A Randomised, Double- Blind, Placebo Controlled, Cross-over Efficacy and Safety Comparison of Tiotropium 5 µg Once Daily and Tiotropium 2.5 µg Twice Daily for Four Weeks in Patients With Moderate Persistent Asthma

• ClinicalTrials.gov Identifier: NCT01152450
• Recruitment Status: Completed
• First Posted: June 29, 2010
• Results First Posted: October 30, 2012
• Last Update Posted: May 16, 2014
• Sponsor: Boehringer Ingelheim
• Collaborator: Pfizer
• Information provided by (Responsible Party): Boehringer Ingelheim

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double; Primary Purpose: Treatment
• Condition: Asthma
• Interventions: Drug: Tiotropium 2.5 µg b.i.d; Drug: Placebo; Drug: Tiotropium 5 µg q.d.
• Enrollment: 94

Participant Flow

Recruitment Details	A total of 94 patients entered the study and was treated whilst 89 patients completed the trial.
Pre-assignment Details	Randomised, double-blind, placebo controlled, cross-over design without washout phase between the three periods. Patients were randomized equally to one of the six sequences (ABC, ACB, BAC, BCA, CAB, CBA).

Arm/Group Title	Tio R2.5 Twice Daily (Bid) /Tio R5 Once Daily (qd) /Placebo	Tio R2.5 Bid/Placebo/Tio R5 qd	Tio R5 qd/Tio R2.5 Bid/Placebo	Tio R5 qd/Placebo/Tio R2.5 Bid	Placebo/Tio R2.5 Bid/Tio R5 qd	Placebo/Tio R5 qd/Tio R2.5 Bid
Arm/Group Description	Patients treated with Tiotropium 2.5 mcg in period 1 (morning and evening), with a matching placebo in the morning and Tiotropium 5 mcg in the evening in period 2 and with a matching Placebo in period 3 (morning and evening). All products were delivered by the Respimat inhaler, on top on maintenance therapy with inhaled corticosteroid (iCS). No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.	Patients treated with Tiotropium 2.5 mcg in period 1 (morning and evening), with a matching Placebo in period 2 (morning and evening) and with a matching placebo in the morning and Tiotropium 5 mcg in the evening in period 3. All products were delivered by the Respimat inhaler, on top on maintenance therapy with iCS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.	Patients treated with a matching placebo in the morning and Tiotropium 5 mcg in the evening in period 1, with Tiotropium 2.5 mcg in period 2 (morning and evening) and with matching Placebo in period 3 (morning and evening) . All products were delivered by the Respimat inhaler, on top on maintenance therapy with iCS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.	Patients treated with a matching placebo in the morning and Tiotropium 5 mcg in the evening in period 1, with matching Placebo in period 2 (morning and evening) and with Tiotropium 2.5 mcg in period 3 (morning and evening) . All products were delivered by the Respimat inhaler, on top on maintenance therapy with iCS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.	Patients treated with matching Placebo in period 1 (morning and evening), with Tiotropium 2.5 mcg in period 2 (morning and evening) and with a matching placebo in the morning and Tiotropium 5 mcg in the evening in period 3. All products were delivered by the Respimat inhaler, on top on maintenance therapy with iCS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.	Patients treated with a matching Placebo in period 1 (morning and evening), with a matching placebo in the morning and Tiotropium 5 mcg in the evening in period 2 and with Tiotropium 2.5 mcg in period 3 (morning and evening) . All products were delivered by the Respimat inhaler, on top on maintenance therapy with iCS. No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.
Period Title: Period 1 (4 Weeks)
Started	15	16	17	15	18	13
Completed	15	15	16	15	16	12
Not Completed	0	1	1	0	2	1
Reason Not Completed
Adverse Event	0	0	0	0	1	1
Protocol Violation	0	0	0	0	1	0
Lost to Follow-up	0	1	1	0	0	0
Period Title: Period 2 (4 Weeks)
Started	15	15	16	15	16	12
Completed	15	15	16	15	16	12
Not Completed	0	0	0	0	0	0
Period Title: Period 3 (4 Weeks)
Started	15	15	16	15	16	12
Completed	15	15	16	15	16	12
Not Completed	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title		Baseline Total
Arm/Group Description		Total number of patients randomised and treated in the study.
Overall Number of Baseline Participants		94
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	94 participants
		44.3 (13.2)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	94 participants
	Female	55 58.5%
	Male	39 41.5%

Outcome Measures

1. Primary Outcome

Title	Forced Expiratory Volume in One Second (FEV1) Area Under the Curve 0-24 Hours (AUC0-24h) Response
Description	Mixed Model Repeated Measure (MMRM) results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measurements performed in relation to evening dosing. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.
Time Frame	10 minutes (min) prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 hours (h) , 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) defined as all treated patients who had baseline data and at least 1 on-treatment efficacy measurement after 4 weeks on treatment within a period.

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L
	0.091 (0.043)	0.241 (0.044)	0.250 (0.044)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM, adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.149
	Confidence Interval	95%; 0.102 to 0.196
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.024
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM, adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.158
	Confidence Interval	95%; 0.111 to 0.205
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.024
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM, adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.009
	Confidence Interval	95%; -0.038 to 0.056
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.024
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

2. Secondary Outcome

Title	Mean Pre-dose Morning Peak Expiratory Flow (PEF a.m.) Response During the Last Week on Treatment
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device.
Time Frame	Baseline and during week 4 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	91	89	88
Mean (Standard Error); Unit of Measure: L/min
	1.953 (5.864)	23.281 (5.907)	24.310 (5.924)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	21.328
	Confidence Interval	95%; 11.084 to 31.573
	Parameter Dispersion	Type: Standard Error of the mean; Value: 5.190
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	22.357
	Confidence Interval	95%; 12.044 to 32.670
	Parameter Dispersion	Type: Standard Error of the mean; Value: 5.225
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.029
	Confidence Interval	95%; -9.318 to 11.376
	Parameter Dispersion	Type: Standard Error of the mean; Value: 5.242
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

3. Secondary Outcome

Title	Mean Pre-dose Evening Peak Expiratory Flow (PEF p.m.) Response During the Last Week on Treatment
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device.
Time Frame	Baseline and during week 4 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	91	89	89
Mean (Standard Error); Unit of Measure: L/min
	-1.560 (5.891)	28.360 (5.932)	27.096 (5.931)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	29.920
	Confidence Interval	95%; 20.001 to 39.839
	Parameter Dispersion	Type: Standard Error of the mean; Value: 5.026
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	28.657
	Confidence Interval	95%; 18.707 to 38.606
	Parameter Dispersion	Type: Standard Error of the mean; Value: 5.042
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.264
	Confidence Interval	95%; -11.243 to 8.716
	Parameter Dispersion	Type: Standard Error of the mean; Value: 5.056
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

4. Secondary Outcome

Title	FEV1 Area Under the Curve 0-12 Hours (AUC0-12h) Response
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time Frame	10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L
	0.048 (0.044)	0.217 (0.044)	0.233 (0.044)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.169
	Confidence Interval	95%; 0.120 to 0.218
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.025
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.185
	Confidence Interval	95%; 0.136 to 0.234
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.025
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.016
	Confidence Interval	95%; -0.033 to 0.065
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.025
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

5. Secondary Outcome

Title	FEV1 Area Under the Curve 12-24 Hours (AUC12-24h) Response
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time Frame	10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L
	0.135 (0.044)	0.264 (0.045)	0.266 (0.044)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.129
	Confidence Interval	95%; 0.077 to 0.181
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.026
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.131
	Confidence Interval	95%; 0.079 to 0.183
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.026
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.002
	Confidence Interval	95%; -0.050 to 0.054
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.026
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

6. Secondary Outcome

Title	Peak FEV1 Within 24 Hours Post-dose Response
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the evening trial-drug inhalation at the end of each 4 week period of randomised treatment.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L
	0.337 (0.045)	0.469 (0.045)	0.468 (0.045)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.132
	Confidence Interval	95%; 0.084 to 0.179
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.024
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.131
	Confidence Interval	95%; 0.084 to 0.179
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.024
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.000
	Confidence Interval	95%; -0.048 to 0.047
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.024
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

7. Secondary Outcome

Title	Trough FEV1 Response
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FEV1 is defined as FEV1 value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L
	0.143 (0.044)	0.254 (0.044)	0.275 (0.044)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.111
	Confidence Interval	95%; 0.053 to 0.170
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.030
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.133
	Confidence Interval	95%; 0.074 to 0.191
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.029
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.021
	Confidence Interval	95%; -0.037 to 0.080
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.030
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

8. Secondary Outcome

Title	Trough Forced Vital Capacity (FVC) Response
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FVC is defined as FVC value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L
	0.112 (0.046)	0.179 (0.046)	0.168 (0.046)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0515
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.068
	Confidence Interval	95%; 0.000 to 0.136
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.035
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1058
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.056
	Confidence Interval	95%; -0.012 to 0.124
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.035
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.012
	Confidence Interval	95%; -0.080 to 0.057
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.035
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

9. Secondary Outcome

Title	FVC Area Under the Curve 0-12 Hours (AUC0-12h) Response
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time Frame	10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L
	-0.026 (0.046)	0.099 (0.046)	0.074 (0.046)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.125
	Confidence Interval	95%; 0.073 to 0.177
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.026
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.100
	Confidence Interval	95%; 0.048 to 0.152
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.026
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.025
	Confidence Interval	95%; -0.077 to 0.027
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.026
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

10. Secondary Outcome

Title	FVC Area Under the Curve 12-24 Hours (AUC12-24h) Response
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time Frame	10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L
	0.032 (0.045)	0.108 (0.045)	0.100 (0.045)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0051
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.076
	Confidence Interval	95%; 0.023 to 0.129
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.027
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0123
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.068
	Confidence Interval	95%; 0.015 to 0.120
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.027
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.008
	Confidence Interval	95%; -0.061 to 0.045
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.027
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

11. Secondary Outcome

Title	Peak FVC Within 24 Hours Post-dose Response
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L
	0.302 (0.045)	0.380 (0.045)	0.350 (0.045)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0042
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.077
	Confidence Interval	95%; 0.025 to 0.130
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.027
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0747
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.048
	Confidence Interval	95%; -0.005 to 0.100
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.027
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.029
	Confidence Interval	95%; -0.082 to 0.023
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.027
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

12. Secondary Outcome

Title	Individual FEV1 Over Time (at Each Timepoint at Visits) Response
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L
Timepoint -0:10 (hours:minutes)	0.143 (0.044)	0.254 (0.044)	0.275 (0.044)
Timepoint 0:30 (hours:minutes)	0.132 (0.044)	0.281 (0.044)	0.304 (0.044)
Timepoint 1:00 (hours:minutes)	0.123 (0.044)	0.274 (0.044)	0.289 (0.044)
Timepoint 2:00 (hours:minutes)	0.103 (0.044)	0.270 (0.044)	0.297 (0.044)
Timepoint 3:00 (hours:minutes)	0.082 (0.044)	0.264 (0.044)	0.268 (0.044)
Timepoint 4:00 (hours:minutes)	0.062 (0.045)	0.248 (0.045)	0.263 (0.045)
Timepoint 11:50 (hours:minutes)	-0.021 (0.049)	0.134 (0.049)	0.150 (0.049)
Timepoint 12:30 (hours:minutes)	0.075 (0.047)	0.198 (0.047)	0.217 (0.047)
Timepoint 13:00 (hours:minutes)	0.101 (0.047)	0.250 (0.047)	0.237 (0.047)
Timepoint 14:00 (hours:minutes)	0.138 (0.045)	0.288 (0.045)	0.282 (0.045)
Timepoint 15:00 (hours:minutes)	0.163 (0.046)	0.299 (0.046)	0.308 (0.046)
Timepoint 16:00 (hours:minutes)	0.161 (0.046)	0.306 (0.046)	0.313 (0.046)
Timepoint 18:00 (hours:minutes)	0.177 (0.047)	0.300 (0.047)	0.308 (0.047)
Timepoint 20:00 (hours:minutes)	0.127 (0.045)	0.256 (0.046)	0.245 (0.045)
Timepoint 22:00 (hours:minutes)	0.117 (0.047)	0.221 (0.047)	0.244 (0.047)
Timepoint 23:00 (hours:minutes)	0.124 (0.045)	0.243 (0.045)	0.223 (0.045)
Timepoint 23:50 (hours:minutes)	0.125 (0.047)	0.232 (0.047)	0.224 (0.047)

13. Secondary Outcome

Title	Individual FVC Over Time (at Each Timepoint at Visits) Response
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L
Timepoint -0:10 (hours:minutes)	0.112 (0.046)	0.179 (0.046)	0.168 (0.046)
Timepoint 0:30 (hours:minutes)	0.053 (0.047)	0.158 (0.048)	0.130 (0.047)
Timepoint 1:00 (hours:minutes)	0.055 (0.047)	0.152 (0.047)	0.124 (0.047)
Timepoint 2:00 (hours:minutes)	0.033 (0.047)	0.131 (0.047)	0.093 (0.047)
Timepoint 3:00 (hours:minutes)	-0.003 (0.047)	0.100 (0.047)	0.057 (0.047)
Timepoint 4:00 (hours:minutes)	-0.040 (0.049)	0.096 (0.049)	0.065 (0.049)
Timepoint 11:50 (hours:minutes)	-0.064 (0.049)	0.070 (0.049)	0.060 (0.049)
Timepoint 12:30 (hours:minutes)	0.004 (0.046)	0.133 (0.046)	0.103 (0.046)
Timepoint 13:00 (hours:minutes)	0.010 (0.047)	0.114 (0.047)	0.102 (0.047)
Timepoint 14:00 (hours:minutes)	0.038 (0.047)	0.106 (0.047)	0.120 (0.047)
Timepoint 15:00 (hours:minutes)	0.034 (0.047)	0.109 (0.047)	0.124 (0.047)
Timepoint 16:00 (hours:minutes)	0.050 (0.047)	0.111 (0.047)	0.116 (0.047)
Timepoint 18:00 (hours:minutes)	0.062 (0.046)	0.123 (0.046)	0.113 (0.046)
Timepoint 20:00 (hours:minutes)	0.036 (0.047)	0.125 (0.047)	0.088 (0.047)
Timepoint 22:00 (hours:minutes)	0.028 (0.048)	0.077 (0.048)	0.096 (0.048)
Timepoint 23:00 (hours:minutes)	0.018 (0.048)	0.094 (0.048)	0.062 (0.048)
Timepoint 23:50 (hours:minutes)	-0.015 (0.049)	0.078 (0.049)	0.052 (0.049)

14. Secondary Outcome

Title	Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L/min
Timepoint -0:10 (hours:minutes)	19.770 (7.357)	42.428 (7.378)	57.897 (7.359)
Timepoint 0:30 (hours:minutes)	12.994 (7.275)	46.272 (7.295)	58.436 (7.277)
Timepoint 1:00 (hours:minutes)	13.783 (7.027)	43.049 (7.043)	53.138 (7.028)
Timepoint 2:00 (hours:minutes)	11.366 (7.246)	48.328 (7.263)	55.826 (7.248)
Timepoint 3:00 (hours:minutes)	9.769 (7.457)	48.723 (7.474)	50.747 (7.458)
Timepoint 4:00 (hours:minutes)	7.499 (7.242)	42.599 (7.260)	50.077 (7.244)
Timepoint 11:50 (hours:minutes)	-11.219 (7.747)	20.011 (7.765)	26.201 (7.749)
Timepoint 12:30 (hours:minutes)	4.345 (7.314)	27.436 (7.335)	33.887 (7.316)
Timepoint 13:00 (hours:minutes)	6.820 (7.479)	33.810 (7.499)	34.582 (7.481)
Timepoint 14:00 (hours:minutes)	13.879 (7.323)	44.786 (7.348)	43.371 (7.325)
Timepoint 15:00 (hours:minutes)	16.125 (6.992)	47.991 (7.012)	45.699 (6.994)
Timepoint 16:00 (hours:minutes)	19.616 (7.304)	47.697 (7.330)	46.441 (7.306)
Timepoint 18:00 (hours:minutes)	20.084 (7.303)	47.795 (7.326)	48.790 (7.306)
Timepoint 20:00 (hours:minutes)	13.348 (7.213)	42.240 (7.232)	40.888 (7.215)
Timepoint 22:00 (hours:minutes)	14.275 (7.317)	33.567 (7.339)	41.635 (7.319)
Timepoint 23:00 (hours:minutes)	13.590 (7.360)	36.712 (7.384)	38.384 (7.362)
Timepoint 23:50 (hours:minutes)	15.169 (7.670)	36.837 (7.697)	37.595 (7.673)

15. Secondary Outcome

Title	FVC Area Under the Curve 0-24 Hours (AUC0-24h) Response
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.
Time Frame	10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L
	0.003 (0.044)	0.104 (0.044)	0.087 (0.044)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.101
	Confidence Interval	95%; 0.055 to 0.147
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.023
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0004
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.084
	Confidence Interval	95%; 0.038 to 0.130
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.023
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.016
	Confidence Interval	95%; -0.063 to 0.030
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.023
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

16. Secondary Outcome

Title	PEF Area Under the Curve 0-24 Hours (AUC0-24h) Response
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres/min.
Time Frame	10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	90	89	90
Mean (Standard Error); Unit of Measure: L/min
	8.589 (6.870)	38.831 (6.883)	42.899 (6.871)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	30.242
	Confidence Interval	95%; 22.167 to 38.317
	Parameter Dispersion	Type: Standard Error of the mean; Value: 4.091
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	34.310
	Confidence Interval	95%; 26.240 to 42.380
	Parameter Dispersion	Type: Standard Error of the mean; Value: 4.089
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.068
	Confidence Interval	95%; -4.012 to 12.148
	Parameter Dispersion	Type: Standard Error of the mean; Value: 4.094
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

17. Secondary Outcome

Title	PEF Variability Response (Last Week on Treatment)
Description	MMRM results. Response was defined as change from baseline. 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).
Time Frame	Baseline and during week 4

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	91	89	88
Mean (Standard Error); Unit of Measure: Percent
	0.296 (0.711)	0.619 (0.718)	0.685 (0.721)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6747
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.323
	Confidence Interval	95%; -1.195 to 1.841
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.769
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6159
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.389
	Confidence Interval	95%; -1.138 to 1.916
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.774
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.065
	Confidence Interval	95%; -1.468 to 1.599
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.777
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

18. Secondary Outcome

Title	Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values)
Description	MMRM results. Response was defined as change from baseline. 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.
Time Frame	Baseline and during week 4

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	91	89	89
Mean (Standard Error); Unit of Measure: Puffs
	-0.841 (0.189)	-0.917 (0.190)	-1.016 (0.190)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5906
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.077
	Confidence Interval	95%; -0.358 to 0.204
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.142
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2208
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.176
	Confidence Interval	95%; -0.458 to 0.106
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.143
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.099
	Confidence Interval	95%; -0.382 to 0.184
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.143
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

19. Secondary Outcome

Title	Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values)
Description	MMRM results. Response was defined as change from baseline. 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.
Time Frame	Baseline and during week 4

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	91	89	89
Mean (Standard Error); Unit of Measure: Puffs
	-0.562 (0.106)	-0.564 (0.106)	-0.624 (0.106)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9797
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.002
	Confidence Interval	95%; -0.163 to 0.159
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.082
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4518
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.062
	Confidence Interval	95%; -0.223 to 0.100
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.082
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.060
	Confidence Interval	95%; -0.222 to 0.102
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.082
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

20. Secondary Outcome

Title	Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values)
Description	MMRM results. Response was defined as change from baseline. 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.
Time Frame	Baseline and during week 4

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	91	89	88
Mean (Standard Error); Unit of Measure: Puffs
	-0.358 (0.092)	-0.419 (0.093)	-0.432 (0.093)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4089
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.061
	Confidence Interval	95%; -0.207 to 0.085
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.074
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3185
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.074
	Confidence Interval	95%; -0.221 to 0.072
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.074
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.013
	Confidence Interval	95%; -0.160 to 0.134
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.074
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

21. Secondary Outcome

Title	Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values)
Description	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Assessed by the patient's electronic diary (eDiary incorporated in the AM2+ device), obtained during the last week of each period of randomised treatment.
Time Frame	Baseline and during week 4

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5 Bid	Tio R5 qd
Arm/Group Description:	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
Overall Number of Participants Analyzed	91	89	88
Mean (Standard Error); Unit of Measure: Night awakenings
	-0.106 (0.028)	-0.104 (0.029)	-0.102 (0.029)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5 Bid
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9626
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.001
	Confidence Interval	95%; -0.059 to 0.062
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.031
	Estimation Comments	Tio R2.5 bid - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9102
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.003
	Confidence Interval	95%; -0.058 to 0.065
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.031
	Estimation Comments	Tio R5 qd - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Tio R2.5 Bid, Tio R5 qd
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	MMRM adjusted for treatment, period, patient and study baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.002
	Confidence Interval	95%; -0.059 to 0.063
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.031
	Estimation Comments	Tio R5 qd - Tio R2.5 bid

Adverse Events

Time Frame	4 weeks + 30 days if in last period
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Placebo	Tio R2.5	Tio R5 qd
Arm/Group Description	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
All-Cause Mortality
	Placebo	Tio R2.5	Tio R5 qd
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Placebo	Tio R2.5	Tio R5 qd
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/92 (1.09%)	0/90 (0.00%)	2/90 (2.22%)
Injury, poisoning and procedural complications
Rib fracture † 1	0/92 (0.00%)	0/90 (0.00%)	1/90 (1.11%)
Road traffic accident † 1	0/92 (0.00%)	0/90 (0.00%)	1/90 (1.11%)
Vascular disorders
Haemorrhage † 1	0/92 (0.00%)	0/90 (0.00%)	1/90 (1.11%)
Hypertensive crisis † 1	1/92 (1.09%)	0/90 (0.00%)	0/90 (0.00%)
Venous thrombosis limb † 1	0/92 (0.00%)	0/90 (0.00%)	1/90 (1.11%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 14.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo	Tio R2.5	Tio R5 qd
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	4/92 (4.35%)	7/90 (7.78%)	5/90 (5.56%)
Nervous system disorders
Headache † 1	4/92 (4.35%)	7/90 (7.78%)	5/90 (5.56%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 14.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Boehringer Ingelheim Call Center
• Organization: Boehringer Ingelheim Pharmaceuticals
• Phone: 1-800-243-0127
• EMail: clintriage.rdg@boehringer-ingelheim.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Timmer W, Moroni-Zentgraf P, Cornelissen P, Unseld A, Pizzichini E, Buhl R. Once-daily tiotropium Respimat((R)) 5 mug is an efficacious 24-h bronchodilator in adults with symptomatic asthma. Respir Med. 2015 Mar;109(3):329-38. doi: 10.1016/j.rmed.2014.12.005. Epub 2014 Dec 27.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01152450
• Other Study ID Numbers: 205.420; 2009-018006-21 ( EudraCT Number: EudraCT )
• First Submitted: June 28, 2010
• First Posted: June 29, 2010
• Results First Submitted: August 17, 2012
• Results First Posted: October 30, 2012
• Last Update Posted: May 16, 2014