Evaluation of Tiotropium 5 µg/Day Delivered Via the Respimat® Inhaler Over 48 Weeks in Patients With Severe Persistent Asthma on Top of Usual Care (Study I)

• ClinicalTrials.gov Identifier: NCT00772538
• Recruitment Status: Completed
• First Posted: October 15, 2008
• Results First Posted: September 27, 2012
• Last Update Posted: August 18, 2014
• Sponsor: Boehringer Ingelheim
• Collaborator: Pfizer
• Information provided by (Responsible Party): Boehringer Ingelheim

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double; Primary Purpose: Treatment
• Condition: Asthma
• Interventions: Drug: tiotropium 5mcg/day; Drug: placebo
• Enrollment: 459

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Placebo	Tio R5
Arm/Group Description	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Period Title: Overall Study
Started	222	237
Completed	202	211
Not Completed	20	26
Reason Not Completed
Adverse Event	6	6
Protocol Violation	3	3
Lost to Follow-up	1	1
Withdrawal by Subject	3	8
Lack of Efficacy	0	1
Other	7	7

Baseline Characteristics

Arm/Group Title		Placebo	Tio R5	Total
Arm/Group Description		Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd	Total of all reporting groups
Overall Number of Baseline Participants		222	237	459
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	222 participants	237 participants	459 participants
		53.9 (12.8)	52.9 (12.4)	53.4 (12.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	222 participants	237 participants	459 participants
	Female	143 64.4%	146 61.6%	289 63.0%
	Male	79 35.6%	91 38.4%	170 37.0%

Outcome Measures

1. Primary Outcome

Title	Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 24 Weeks.
Description	Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 24 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

All patients from Full Analysis Set (FAS) FAS is defined as all patients in the treated set who have baseline data and at least one on-treatment efficacy value.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	0.315 (0.026)	0.401 (0.025)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0110
	Comments	Step-wise testing for co-primary endpoints, confirmatory only if previous hypotheses had been successful, significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.086
	Confidence Interval	95%; 0.020 to 0.152
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.034
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

2. Primary Outcome

Title	Trough FEV1 Response Determined After a Treatment Period of 24 Weeks.
Description	The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 24 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	0.056 (0.025)	0.144 (0.024)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0050
	Comments	Step-wise testing for co-primary endpoints, confirmatory only if previous hypotheses had been successful, significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.088
	Confidence Interval	95%; 0.027 to 0.149
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.031
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

3. Primary Outcome

Title	Time to First Severe Asthma Exacerbation During the 48-week Treatment of the Pooled Data From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984).
Description	Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS of the pooled twin studies 205.416 and 205.417. As <50percent (149 of 454 patients in the placebo group and 122 of 453 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	454	453
Median (Inter-Quartile Range); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [2]; (NA to NA)

[1]

As <50percent (149 of 454 patients in the placebo group) of patients had severe exacerbation, the median time was not calculable.

[2]

As <50percent (122 of 453 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0343
	Comments	Confirmatory only if previous hypotheses for each of the 2 twin studies had been successful, significance level of alpha=0.05 (2-sided). A pre-specified interim analysis was performed. Cui et al (Biometrics,1999) was used to calculate the p-value.
	Method	Regression, Cox
	Comments	Parameter estimates of Cox proportional hazard model regression regarding. Only treatment was fitted as an effect in the model.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.790
	Estimation Comments	If HR is below 1 then favours tiotropium.

4. Secondary Outcome

Title	Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 24-week Treatment Period.
Description	Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 24 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	0.355 (0.033)	0.445 (0.032)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0362
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.089
	Confidence Interval	95%; 0.006 to 0.173
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.043
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

5. Secondary Outcome

Title	Trough FVC Response at the End of the 24-week Treatment Period.
Description	The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 24 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	0.022 (0.031)	0.157 (0.031)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0007
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.136
	Confidence Interval	95%; 0.058 to 0.214
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.040
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

6. Secondary Outcome

Title	FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 24-week Treatment Period.
Description	The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	0.229 (0.024)	0.315 (0.024)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0067
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.086
	Confidence Interval	95%; 0.024 to 0.149
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.032
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

7. Secondary Outcome

Title	FVC (AUC0-3h) Response at the End of the 24-week Treatment Period.
Description	The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	0.230 (0.031)	0.328 (0.030)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0139
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.098
	Confidence Interval	95%; 0.020 to 0.176
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.040
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

8. Secondary Outcome

Title	Peak FEV1 0-3h Response at the End of the 48-week Treatment Period.
Description	Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 48 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	0.295 (0.026)	0.367 (0.026)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0347
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.073
	Confidence Interval	95%; 0.005 to 0.140
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.034
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

9. Secondary Outcome

Title	Trough FEV1 Response at the End of the 48-week Treatment Period.
Description	The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 48 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	0.087 (0.025)	0.129 (0.025)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1896
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.042
	Confidence Interval	95%; -0.021 to 0.104
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.032
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

10. Secondary Outcome

Title	AUC0-3h FEV1 Response at the End of the 48-week Treatment Period.
Description	The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit.
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	0.217 (0.025)	0.289 (0.024)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0247
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.073
	Confidence Interval	95%; 0.009 to 0.136
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.032
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

11. Secondary Outcome

Title	Peak FVC 0-3h Response at the End of the 48-week Treatment Period.
Description	Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 48 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	0.337 (0.033)	0.462 (0.032)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0039
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.125
	Confidence Interval	95%; 0.040 to 0.210
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.043
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

12. Secondary Outcome

Title	Trough FVC Response at the End of the 48-week Treatment Period.
Description	The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 48 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	0.062 (0.032)	0.173 (0.031)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0063
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.111
	Confidence Interval	95%; 0.031 to 0.190
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.040
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

13. Secondary Outcome

Title	FVC AUC0-3h Response at the End of the 48-week Treatment Period.
Description	The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit.
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	0.223 (0.031)	0.344 (0.030)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0027
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.122
	Confidence Interval	95%; 0.042 to 0.201
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.041
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

14. Secondary Outcome

Title	Mean Pre-dose Morning Peak Expiratory Flow (PEFa.m.) Response (Diary Data) of Last-7-days-before-week-24-visit .
Description	Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: L/min
	-6.996 (3.754)	15.297 (3.602)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	22.293
	Confidence Interval	95%; 13.279 to 31.308
	Parameter Dispersion	Type: Standard Error of the mean; Value: 4.584
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

15. Secondary Outcome

Title	Mean Pre-dose Evening Peak Expiratory Flow (PEFp.m.) Response (Diary Data) of Last-7-days-before-week 24-visit.
Description	Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: L/min
	-3.865 (3.856)	19.402 (3.670)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	23.267
	Confidence Interval	95%; 14.027 to 32.507
	Parameter Dispersion	Type: Standard Error of the mean; Value: 4.699
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

16. Secondary Outcome

Title	Mean Pre-dose FEV1 a.m. Response (Diary Data) of Last-7-days-before-week 24-visit.
Description	Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	-0.055 (0.023)	0.062 (0.022)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.117
	Confidence Interval	95%; 0.061 to 0.173
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.028
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

17. Secondary Outcome

Title	Mean Pre-dose FEV1-p.m.Response (Diary Data) of Last-7-days-before-week 24-visit.
Description	Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Liter
	-0.050 (0.024)	0.075 (0.023)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.124
	Confidence Interval	95%; 0.068 to 0.181
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.029
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

18. Secondary Outcome

Title	Mean PEF Variability Response (Absolute Difference Between Morning and Evening PEF Value Divided by Their Mean) of Last-7-days-before-week 24-visit.
Description	Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The PEF variability is the absolute difference between morning and evening PEF value divided by their mean, expressed as a percent. Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Percent
	-0.997 (0.602)	-0.714 (0.578)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7012
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.283
	Confidence Interval	95%; -1.165 to 1.731
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.736
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

19. Secondary Outcome

Title	Time to First Severe Asthma Exacerbation During the 48-week Treatment.
Description	Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS. As <50percent (68 of 222 patients in the placebo group and 53 of 237 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

20. Secondary Outcome

Title	Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period.
Description	Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS..

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Measure Type: Number; Unit of Measure: Participants
0 exacerbations	85	121
1 exacerbation	47	49
2 exacerbations	21	23
3 exacerbations	18	13
4 exacerbations	8	6
5 exacerbations	12	4
6 exacerbations	12	2
7-10 exacerbations	13	14
11-20 exacerbations	4	5
21+ exacerbations	2	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0102
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Poisson Regression
	Comments	Parameter estimates of Poisson regression model. Log exposure was used as offset and adjusted for overdispersion.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.71
	Confidence Interval	95%; 0.55 to 0.92
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.09
	Estimation Comments	Tio R5 - Placebo

21. Secondary Outcome

Title	Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period.
Description	Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS..

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Measure Type: Number; Unit of Measure: Participants
0 exacerbations	154	184
1 exacerbation	39	37
2 exacerbations	15	10
3 exacerbations	5	3
4 exacerbations	6	0
5 exacerbations	2	2
6 exacerbations	1	0
7-10 exacerbations	0	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0062
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Poisson Regression
	Comments	Parameter estimates of Poisson regression model. Log exposure was used as offset and adjusted for overdispersion.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.64
	Confidence Interval	95%; 0.46 to 0.88
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.10
	Estimation Comments	Tio R5 - Placebo

22. Secondary Outcome

Title	Number of Patients With at Least One Asthma Exacerbation During the 48-week Treatment Period.
Description	Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Measure Type: Number; Unit of Measure: Participants
	137	116

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0065
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Fisher Exact
	Comments	Exact 95percent confidence interval by Clopper and Pearson.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.59
	Confidence Interval	95%; 0.40 to 0.88
	Estimation Comments	Tio R5 vs Placebo

23. Secondary Outcome

Title	Number of Patients With at Least One Severe Asthma Exacerbation During the 48-week Treatment Period.
Description	Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Measure Type: Number; Unit of Measure: Participants
	68	53

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0561
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Fisher Exact
	Comments	Exact 95percent confidence interval by Clopper and Pearson.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.65
	Confidence Interval	95%; 0.42 to 1.01
	Estimation Comments	Tio R5 vs Placebo

24. Secondary Outcome

Title	Time to First Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period.
Description	Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS. As <50percent (10 of 222 patients in the placebo group and 8 of 237 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

25. Secondary Outcome

Title	Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period.
Description	[Not Specified]
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Measure Type: Number; Unit of Measure: Participants
0 hospitalisations	212	229
1 hospitalisations	9	6
2+ hospitalisations	1	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5538
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Poisson Regression
	Comments	Parameter estimates of Poisson regression model. Log exposure was used as offset and adjusted for overdispersion.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.87
	Confidence Interval	95%; 0.54 to 1.39
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.21
	Estimation Comments	Tio R5 - Placebo

26. Secondary Outcome

Title	Number of Patients With at Least One Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period.
Description	[Not Specified]
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Measure Type: Number; Unit of Measure: Participants
	10	8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6330
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Fisher Exact
	Comments	Exact 95percent confidence interval by Clopper and Pearson.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.74
	Confidence Interval	95%; 0.25 to 2.13
	Estimation Comments	Tio R5 vs Placebo

27. Secondary Outcome

Title	Quality of Life as Assessed by Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) at the End of the 24-week Treatment Period.
Description	The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Scores on a scale
	5.084 (0.059)	5.125 (0.057)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5714
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.042
	Confidence Interval	95%; -0.103 to 0.186
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.074
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

28. Secondary Outcome

Title	AQLQ(S) Total Score at the End of the 48-week Treatment Period.
Description	The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Scores on a scale
	5.109 (0.060)	5.147 (0.058)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6099
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.038
	Confidence Interval	95%; -0.109 to 0.185
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.075
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

29. Secondary Outcome

Title	Asthma Control as Assessed by Asthma Control Questionnaire (ACQ) at the End of the 24-week Treatment Period.
Description	For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Scores on a scale
	2.120 (0.053)	1.995 (0.051)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0586
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.126
	Confidence Interval	95%; -0.256 to 0.005
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.066
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

30. Secondary Outcome

Title	ACQ at the End of the 48-week Treatment Period.
Description	For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Scores on a scale
	2.107 (0.054)	1.986 (0.052)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0727
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.121
	Confidence Interval	95%; -0.253 to 0.011
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.067
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

31. Secondary Outcome

Title	Asthma Symptom Free Days Response During the Last-7-days-before-week-24-visit .
Description	Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The response is defined as the change of the weekly mean from the baseline weekly mean. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Days
	0.105 (0.020)	0.105 (0.019)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9807
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.001
	Confidence Interval	95%; -0.048 to 0.047
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.024
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

32. Secondary Outcome

Title	Mean Pro Re Nata (as Needed, PRN) Rescue Medication Use Response During the Last-7-days-before-week-24-visit .
Description	Weekly means obtained during the last 7 days before week 24 visit were compared. The response is defined as the change of the weekly mean from the baseline weekly mean. The use of PRN salbutamol (albuterol rescue medication) is determined by the number of puffs of rescue therapy used per day. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.
Time Frame	Baseline and last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

All patients from FAS.

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	222	237
Mean (Standard Error); Unit of Measure: Puffs
	-0.714 (0.140)	-0.806 (0.135)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5927
	Comments	Significance level of alpha=0.05 (two-sided).
	Method	Mixed Models Analysis
	Comments	REML-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.092
	Confidence Interval	95%; -0.430 to 0.246
	Parameter Dispersion	Type: Standard Error of the mean; Value: 0.172
	Estimation Comments	Tio R5 - Placebo. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.

33. Post-Hoc Outcome

Title	The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.417 (NCT00776984) and the Present 205.416 (NCT00772538)
Description	The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at 24-weeks and 48-weeks (on combined data from the two twin trials 205.416 (NCT00772538) and 205.417 (NCT00776984)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points. The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). This outcome definition is taken from the primary outcome definition for the twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821) of the same development program.
Time Frame	24 weeks, 48 weeks

Outcome Measure Data

Analysis Population Description

FAS of combined data from the two twin trials 205.416 (NCT00772538) and 205.417 (NCT00776984)

Arm/Group Title	Placebo	Tio R5
Arm/Group Description:	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Number of Participants Analyzed	454	453
Measure Type: Number; Unit of Measure: percentage of participants
24 weeks	46.9	53.9
48 weeks	45.2	58.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Comparison at 24 weeks
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0427
	Comments	Calculated as 2*one-sided-p-value in the direction corresponding to testing the null hypothesis
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; 1.01 to 1.73
	Estimation Comments	Tio R5 / Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Comparison at 48 weeks
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	Calculated as 2*one-sided-p-value in the direction corresponding to testing the null hypothesis
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.68
	Confidence Interval	(2-Sided) 95%; 1.28 to 2.21
	Estimation Comments	Tio R5 / Placebo

Adverse Events

Time Frame	48 weeks
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Placebo	Tio R5
Arm/Group Description	Patients treated with matching placebo	Patients treated with tiotropium inhalation solution 5 μg qd
All-Cause Mortality
	Placebo	Tio R5
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Placebo	Tio R5
	Affected / at Risk (%)	Affected / at Risk (%)
Total	15/222 (6.76%)	18/237 (7.59%)
Cardiac disorders
Arrhythmia supraventricular † 1	0/222 (0.00%)	1/237 (0.42%)
Atrial fibrillation † 1	0/222 (0.00%)	1/237 (0.42%)
Coronary artery occlusion † 1	0/222 (0.00%)	1/237 (0.42%)
Coronary artery stenosis † 1	0/222 (0.00%)	1/237 (0.42%)
Ventricular tachycardia † 1	0/222 (0.00%)	1/237 (0.42%)
Eye disorders
Cataract † 1	1/222 (0.45%)	0/237 (0.00%)
Gastrointestinal disorders
Abdominal discomfort † 1	0/222 (0.00%)	1/237 (0.42%)
Diverticulum † 1	1/222 (0.45%)	0/237 (0.00%)
Inguinal hernia † 1	0/222 (0.00%)	1/237 (0.42%)
Small intestinal obstruction † 1	1/222 (0.45%)	0/237 (0.00%)
General disorders
Fat necrosis † 1	0/222 (0.00%)	1/237 (0.42%)
Infections and infestations
Cellulitis † 1	1/222 (0.45%)	0/237 (0.00%)
Lobar pneumonia † 1	0/222 (0.00%)	1/237 (0.42%)
Pneumonia † 1	0/222 (0.00%)	1/237 (0.42%)
Injury, poisoning and procedural complications
Burns first degree † 1	0/222 (0.00%)	1/237 (0.42%)
Fall † 1	1/222 (0.45%)	0/237 (0.00%)
Traumatic haematoma † 1	1/222 (0.45%)	0/237 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	0/222 (0.00%)	1/237 (0.42%)
Back disorder † 1	0/222 (0.00%)	1/237 (0.42%)
Bursitis † 1	0/222 (0.00%)	1/237 (0.42%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Small cell lung cancer stage unspecified † 1	0/222 (0.00%)	1/237 (0.42%)
Nervous system disorders
Cerebrovascular accident † 1	0/222 (0.00%)	1/237 (0.42%)
Paraesthesia † 1	0/222 (0.00%)	1/237 (0.42%)
Respiratory, thoracic and mediastinal disorders
Asthma † 1	10/222 (4.50%)	9/237 (3.80%)
Dyspnoea † 1	0/222 (0.00%)	1/237 (0.42%)
Hypoxia † 1	0/222 (0.00%)	1/237 (0.42%)
Sinus polyp † 1	0/222 (0.00%)	1/237 (0.42%)
† 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 R5
	Affected / at Risk (%)	Affected / at Risk (%)
Total	148/222 (66.67%)	136/237 (57.38%)
Infections and infestations
Bronchitis † 1	10/222 (4.50%)	12/237 (5.06%)
Nasopharyngitis † 1	20/222 (9.01%)	19/237 (8.02%)
Upper respiratory tract infection † 1	6/222 (2.70%)	13/237 (5.49%)
Investigations
Peak expiratory flow rate decreased † 1	58/222 (26.13%)	49/237 (20.68%)
Nervous system disorders
Headache † 1	13/222 (5.86%)	12/237 (5.06%)
Respiratory, thoracic and mediastinal disorders
Asthma † 1	99/222 (44.59%)	82/237 (34.60%)
† 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):

Halpin DMG, Meltzer EO, Pisternick-Ruf W, Moroni-Zentgraf P, Engel M, Zaremba-Pechmann L, Casale T, FitzGerald JM. Peak expiratory flow as an endpoint for clinical trials in asthma: a comparison with FEV1. Respir Res. 2019 Jul 18;20(1):159. doi: 10.1186/s12931-019-1119-6.

Casale TB, Bateman ED, Vandewalker M, Virchow JC, Schmidt H, Engel M, Moroni-Zentgraf P, Kerstjens HAM. Tiotropium Respimat Add-on Is Efficacious in Symptomatic Asthma, Independent of T2 Phenotype. J Allergy Clin Immunol Pract. 2018 May-Jun;6(3):923-935.e9. doi: 10.1016/j.jaip.2017.08.037. Epub 2017 Nov 22.

Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, Sigmund R, Seibold W, Moroni-Zentgraf P, Bateman ED. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012 Sep 27;367(13):1198-207. doi: 10.1056/NEJMoa1208606. Epub 2012 Sep 2.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT00772538
• Other Study ID Numbers: 205.416; 2008-001413-14 ( EudraCT Number: EudraCT )
• First Submitted: October 13, 2008
• First Posted: October 15, 2008
• Results First Submitted: July 25, 2012
• Results First Posted: September 27, 2012
• Last Update Posted: August 18, 2014