Trial Outcomes & Findings for Randomised, Double- Blind, Cross-over Efficacy and Safety Comparison of Three Different Doses of Tiotropium Administered Once Daily Versus Placebo in Patients With Moderate Persistent Asthma. (NCT NCT01233284)

Results Overview

Mixed model repeated measurement (MMRM) results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

149 participants

Primary outcome timeframe

10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration

Results posted on

2013-12-24

Participant Flow

A total of 149 patients were randomised and treated, 141 patients completed the trial.

Randomised, double-blind, placebo controlled, cross-over design without washout phase between the four periods. Patients were randomized to one of the 4 sequences (ABCD, DCBA, BDAC, CADB). For one patient treatment 2 and treatment 3 were interchanged (resulting sequence DBCA).

Participant milestones

Participant milestones
Measure	Tio R5 Once Daily(qd)/Tio R1.25 qd/Placebo/Tio R2.5 qd Patients treated with Tiotropium 5 mcg in period 1 (evening), with Tiotropium 1.25 mcg in period 2 (evening), with a matching Placebo in period 3 (evening) and with Tiotropium 2.5 mcg in period 4 (evening). All products were delivered by the Respimat inhaler as add-on therapy to inhaled corticosteroids (ICS). No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.	Tio R2.5 qd/Placebo/Tio R1.25 qd/Tio R5 qd Patients treated with Tiotropium 2.5 mcg in period 1 (evening), with a matching Placebo in period 2 (evening), with Tiotropium 1.25 mcg in period 3 (evening) and with Tiotropium 5 mcg in period 4 (evening). All products were delivered by the Respimat inhaler as add-on therapy to ICS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.	Tio R1.25 qd/Tio R2.5 qd/Tio R5 qd/Placebo Patients treated with Tiotropium 1.25 mcg in period 1 (evening), with Tiotropium 2.5 mcg in period 2 (evening), with Tiotropium 5 mcg in period 3 (evening) and with a matching placebo in period 4 (evening). All products were delivered by the Respimat inhaler as add-on therapy to inhaled corticosteroid ICS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.	Placebo/Tio R5 qd/Tio R2.5 qd/Tio R1.25 qd Patients treated with a matching Placebo in period 1 (evening), with Tiotropium 5 mcg in period 2 (evening), with Tiotropium 2.5 mcg in period 3 (evening) and with Tiotropium 1.25 mcg in period 4 (evening). All products were delivered by the Respimat inhaler as add-on therapy to ICS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.	Placebo/Tio R2.5 qd/Tio R5 qd/Tio R1.25 qd Patient treated with a matching Placebo in period 1 (evening), with Tiotropium 2.5 mcg in period 2 (evening), with Tiotropium 5 mcg in period 3 (evening) and with Tiotropium 1.25 mcg in period 4 (evening). All products were delivered by the Respimat inhaler as add-on therapy to ICS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.
Period 1 (4 Weeks) STARTED	37	38	38	35	1
Period 1 (4 Weeks) COMPLETED	36	37	37	35	1
Period 1 (4 Weeks) NOT COMPLETED	1	1	1	0	0
Period 2 (4 Weeks) STARTED	36	37	37	35	1
Period 2 (4 Weeks) COMPLETED	36	37	36	35	1
Period 2 (4 Weeks) NOT COMPLETED	0	0	1	0	0
Period 3 (4 Weeks) STARTED	36	37	36	35	1
Period 3 (4 Weeks) COMPLETED	36	37	35	34	1
Period 3 (4 Weeks) NOT COMPLETED	0	0	1	1	0
Period 4 (4 Weeks) STARTED	36	37	35	34	1
Period 4 (4 Weeks) COMPLETED	36	36	35	33	1
Period 4 (4 Weeks) NOT COMPLETED	0	1	0	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Tio R5 Once Daily(qd)/Tio R1.25 qd/Placebo/Tio R2.5 qd Patients treated with Tiotropium 5 mcg in period 1 (evening), with Tiotropium 1.25 mcg in period 2 (evening), with a matching Placebo in period 3 (evening) and with Tiotropium 2.5 mcg in period 4 (evening). All products were delivered by the Respimat inhaler as add-on therapy to inhaled corticosteroids (ICS). No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.	Tio R2.5 qd/Placebo/Tio R1.25 qd/Tio R5 qd Patients treated with Tiotropium 2.5 mcg in period 1 (evening), with a matching Placebo in period 2 (evening), with Tiotropium 1.25 mcg in period 3 (evening) and with Tiotropium 5 mcg in period 4 (evening). All products were delivered by the Respimat inhaler as add-on therapy to ICS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.	Tio R1.25 qd/Tio R2.5 qd/Tio R5 qd/Placebo Patients treated with Tiotropium 1.25 mcg in period 1 (evening), with Tiotropium 2.5 mcg in period 2 (evening), with Tiotropium 5 mcg in period 3 (evening) and with a matching placebo in period 4 (evening). All products were delivered by the Respimat inhaler as add-on therapy to inhaled corticosteroid ICS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.	Placebo/Tio R5 qd/Tio R2.5 qd/Tio R1.25 qd Patients treated with a matching Placebo in period 1 (evening), with Tiotropium 5 mcg in period 2 (evening), with Tiotropium 2.5 mcg in period 3 (evening) and with Tiotropium 1.25 mcg in period 4 (evening). All products were delivered by the Respimat inhaler as add-on therapy to ICS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.
Period 1 (4 Weeks) Lost to Follow-up	1	0	0	0
Period 1 (4 Weeks) Withdrawal by Subject	0	1	0	0
Period 1 (4 Weeks) Other	0	0	1	0
Period 2 (4 Weeks) Withdrawal by Subject	0	0	1	0
Period 3 (4 Weeks) Withdrawal by Subject	0	0	1	0
Period 3 (4 Weeks) Other	0	0	0	1
Period 4 (4 Weeks) Adverse Event	0	1	0	0
Period 4 (4 Weeks) Lost to Follow-up	0	0	0	1

Baseline Characteristics

Randomised, Double- Blind, Cross-over Efficacy and Safety Comparison of Three Different Doses of Tiotropium Administered Once Daily Versus Placebo in Patients With Moderate Persistent Asthma.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Baseline Total n=149 Participants Total number of patients randomised and treated in the study.
Age, Continuous	49.3 years STANDARD_DEVIATION 13.3 • n=5 Participants
Sex: Female, Male Female	82 Participants n=5 Participants
Sex: Female, Male Male	67 Participants n=5 Participants

PRIMARY outcome

Timeframe: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration

Population: Full analysis set (FAS) reduced to patients with non-missing FEV1 data. The 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.

Mixed model repeated measurement (MMRM) results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline.

Outcome measures

Outcome measures
Measure	Placebo n=144 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=144 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=144 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=143 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Forced Expiratory Volume in One Second (FEV1) Peak Within 0-3 Hours Post-dose Response	0.116 Litre Standard Error 0.027	0.255 Litre Standard Error 0.027	0.244 Litre Standard Error 0.027	0.304 Litre Standard Error 0.028

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS reduced to patients with non-missing FEV1 data.

MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Trough FEV1 was measured just prior to the last administration of randomised treatment.

Outcome measures

Outcome measures
Measure	Placebo n=144 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=144 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=144 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=143 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Trough FEV1 Response	0.006 Litre Standard Error 0.027	0.131 Litre Standard Error 0.027	0.138 Litre Standard Error 0.027	0.149 Litre Standard Error 0.027

SECONDARY outcome

Timeframe: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration

Population: FAS reduced to patients with non-missing FEV1 data.

MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC0-3h was calculated using the trapezoidal rule divided by the observation time (3 hours) to report in litres.

Outcome measures

Outcome measures
Measure	Placebo n=144 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=144 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=144 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=143 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
FEV1 Area Under the Curve 0-3 Hours (AUC0-3h) Response	0.025 Litre Standard Error 0.027	0.154 Litre Standard Error 0.027	0.152 Litre Standard Error 0.027	0.203 Litre Standard Error 0.027

SECONDARY outcome

Timeframe: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration

Population: FAS reduced to patients with non-missing FVC data.

MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline.

Outcome measures

Outcome measures
Measure	Placebo n=144 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=144 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=144 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=143 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Forced Vital Capacity (FVC) Peak Within 0-3 Hours Post-dose Response	0.092 Litre Standard Error 0.034	0.171 Litre Standard Error 0.034	0.163 Litre Standard Error 0.034	0.229 Litre Standard Error 0.034

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS reduced to patients with non-missing FVC data.

MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Trough FVC was measured just prior to the last administration of randomised treatment.

Outcome measures

Outcome measures
Measure	Placebo n=144 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=144 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=144 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=143 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Trough FVC Response	0.004 Litre Standard Error 0.035	0.058 Litre Standard Error 0.035	0.076 Litre Standard Error 0.035	0.102 Litre Standard Error 0.035

SECONDARY outcome

Timeframe: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration

Population: FAS reduced to patients with non-missing FVC data.

MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FVC AUC0-3h was calculated using the trapezoidal rule divided by the observation time (3 hours) to report in litres.

Outcome measures

Outcome measures
Measure	Placebo n=144 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=144 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=144 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=143 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
FVC AUC0-3h Response	-0.028 Litre Standard Error 0.034	0.036 Litre Standard Error 0.034	0.047 Litre Standard Error 0.034	0.110 Litre Standard Error 0.034

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS reduced to patients with non-missing FEV1 data.

MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline.

Outcome measures

Outcome measures
Measure	Placebo n=144 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=144 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=144 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=143 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Individual FEV1 Over Time (at Each Timepoint at Visits) Response Timepoint -0:10	0.006 Litre Standard Error 0.027	0.131 Litre Standard Error 0.027	0.138 Litre Standard Error 0.027	0.149 Litre Standard Error 0.027
Individual FEV1 Over Time (at Each Timepoint at Visits) Response Timepoint 0:30	0.029 Litre Standard Error 0.028	0.160 Litre Standard Error 0.028	0.163 Litre Standard Error 0.028	0.209 Litre Standard Error 0.028
Individual FEV1 Over Time (at Each Timepoint at Visits) Response Timepoint 1:00	0.026 Litre Standard Error 0.029	0.148 Litre Standard Error 0.029	0.156 Litre Standard Error 0.029	0.205 Litre Standard Error 0.029
Individual FEV1 Over Time (at Each Timepoint at Visits) Response Timepoint 2:00	0.033 Litre Standard Error 0.029	0.158 Litre Standard Error 0.029	0.149 Litre Standard Error 0.029	0.218 Litre Standard Error 0.029
Individual FEV1 Over Time (at Each Timepoint at Visits) Response Timepoint 3:00	0.013 Litre Standard Error 0.029	0.160 Litre Standard Error 0.029	0.148 Litre Standard Error 0.029	0.191 Litre Standard Error 0.029

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS reduced to patients with non-missing FVC data.

MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline.

Outcome measures

Outcome measures
Measure	Placebo n=144 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=144 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=144 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=143 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Individual FVC Over Time (at Each Timepoint at Visits) Response Timepoint -0:10	0.004 Litre Standard Error 0.035	0.058 Litre Standard Error 0.035	0.076 Litre Standard Error 0.035	0.102 Litre Standard Error 0.035
Individual FVC Over Time (at Each Timepoint at Visits) Response Timepoint 0:30	-0.028 Litre Standard Error 0.035	0.042 Litre Standard Error 0.035	0.060 Litre Standard Error 0.035	0.124 Litre Standard Error 0.035
Individual FVC Over Time (at Each Timepoint at Visits) Response Timepoint 1:00	-0.031 Litre Standard Error 0.036	0.024 Litre Standard Error 0.036	0.041 Litre Standard Error 0.036	0.112 Litre Standard Error 0.036
Individual FVC Over Time (at Each Timepoint at Visits) Response Timepoint 2:00	-0.022 Litre Standard Error 0.036	0.037 Litre Standard Error 0.036	0.045 Litre Standard Error 0.036	0.119 Litre Standard Error 0.036
Individual FVC Over Time (at Each Timepoint at Visits) Response Timepoint 3:00	-0.050 Litre Standard Error 0.036	0.036 Litre Standard Error 0.036	0.033 Litre Standard Error 0.036	0.078 Litre Standard Error 0.036

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS reduced to patients with non-missing PEF data.

MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline.

Outcome measures

Outcome measures
Measure	Placebo n=144 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=144 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=144 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=143 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response Timepoint 1:00	6.095 Litre/min Standard Error 5.074	34.070 Litre/min Standard Error 5.072	36.851 Litre/min Standard Error 5.074	41.260 Litre/min Standard Error 5.082
Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response Timepoint 2:00	7.237 Litre/min Standard Error 5.039	34.544 Litre/min Standard Error 5.037	36.972 Litre/min Standard Error 5.039	42.694 Litre/min Standard Error 5.047
Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response Timepoint 3:00	5.046 Litre/min Standard Error 5.024	34.620 Litre/min Standard Error 5.022	37.283 Litre/min Standard Error 5.024	40.624 Litre/min Standard Error 5.033
Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response Timepoint -0:10	11.038 Litre/min Standard Error 4.804	30.567 Litre/min Standard Error 4.802	33.903 Litre/min Standard Error 4.804	34.787 Litre/min Standard Error 4.812
Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response Timepoint 0:30	8.235 Litre/min Standard Error 4.949	32.163 Litre/min Standard Error 4.947	37.149 Litre/min Standard Error 4.949	39.325 Litre/min Standard Error 4.957

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS reduced to patients with non-missing morning PEF data.

MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device).

Outcome measures

Outcome measures
Measure	Placebo n=142 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=146 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=146 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=144 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Mean Pre-dose Morning PEF (PEF a.m.) Response During the Last Week on Treatment	4.395 Litre/min Standard Error 4.573	22.944 Litre/min Standard Error 4.543	22.290 Litre/min Standard Error 4.543	25.241 Litre/min Standard Error 4.559

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS reduced to patients with non-missing evening PEF data.

MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device).

Outcome measures

Outcome measures
Measure	Placebo n=142 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=146 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=146 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=144 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Mean Pre-dose Evening PEF (PEF p.m.) Response During the Last Week on Treatment	3.833 Litre/min Standard Error 4.363	25.084 Litre/min Standard Error 4.331	18.410 Litre/min Standard Error 4.331	25.414 Litre/min Standard Error 4.348

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS reduced to patients with non-missing morning and evening PEF data.

MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. PEF variability is the absolute difference between morning and evening PEF value divided by the mean of these two values, expressed as a percent . Weekly means obtained during the last week of each period of randomised treatment will be compared.

Outcome measures

Outcome measures
Measure	Placebo n=142 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=146 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=146 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=144 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
PEF Variability Response (Last Week on Treatment)	-0.171 Percentage of the mean daily PEF Standard Error 0.615	-0.285 Percentage of the mean daily PEF Standard Error 0.609	-0.711 Percentage of the mean daily PEF Standard Error 0.609	-0.248 Percentage of the mean daily PEF Standard Error 0.612

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS reduced to patients with non-missing data for rescue medication.

MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device).

Outcome measures

Outcome measures
Measure	Placebo n=142 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=146 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=146 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=144 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values)	-0.569 Puffs Standard Error 0.122	-0.802 Puffs Standard Error 0.121	-0.783 Puffs Standard Error 0.121	-0.769 Puffs Standard Error 0.122

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS reduced to patients with non-missing data for rescue medication.

MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device).

Outcome measures

Outcome measures
Measure	Placebo n=142 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=146 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=146 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=144 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values)	-0.314 Puffs Standard Error 0.071	-0.463 Puffs Standard Error 0.071	-0.452 Puffs Standard Error 0.071	-0.425 Puffs Standard Error 0.071

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS reduced to patients with non-missing data for rescue medication.

MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device).

Outcome measures

Outcome measures
Measure	Placebo n=142 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=146 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=146 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=144 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values)	-0.273 Puffs Standard Error 0.064	-0.357 Puffs Standard Error 0.063	-0.341 Puffs Standard Error 0.063	-0.360 Puffs Standard Error 0.064

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Population: FAS reduced to patients with non-missing data for nighttime awakenings

MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device).

Outcome measures

Outcome measures
Measure	Placebo n=142 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=146 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=146 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=144 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values)	-0.156 Night awakenings Standard Error 0.034	-0.166 Night awakenings Standard Error 0.034	-0.162 Night awakenings Standard Error 0.034	-0.187 Night awakenings Standard Error 0.034

SECONDARY outcome

Timeframe: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h, 4h, 11h 50min, 12h 30min, 13h, 14h, 15h, 16h, 18h, 20h, 22h, 23h, 23h 50min after drug administration

Population: FAS24 was defined as all patients in the FAS who gave informed consent for the 24-h PFT and who participated in this optional PFT.

MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC0-12, FEV1 AUC12-24 and FEV1 AUC0-24 were calculated using the trapezoidal rule divided by the observation time (12h resp. 24h) to report in litres.

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=24 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=24 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=24 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) FEV1 AUC0-12h	-0.013 Litres Standard Error 0.058	0.105 Litres Standard Error 0.055	0.134 Litres Standard Error 0.054	0.128 Litres Standard Error 0.054
FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) FEV1 AUC12-24h	0.012 Litres Standard Error 0.061	0.093 Litres Standard Error 0.058	0.148 Litres Standard Error 0.058	0.208 Litres Standard Error 0.057
FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) FEV1 AUC0-24h	-0.001 Litres Standard Error 0.057	0.099 Litres Standard Error 0.054	0.141 Litres Standard Error 0.054	0.168 Litres Standard Error 0.053

SECONDARY outcome

Timeframe: 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h, 4h, 11h 50min, 12h 30min, 13h, 14h, 15h, 16h, 18h, 20h, 22h, 23h, 23h 50min after drug administration

Population: FAS24 was defined as all patients in the FAS who gave informed consent for the 24-h PFT and who participated in this optional PFT.

MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FVC AUC0-12, FVC AUC12-24 and FVC AUC0-24 were calculated using the trapezoidal rule divided by the observation time (12h resp. 24h) to report in litres.

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=24 Participants Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=24 Participants Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=24 Participants Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) FVC AUC0-12h	-0.052 Litres Standard Error 0.072	0.064 Litres Standard Error 0.068	0.157 Litres Standard Error 0.068	0.115 Litres Standard Error 0.068
FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) FVC AUC12-24h	-0.021 Litres Standard Error 0.076	0.046 Litres Standard Error 0.071	0.177 Litres Standard Error 0.071	0.160 Litres Standard Error 0.071
FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) FVC AUC0-24h	-0.036 Litres Standard Error 0.072	0.055 Litres Standard Error 0.067	0.167 Litres Standard Error 0.067	0.137 Litres Standard Error 0.067

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Tio R1.25 qd

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Tio R2.5 qd

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Tio R5 qd

Serious events: 2 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=144 participants at risk Matching Placebo qd in the evening delivered by the Respimat inhaler.	Tio R1.25 qd n=146 participants at risk Tiotropium 1.25 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R2.5 qd n=147 participants at risk Tiotropium 2.5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.	Tio R5 qd n=146 participants at risk Tiotropium 5 mcg qd in the evening delivered by the Respimat inhaler as add-on therapy to ICS.
Gastrointestinal disorders Inguinal hernia	0.00% 0/144 • 4 weeks + 30 days if in last period	0.00% 0/146 • 4 weeks + 30 days if in last period	0.00% 0/147 • 4 weeks + 30 days if in last period	0.68% 1/146 • 4 weeks + 30 days if in last period
Psychiatric disorders Alcohol abuse	0.00% 0/144 • 4 weeks + 30 days if in last period	0.00% 0/146 • 4 weeks + 30 days if in last period	0.00% 0/147 • 4 weeks + 30 days if in last period	0.68% 1/146 • 4 weeks + 30 days if in last period
Psychiatric disorders Panic attack	0.00% 0/144 • 4 weeks + 30 days if in last period	0.00% 0/146 • 4 weeks + 30 days if in last period	0.00% 0/147 • 4 weeks + 30 days if in last period	0.68% 1/146 • 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