Trial Outcomes & Findings for Efficacy and Safety of 3 Doses of Tiotropium Compared to Placebo in Adolescents (12 to 17 Yrs) With Moderate Asthma (NCT NCT01122680)

Results Overview

The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

105 participants

Primary outcome timeframe

Baseline and 4 weeks

Results posted on

2014-05-16

Participant Flow

In this incomplete crossover design, 105 patients were randomised to one of four sequences (in general terms, ABC, BDA, CAD or DCB). Whilst there were 4 possible treatments, A, B, C and D, each patient would receive a maximum of 3 different treatments. Hence, approximately 75 patients would receive each of A, B, C and D at any timepoint.

Participant milestones

Participant milestones
Measure	Tio R5/Placebo/Tio R1.25 Patients treated with Tiotropium 5 mcg in Phase I, with a matching Placebo in Phase II and with Tiotropium 1.25 mcg in Phase III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.	Tio R1.25/Tio R5/Tio R2.5 Patients treated with Tiotropium 1.25 mcg in Phase I, with Tiotropium 5 mcg in Phase II and with Tiotropium 2.5 mcg in Phase III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.	Placebo/Tio R2.5/Tio R5 Patients treated with a matching Placebo in Phase I, with Tiotropium 2.5 mcg in Phase II and with Tiotropium 5 mcg in Phase III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.	Tio R2.5/Tio R1.25/Placebo Patients treated with Tiotropium 2.5 mcg in Phase I, with Tiotropium 1.25 mcg in Phase II and with a matching Placebo in Phase III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
Period 1 (4 Weeks) STARTED	29	26	26	24
Period 1 (4 Weeks) COMPLETED	26	25	26	24
Period 1 (4 Weeks) NOT COMPLETED	3	1	0	0
Period 2 (4 Weeks) STARTED	26	25	26	24
Period 2 (4 Weeks) COMPLETED	25	25	26	23
Period 2 (4 Weeks) NOT COMPLETED	1	0	0	1
Period 3 (4 Weeks) STARTED	25	25	26	23
Period 3 (4 Weeks) COMPLETED	24	24	26	23
Period 3 (4 Weeks) NOT COMPLETED	1	1	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Tio R5/Placebo/Tio R1.25 Patients treated with Tiotropium 5 mcg in Phase I, with a matching Placebo in Phase II and with Tiotropium 1.25 mcg in Phase III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.	Tio R1.25/Tio R5/Tio R2.5 Patients treated with Tiotropium 1.25 mcg in Phase I, with Tiotropium 5 mcg in Phase II and with Tiotropium 2.5 mcg in Phase III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.	Tio R2.5/Tio R1.25/Placebo Patients treated with Tiotropium 2.5 mcg in Phase I, with Tiotropium 1.25 mcg in Phase II and with a matching Placebo in Phase III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
Period 1 (4 Weeks) Adverse Event	1	0	0
Period 1 (4 Weeks) Protocol Violation	1	0	0
Period 1 (4 Weeks) Other	1	1	0
Period 2 (4 Weeks) Protocol Violation	0	0	1
Period 2 (4 Weeks) Other	1	0	0
Period 3 (4 Weeks) Adverse Event	1	0	0
Period 3 (4 Weeks) Withdrawal by Subject	0	1	0

Baseline Characteristics

Efficacy and Safety of 3 Doses of Tiotropium Compared to Placebo in Adolescents (12 to 17 Yrs) With Moderate Asthma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Total. n=105 Participants Total number of patients randomised and treated at all in the study.
Age, Continuous	14.0 Years STANDARD_DEVIATION 1.5 • n=5 Participants
Sex: Female, Male Female	38 Participants n=5 Participants
Sex: Female, Male Male	67 Participants n=5 Participants
Forced expiratory volume in 1s (FEV1)	2.742 Litre STANDARD_DEVIATION 0.697 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 4 weeks

Population: The Full analysis set (FAS) is defined as patients randomised, treated, with baseline data and at least one on-treatment efficacy measurement after 4 weeks on treatment within a period. This patient set is therefore FAS reduced to patients with non-missing FEV1 data.

The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=74 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=73 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=74 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=77 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
Forced Expiratory Volume (FEV1) Peak (0-3h) Response	0.489 Litre Standard Error 0.047	0.556 Litre Standard Error 0.047	0.546 Litre Standard Error 0.047	0.602 Litre Standard Error 0.046

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS with non-missing FEV1 data.

The trough FEV1 is defined as the pre-dose FEV1 measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=74 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=73 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=74 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=77 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
Trough FEV1 Response	0.292 Litre Standard Error 0.045	0.384 Litre Standard Error 0.045	0.353 Litre Standard Error 0.045	0.442 Litre Standard Error 0.045

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS with non-missing FEV1 data.

FEV1 (AUC0-3h) will be calculated as the area under the curve from 0 to 3hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=74 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=73 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=74 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=77 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response	0.363 Litre Standard Error 0.045	0.455 Litre Standard Error 0.045	0.434 Litre Standard Error 0.045	0.497 Litre Standard Error 0.045

SECONDARY outcome

Timeframe: Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose)

Population: FAS with non-missing FEV1 data.

Individual FEV1 measurements at each time-point ("personal best"). Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=74 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=73 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=74 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=77 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
FEV1 Individual Measurements Response at Each Time-point Timepoint 0:30 hr response	0.337 Litre Standard Error 0.047	0.456 Litre Standard Error 0.047	0.407 Litre Standard Error 0.047	0.486 Litre Standard Error 0.047
FEV1 Individual Measurements Response at Each Time-point Timepoint -0:10 hr response	0.292 Litre Standard Error 0.045	0.384 Litre Standard Error 0.045	0.353 Litre Standard Error 0.045	0.442 Litre Standard Error 0.045
FEV1 Individual Measurements Response at Each Time-point Timepoint 1:00 hr response	0.353 Litre Standard Error 0.048	0.456 Litre Standard Error 0.048	0.416 Litre Standard Error 0.048	0.505 Litre Standard Error 0.047
FEV1 Individual Measurements Response at Each Time-point Timepoint 2:00 hr response	0.394 Litre Standard Error 0.047	0.467 Litre Standard Error 0.048	0.453 Litre Standard Error 0.047	0.501 Litre Standard Error 0.047
FEV1 Individual Measurements Response at Each Time-point Timepoint 3:00 hr response	0.396 Litre Standard Error 0.048	0.467 Litre Standard Error 0.048	0.489 Litre Standard Error 0.048	0.497 Litre Standard Error 0.047

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS with non-missing FVC data.

The FVC peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FVC measured within the first 3 hours post dosing and the FVC baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=74 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=73 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=74 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=77 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
Forced Vital Capacity (FVC) Peak (0-3h) Response	0.546 Litre Standard Error 0.049	0.554 Litre Standard Error 0.049	0.554 Litre Standard Error 0.048	0.548 Litre Standard Error 0.048

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS with non-missing FVC data.

The trough FVC response is defined as the pre-dose FVC measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=74 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=73 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=74 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=77 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
FVC Trough Response	0.357 Litre Standard Error 0.047	0.375 Litre Standard Error 0.047	0.381 Litre Standard Error 0.047	0.400 Litre Standard Error 0.047

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS with non-missing FVC data.

FVC (AUC0-3h) will be calculated as the area under the curve from 0 to 3hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=74 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=73 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=74 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=77 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response	0.413 Litre Standard Error 0.046	0.441 Litre Standard Error 0.046	0.417 Litre Standard Error 0.045	0.429 Litre Standard Error 0.045

SECONDARY outcome

Timeframe: Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose)

Population: FAS with non-missing FVC data.

Individual FVC measurements at each time-point ("personal best"). Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=74 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=73 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=74 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=77 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
FVC Individual Measurements at Each Time-point Timepoint 0:30 hr response	0.397 Litre Standard Error 0.049	0.434 Litre Standard Error 0.049	0.394 Litre Standard Error 0.049	0.409 Litre Standard Error 0.049
FVC Individual Measurements at Each Time-point Timepoint 1:00 hr response	0.417 Litre Standard Error 0.049	0.443 Litre Standard Error 0.050	0.387 Litre Standard Error 0.049	0.448 Litre Standard Error 0.049
FVC Individual Measurements at Each Time-point Timepoint 2:00 hr response	0.429 Litre Standard Error 0.048	0.438 Litre Standard Error 0.048	0.444 Litre Standard Error 0.048	0.423 Litre Standard Error 0.048
FVC Individual Measurements at Each Time-point Timepoint 3:00 hr response	0.430 Litre Standard Error 0.048	0.461 Litre Standard Error 0.048	0.454 Litre Standard Error 0.048	0.456 Litre Standard Error 0.048
FVC Individual Measurements at Each Time-point Timepoint -0:10 hr response	0.357 Litre Standard Error 0.047	0.375 Litre Standard Error 0.047	0.381 Litre Standard Error 0.047	0.400 Litre Standard Error 0.047

SECONDARY outcome

Timeframe: Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose)

Population: FAS with non-missing FEF data

FEF 25-75% is the mean forced expiratory flow between 25% and 75% of the FVC determined at the end of the 4-week treatment period. This is often referred to as the maximum midexpiratory flow. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=49 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=47 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=47 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=50 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point Timepoint 2:00 hr response	0.357 Litre Standard Error 0.088	0.678 Litre Standard Error 0.089	0.607 Litre Standard Error 0.089	0.622 Litre Standard Error 0.087
Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point Timepoint 3:00 hr response	0.329 Litre Standard Error 0.083	0.662 Litre Standard Error 0.084	0.616 Litre Standard Error 0.084	0.620 Litre Standard Error 0.083
Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point Timepoint -0:10 hr response	0.242 Litre Standard Error 0.081	0.533 Litre Standard Error 0.082	0.380 Litre Standard Error 0.082	0.566 Litre Standard Error 0.080
Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point Timepoint 0:30 hr response	0.268 Litre Standard Error 0.083	0.643 Litre Standard Error 0.084	0.513 Litre Standard Error 0.084	0.647 Litre Standard Error 0.082
Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point Timepoint 1:00 hr response	0.321 Litre Standard Error 0.087	0.655 Litre Standard Error 0.087	0.569 Litre Standard Error 0.087	0.641 Litre Standard Error 0.086

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS with non-missing morning PEF data

Mean morning PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=73 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=75 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=73 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=79 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
Mean Morning Peak Expiratory Flow (PEF) Response	7.267 Litre/min Standard Error 6.152	18.613 Litre/min Standard Error 6.118	23.185 Litre/min Standard Error 6.146	20.491 Litre/min Standard Error 6.031

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS with non-missing evening PEF data

Mean evening PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=73 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=74 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=75 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=79 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
Mean Evening PEF Response	-0.552 Litre/min Standard Error 6.098	5.985 Litre/min Standard Error 6.089	18.971 Litre/min Standard Error 6.043	16.565 Litre/min Standard Error 5.970

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS with non-missing data for rescue medication

Mean number of inhalations (puffs) of unscheduled rescue salbutamol therapy during whole day. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=73 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=73 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=73 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=79 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
Change From Baseline in the Number of Puffs of Rescue Medication Per Day	-0.412 Puffs/day Standard Error 0.155	-0.635 Puffs/day Standard Error 0.156	-0.521 Puffs/day Standard Error 0.154	-0.528 Puffs/day Standard Error 0.151

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS with non-missing ACQ data

ACQ is a questionnaire consisting of a seven point Likert scale ranging from 0 to 6, whereby 0 represents good control and 6 represents poor control of asthma. The scale describes the frequency and severity of asthma symptoms. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=74 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=73 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=74 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=77 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ)	1.371 Units on a scale Standard Error 0.078	1.189 Units on a scale Standard Error 0.079	1.366 Units on a scale Standard Error 0.078	1.287 Units on a scale Standard Error 0.078

SECONDARY outcome

Timeframe: Baseline and last week of treatment (week 4)

Population: FAS with non-missing data for nighttime awakenings

Mean number of nighttime awakenings due to asthma symptoms as assessed by patients eDiary incorporated in the AM3® device. Analysis adjusted for treatment, period, patient and baseline using a mixed model.

Outcome measures

Outcome measures
Measure	Placebo n=73 Participants Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=75 Participants Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=73 Participants Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=79 Participants Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
Change From Baseline in Mean Number of Nighttime Awakenings	-0.086 Night awakenings per week Standard Error 0.030	-0.027 Night awakenings per week Standard Error 0.030	-0.074 Night awakenings per week Standard Error 0.030	-0.066 Night awakenings per week Standard Error 0.029

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Tio R1.25

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Tio R2.5

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Tio R5

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=75 participants at risk Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R1.25 n=75 participants at risk Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R2.5 n=75 participants at risk Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.	Tio R5 n=80 participants at risk Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
Infections and infestations H1N1 influenza	0.00% 0/75 • 4 weeks + 30 days if in last period	1.3% 1/75 • 4 weeks + 30 days if in last period	0.00% 0/75 • 4 weeks + 30 days if in last period	0.00% 0/80 • 4 weeks + 30 days if in last period
Infections and infestations Pneumonia mycoplasmal	0.00% 0/75 • 4 weeks + 30 days if in last period	1.3% 1/75 • 4 weeks + 30 days if in last period	0.00% 0/75 • 4 weeks + 30 days if in last period	0.00% 0/80 • 4 weeks + 30 days if in last period
Nervous system disorders Presyncope	0.00% 0/75 • 4 weeks + 30 days if in last period	0.00% 0/75 • 4 weeks + 30 days if in last period	0.00% 0/75 • 4 weeks + 30 days if in last period	1.2% 1/80 • 4 weeks + 30 days if in last period
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/75 • 4 weeks + 30 days if in last period	1.3% 1/75 • 4 weeks + 30 days if in last period	0.00% 0/75 • 4 weeks + 30 days if in last period	0.00% 0/80 • 4 weeks + 30 days if in last period

Other adverse events

Adverse event data not reported

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