0.239 Units on a scale Standard Error 0.041

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in daytime activity limitations based on the weekly mean at week 12.

Daytime activity limitations was assessed by the question "how limited were you in your activities today because of your asthma?" from the e-diary. Scores range from 1 (not limited) to 5 (totally limited).

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=127 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=126 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Change From Baseline in Daytime Activity Limitations	-0.210 Units on a scale Standard Error 0.039	-0.203 Units on a scale Standard Error 0.038	-0.222 Units on a scale Standard Error 0.039

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in daytime experiences of shortness of breath based on the weekly mean at week 12.

Daytime experiences of shortness of breath was assessed by the question "how much shortness of breath did you experience during the day" from the e-diary. Scores range from 1 (none) to 5 (a very great deal).

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=127 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=126 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Change From Baseline in Daytime Experiences of Shortness of Breath	-0.204 Units on a scale Standard Error 0.039	-0.187 Units on a scale Standard Error 0.038	-0.287 Units on a scale Standard Error 0.040

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in daytime experiences of wheeze or cough based on the weekly mean at week 12.

Daytime experiences of wheeze or cough was assessed by the question "did you experience wheeze or cough during the day?" from the e-diary. Scores range from 1 (not at all) to 5 (all the time).

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=127 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=126 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Change From Baseline in Daytime Experiences of Wheeze or Cough	-0.249 Units on a scale Standard Error 0.045	-0.263 Units on a scale Standard Error 0.044	-0.320 Units on a scale Standard Error 0.046

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: FAS, missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

Change from baseline in asthma symptom-free days based on the weekly mean at week 12.

A day was considered as an asthma symptom-free day if there were no symptoms reported via the e-Diary and no use of rescue medication reported via the eDiary during that day.

Measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=128 Participants Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 Participants Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=127 Participants Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Change From Baseline in Asthma Symptom-free Days	0.147 Days Standard Error 0.031	0.130 Days Standard Error 0.030	0.172 Days Standard Error 0.031

Adverse Events

Placebo Respimat

Serious events: 2 serious events

Other events: 49 other events

Deaths: 0 deaths

Tio R2.5

Serious events: 2 serious events

Other events: 36 other events

Deaths: 0 deaths

Tio R5

Serious events: 4 serious events

Other events: 35 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo Respimat n=134 participants at risk Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 participants at risk Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=130 participants at risk Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Infections and infestations Appendicitis	0.00% 0/134 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	0.00% 0/136 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	0.77% 1/130 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.
Nervous system disorders Epilepsy	0.00% 0/134 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	0.74% 1/136 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	0.00% 0/130 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.
Respiratory, thoracic and mediastinal disorders Asthma	0.75% 1/134 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	0.74% 1/136 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	2.3% 3/130 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.
Respiratory, thoracic and mediastinal disorders Asthmatic crisis	0.75% 1/134 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	0.00% 0/136 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	0.00% 0/130 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.

Other adverse events

Measure	Placebo Respimat n=134 participants at risk Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R2.5 n=136 participants at risk Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.	Tio R5 n=130 participants at risk Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.
Respiratory, thoracic and mediastinal disorders Asthma	21.6% 29/134 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	14.7% 20/136 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	16.9% 22/130 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.
Infections and infestations Nasopharyngitis	8.2% 11/134 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	4.4% 6/136 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	4.6% 6/130 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.
Investigations Peak expiratory flow rate decreased	14.9% 20/134 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	11.0% 15/136 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.	11.5% 15/130 • From first drug intake until 30 days after last drug intake, up to 164 days The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

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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