Trial Outcomes & Findings for 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 II) (NCT NCT00776984)

Last Updated: 2014-09-10

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

453 participants

Primary outcome timeframe

Baseline and 24 weeks

Results posted on

2014-09-10

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Patients treated with matching placebo	Tio R5 Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Study STARTED	234	219
Overall Study COMPLETED	203	198
Overall Study NOT COMPLETED	31	21

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Patients treated with matching placebo	Tio R5 Patients treated with tiotropium inhalation solution 5 microgram qd
Overall Study Adverse Event	8	2
Overall Study Protocol Violation	4	2
Overall Study Lost to Follow-up	2	0
Overall Study Withdrawal by Subject	12	7
Overall Study Lack of Efficacy	0	1
Overall Study Other	5	9

Baseline Characteristics

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 II)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=234 Participants Patients treated with matching placebo	Tio R5 n=219 Participants Patients treated with tiotropium inhalation solution 5 microgram qd	Total n=453 Participants Total of all reporting groups
Age, Continuous	53.6 Years STANDARD_DEVIATION 11.7 • n=5 Participants	51.4 Years STANDARD_DEVIATION 12.5 • n=7 Participants	52.5 Years STANDARD_DEVIATION 12.1 • n=5 Participants
Sex: Female, Male Female	135 Participants n=5 Participants	127 Participants n=7 Participants	262 Participants n=5 Participants
Sex: Female, Male Male	99 Participants n=5 Participants	92 Participants n=7 Participants	191 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 24 weeks

Population: 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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 24 Weeks.	0.248 Liter Standard Error 0.024	0.401 Liter Standard Error 0.025

PRIMARY outcome

Timeframe: Baseline and 24 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Trough FEV1 Response Determined After a Treatment Period of 24 Weeks.	0.044 Liter Standard Error 0.022	0.155 Liter Standard Error 0.023

PRIMARY outcome

Timeframe: 48 weeks

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=454 Participants Patients treated with matching placebo	Tio R5 n=453 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
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).	NA Days Inter-Quartile Range NA As \<50percent (149 of 454 patients in the placebo group) of patients had severe exacerbation, the median time was not calculable.	NA Days Inter-Quartile Range NA As \<50percent (122 of 453 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 24-week Treatment Period.	0.323 Liter Standard Error 0.032	0.416 Liter Standard Error 0.033

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Trough FVC Response at the End of the 24-week Treatment Period.	0.044 Liter Standard Error 0.030	0.150 Liter Standard Error 0.032

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 24-week Treatment Period.	0.164 Liter Standard Error 0.022	0.307 Liter Standard Error 0.023

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
FVC (AUC0-3h) Response at the End of the 24-week Treatment Period.	0.187 Liter Standard Error 0.030	0.295 Liter Standard Error 0.031

SECONDARY outcome

Timeframe: Baseline and 48 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Peak FEV1 0-3h Response at the End of the 48-week Treatment Period.	0.245 Liter Standard Error 0.025	0.397 Liter Standard Error 0.026

SECONDARY outcome

Timeframe: Baseline and 48 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Trough FEV1 Response at the End of the 48-week Treatment Period.	0.063 Liter Standard Error 0.023	0.155 Liter Standard Error 0.023

SECONDARY outcome

Timeframe: Baseline and 48 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
AUC0-3h FEV1 Response at the End of the 48-week Treatment Period.	0.172 Liter Standard Error 0.023	0.310 Liter Standard Error 0.024

SECONDARY outcome

Timeframe: Baseline and 48 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Peak FVC 0-3h Response at the End of the 48-week Treatment Period.	0.305 Liter Standard Error 0.033	0.420 Liter Standard Error 0.034

SECONDARY outcome

Timeframe: Baseline and 48 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Trough FVC Response at the End of the 48-week Treatment Period.	0.072 Liter Standard Error 0.031	0.142 Liter Standard Error 0.032

SECONDARY outcome

Timeframe: Baseline and 48 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
FVC AUC0-3h Response at the End of the 48-week Treatment Period.	0.190 Liter Standard Error 0.031	0.299 Liter Standard Error 0.032

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Mean Pre-dose Morning Peak Expiratory Flow (PEFa.m.) Response (Diary Data) of Last-7-days-before-week-24-visit .	-3.258 L/min Standard Error 3.954	17.396 L/min Standard Error 4.136

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: All patients from FAS.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Mean Pre-dose Evening Peak Expiratory Flow (PEFp.m.) Response (Diary Data) of Last-7-days-before-week 24-visit.	-7.295 L/min Standard Error 4.188	25.158 L/min Standard Error 4.397

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: All patients from FAS.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Mean Pre-dose FEV1 a.m. Response (Diary Data) of Last-7-days-before-week 24-visit.	0.006 Liter Standard Error 0.025	0.096 Liter Standard Error 0.026

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: All patients from FAS.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Mean Pre-dose FEV1-p.m.Response (Diary Data) of Last-7-days-before-week 24-visit.	-0.015 Liter Standard Error 0.027	0.122 Liter Standard Error 0.028

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Mean PEF Variability Response (Absolute Difference Between Morning and Evening PEF Value Divided by Their Mean) of Last-7-days-before-week 24-visit.	-1.808 Percent Standard Error 0.617	-0.611 Percent Standard Error 0.641

SECONDARY outcome

Timeframe: 48 weeks

Population: All patients from FAS. As \< 50 percent (81 of 232 patients in the placebo group and 69 of 216 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 48 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. 0 asthma exacerbations	82 Participants	106 Participants
Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. 1 asthma exacerbation	53 Participants	44 Participants
Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. 2 asthma exacerbations	27 Participants	22 Participants
Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. 3 asthma exacerbations	13 Participants	8 Participants
Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. 4 asthma exacerbations	14 Participants	10 Participants
Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. 5 asthma exacerbations	9 Participants	3 Participants
Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. 6 asthma exacerbations	9 Participants	2 Participants
Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. 7-10 asthma exacerbations	10 Participants	8 Participants
Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. 11-20 asthma exacerbations	13 Participants	11 Participants
Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period. 21+ asthma exacerbations	2 Participants	2 Participants

SECONDARY outcome

Timeframe: 48 weeks

Population: All patients from FAS.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. 0 severe asthma exacerbations	151 Participants	147 Participants
Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. 1 severe asthma exacerbation	51 Participants	38 Participants
Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. 2 severe asthmaexacerbations	19 Participants	17 Participants
Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. 3 severe asthma exacerbations	5 Participants	8 Participants
Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. 4 severe asthma exacerbations	3 Participants	3 Participants
Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. 5 severe asthma exacerbations	2 Participants	1 Participants
Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. 6 severe asthma exacerbations	0 Participants	1 Participants
Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. 7-10 severe asthma exacerbations	0 Participants	1 Participants
Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period. 11-20 severe asthma exacerbations	1 Participants	0 Participants

SECONDARY outcome

Timeframe: 48 weeks

Population: All patients from FAS.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Number of Patients With at Least One Asthma Exacerbation During the 48-week Treatment Period.	150 Participants	110 Participants

SECONDARY outcome

Timeframe: 48 weeks

Population: All patients from FAS.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Number of Patients With at Least One Severe Asthma Exacerbation During the 48-week Treatment Period.	81 Participants	69 Participants

SECONDARY outcome

Timeframe: 48 weeks

Population: All patients from FAS. As \< 50 percent (10 of 232 patients in the placebo group and 8 of 216 patients in the Tio R5 group) of patients had severe exacerbation, the median time was not calculable.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 48 weeks

Population: All patients from FAS.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period. 0 hospitalisations	222 Participants	208 Participants
Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period. 1 hospitalisations	9 Participants	6 Participants
Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period. 2+ hospitalisations	1 Participants	2 Participants

SECONDARY outcome

Timeframe: 48 weeks

Population: All patients from FAS.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Number of Patients With at Least One Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period.	10 Participants	8 Participants

SECONDARY outcome

Timeframe: 24 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Quality of Life as Assessed by Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) at the End of the 24-week Treatment Period.	4.869 Scores on a scale Standard Error 0.058	5.047 Scores on a scale Standard Error 0.061

SECONDARY outcome

Timeframe: 48 weeks

Population: All patients from FAS.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
AQLQ(S) Total Score at the End of the 48-week Treatment Period.	4.945 Scores on a scale Standard Error 0.060	5.085 Scores on a scale Standard Error 0.062

SECONDARY outcome

Timeframe: 24 weeks

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Asthma Control as Assessed by Asthma Control Questionnaire (ACQ) at the End of the 24-week Treatment Period.	2.210 Score on a scale Standard Error 0.050	2.011 Score on a scale Standard Error 0.052

SECONDARY outcome

Timeframe: 48 weeks

Population: All patients from FAS.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
ACQ Score at the End of the 48-week Treatment Period.	2.159 Scores on a scale Standard Error 0.051	2.027 Scores on a scale Standard Error 0.053

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Asthma Symptom Free Days Response During the Last-7-days-before-week-24-visit .	0.065 Days Standard Error 0.023	0.077 Days Standard Error 0.024

SECONDARY outcome

Timeframe: Baseline and last 7 days before week 24 visit

Population: All patients from FAS.

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.

Outcome measures

Outcome measures
Measure	Placebo n=232 Participants Patients treated with matching placebo	Tio R5 n=216 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
Mean Pro Re Nata (as Needed, PRN) Rescue Medication Use Response During the Last-7-days-before-week-24-visit .	-0.881 Puffs Standard Error 0.158	-1.144 Puffs Standard Error 0.163

POST_HOC outcome

Timeframe: 24 weeks, 48 weeks

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

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.

Outcome measures

Outcome measures
Measure	Placebo n=454 Participants Patients treated with matching placebo	Tio R5 n=453 Participants Patients treated with tiotropium inhalation solution 5 microgram qd
The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984) 24 weeks	46.9 percentage of participants	53.9 percentage of participants
The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984) 48 weeks	45.2 percentage of participants	58.1 percentage of participants

Adverse Events

Placebo

Serious events: 25 serious events

Other events: 171 other events

Deaths: 0 deaths

Tio R5

Serious events: 19 serious events

Other events: 134 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=234 participants at risk Patients treated with matching placebo	Tio R5 n=219 participants at risk Patients treated with tiotropium inhalation solution 5 microgram qd
Respiratory, thoracic and mediastinal disorders Asthma	4.7% 11/234 • 48 weeks	3.7% 8/219 • 48 weeks
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Respiratory, thoracic and mediastinal disorders Nasal polyps	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Infections and infestations Pneumonia	0.85% 2/234 • 48 weeks	0.46% 1/219 • 48 weeks
Infections and infestations Abscess limb	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Infections and infestations Bronchopneumonia	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Infections and infestations Cellulitis	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Infections and infestations Cystitis	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Infections and infestations Enterocolitis infectious	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Infections and infestations H1N1 influenza	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bone neoplasm malignant	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ocular neoplasm	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Hepatobiliary disorders Cholelithiasis	0.43% 1/234 • 48 weeks	0.46% 1/219 • 48 weeks
Hepatobiliary disorders Cirrhosis alcoholic	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Hepatobiliary disorders Post cholecystectomy syndrome	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.85% 2/234 • 48 weeks	0.00% 0/219 • 48 weeks
Musculoskeletal and connective tissue disorders Back pain	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Musculoskeletal and connective tissue disorders Vertebral foraminal stenosis	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Gastrointestinal disorders Colonic polyp	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Gastrointestinal disorders Mechanical ileus	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Gastrointestinal disorders Umbilical hernia	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Injury, poisoning and procedural complications Eye injury	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Injury, poisoning and procedural complications Road traffic accident	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Metabolism and nutrition disorders Hypocalcaemia	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Metabolism and nutrition disorders Hypokalaemia	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Metabolism and nutrition disorders Hyponatraemia	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Nervous system disorders Cerebral infarction	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Nervous system disorders Carpal tunnel syndrome	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Nervous system disorders Facial paresis	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Psychiatric disorders Major depression	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Psychiatric disorders Mental status changes	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Renal and urinary disorders Renal failure	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Renal and urinary disorders Renal failure acute	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
Surgical and medical procedures Hip arthroplasty	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Vascular disorders Hypotension	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Vascular disorders Shock	0.00% 0/234 • 48 weeks	0.46% 1/219 • 48 weeks
Vascular disorders Labile hypertension	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks
General disorders Adverse drug reaction	0.43% 1/234 • 48 weeks	0.00% 0/219 • 48 weeks

Other adverse events

Other adverse events
Measure	Placebo n=234 participants at risk Patients treated with matching placebo	Tio R5 n=219 participants at risk Patients treated with tiotropium inhalation solution 5 microgram qd
Infections and infestations Bronchitis	4.3% 10/234 • 48 weeks	5.9% 13/219 • 48 weeks
Infections and infestations Nasopharyngitis	15.4% 36/234 • 48 weeks	14.6% 32/219 • 48 weeks
Infections and infestations Sinusitis	5.1% 12/234 • 48 weeks	5.9% 13/219 • 48 weeks
Investigations Peak expiratory flow rate decreased	27.4% 64/234 • 48 weeks	20.1% 44/219 • 48 weeks
Nervous system disorders Headache	8.5% 20/234 • 48 weeks	7.8% 17/219 • 48 weeks
Respiratory, thoracic and mediastinal disorders Asthma	47.9% 112/234 • 48 weeks	37.9% 83/219 • 48 weeks

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
Publication restrictions are in place

Restriction type: OTHER