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Comparison of Two Daily Dose Regimens of Tiotropium 5 µg Once Daily and Tiotropium 2.5 µg Twice Daily for 4 Weeks on Top of Maintenance Therapy With Inhaled Corticosteroid Controller Medication

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ClinicalTrials.gov Identifier: NCT01696071
Recruitment Status : Completed
First Posted : September 28, 2012
Results First Posted : August 13, 2014
Last Update Posted : August 13, 2014
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double;   Primary Purpose: Treatment
Condition Asthma
Interventions Drug: Tiotropium 5 mcg qd
Drug: Tiotropium 2.5 mcg bid
Enrollment 98
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Tio R2.5 Twice Daily (BID) / Tio R5 Once Daily (QD) Tio R5 QD / Tio R2.5 BID
Hide Arm/Group Description

Subjects were randomised to receive treatment with 2.5 μg tiotropium inhalation solution twice daily (i.e. in the morning and in the evening) and 5 μg tiotropium inhalation solution once daily in the evening via Respimat inhaler in a crossover manner using a predefined randomisation sequence.

Treatment 1: Tio 2.5 µg BID (twice daily):Oral inhalation via the( Tiotropium–Respimat) inhaler of 2.5 µg twice daily i.e 2 actuations of 1.25 µg tiotropium in the morning and in the evening (total daily dose of 5 μg) Treatment 2: Tio 5 µg QD (once daily):Oral inhalation via the( Tiotropium–Respimat) inhaler of 5 µg once daily i.e 2 actuations of 2.5 µg tiotropium in the evening and 2 actuations of placebo in the morning (total daily dose of 5 μg)

Subjects were randomised to receive treatment with 2.5 μg tiotropium inhalation solution twice daily (i.e. in the morning and in the evening) and 5 μg tiotropium inhalation solution once daily in the evening via Respimat inhaler in a crossover manner using a predefined randomisation sequence.

Treatment 1: Tio 5 µg QD (once daily):Oral inhalation via the( Tiotropium–Respimat) inhaler of 5 µg once daily i.e 2 actuations of 2.5 µg tiotropium in the evening and 2 actuations of placebo in the morning (total daily dose of 5 μg) Treatment 2: Tio 2.5 µg BID (twice daily):Oral inhalation via the( Tiotropium–Respimat) inhaler of 2.5 µg twice daily i.e 2 actuations of 1.25 µg tiotropium in the morning and in the evening (total daily dose of 5 μg)

Period Title: Treatment Period 1: 4 Weeks
Started 51 47
Completed 51 47
Not Completed 0 0
Period Title: Treatment Period 2: 4 Weeks
Started 51 47
Completed 50 47
Not Completed 1 0
Reason Not Completed
Adverse Event             1             0
Arm/Group Title Baseline Total
Hide Arm/Group Description Total number of patients randomised and treated in the study.
Overall Number of Baseline Participants 98
Hide Baseline Analysis Population Description
Treated Set (TS) : All patients who were dispensed study medication and were documented as having taken at least one dose of investigational treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 98 participants
43.8  (12.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 98 participants
Female
44
  44.9%
Male
54
  55.1%
1.Primary Outcome
Title Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 - 24h (AUC 0-24) Response.
Hide Description

Mixed Model Repeated Measure (MMRM) results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.

The values recorded at 11 hours 50 minutes and at 23 hours 50 minutes post dosing were assigned to 12 and 24 hours, respectively.

Time Frame Baseline FEV1 taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes (min) prior to dose to 30 min,1 hour (h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): The full analysis set (FAS) includes all patients in the treated set who had baseline data and at least one on-treatment efficacy value after 4 weeks on treatment within a period.
Arm/Group Title Tio R2.5 BID Tio R5 QD
Hide Arm/Group Description:
Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with inhaled corticosteroid (iCS).
Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Overall Number of Participants Analyzed 98 97
Least Squares Mean (Standard Error)
Unit of Measure: Liters
0.219  (0.031) 0.217  (0.031)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tio R2.5 BID, Tio R5 QD
Comments No p-values are presented as no formal statistical hypothesis was tested.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.002
Confidence Interval 95%
-0.038 to 0.034
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Tio R5 QD – Tio R2.5 BID
2.Secondary Outcome
Title FEV1 AUC0-12h Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time Frame Baseline FEV1 taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): The full analysis set (FAS) includes all patients in the treated set who had baseline data and at least one on-treatment efficacy value after 4 weeks on treatment within a period.
Arm/Group Title Tio R2.5 BID Tio R5 QD
Hide Arm/Group Description:
Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Overall Number of Participants Analyzed 98 97
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.182  (0.031) 0.192  (0.031)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tio R2.5 BID, Tio R5 QD
Comments No p-values are presented as no formal statistical hypothesis was tested.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.010
Confidence Interval 95%
-0.032 to 0.052
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.021
Estimation Comments Tio R5 qd – Tio R2.5 bid
3.Secondary Outcome
Title FEV1 AUC12-24h Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC12 -24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time Frame Baseline FEV1 taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): The full analysis set (FAS) includes all patients in the treated set who had baseline data and at least one on-treatment efficacy value after 4 weeks on treatment within a period.
Arm/Group Title Tio R2.5 BID Tio R5 QD
Hide Arm/Group Description:
Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Overall Number of Participants Analyzed 98 97
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.256  (0.033) 0.243  (0.033)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tio R2.5 BID, Tio R5 QD
Comments No p-values are presented as no formal statistical hypothesis was tested
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.014
Confidence Interval 95%
-0.050 to 0.022
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Tio R5 qd – Tio R2.5 bid
4.Secondary Outcome
Title Peak FEV1 Response.
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. Peak FEV1 was defined as the highest FEV1 reading observed within the 24 hour period following inhalation of the last evening dose of study medication (FEV1 Peak0-24h). The values recorded at 11 hours 50 minutes and at 23 hours 50 minutes post dosing were assigned to 12 and 24 hours, respectively.
Time Frame 10 minutes (min) prior to dose to 30 min,1 hour (h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks.
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): The full analysis set (FAS) includes all patients in the treated set who had baseline data and at least one on-treatment efficacy value after 4 weeks on treatment within a period.
Arm/Group Title Tio R2.5 BID Tio R5 QD
Hide Arm/Group Description:
Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Overall Number of Participants Analyzed 98 97
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.465  (0.031) 0.451  (0.031)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tio R2.5 BID, Tio R5 QD
Comments No p-values are presented as no formal statistical hypothesis was tested.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.014
Confidence Interval 95%
-0.051 to 0.023
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.018
Estimation Comments Tio R5 qd – Tio R2.5 bid
5.Secondary Outcome
Title Trough FEV1 (L) Response.
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. Trough FEV1 was defined as the FEV1 value just prior to the last evening dose of study medication.
Time Frame 10 minutes (min) prior to dose after 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): The full analysis set (FAS) includes all patients in the treated set who had baseline data and at least one on-treatment efficacy value after 4 weeks on treatment within a period.
Arm/Group Title Tio R2.5 BID Tio R5 QD
Hide Arm/Group Description:
Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Overall Number of Participants Analyzed 98 97
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.203  (0.033) 0.207  (0.034)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tio R2.5 BID, Tio R5 QD
Comments No p-values are presented as no formal statistical hypothesis was tested.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.004
Confidence Interval 95%
-0.060 to 0.068
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.032
Estimation Comments Tio R5 qd – Tio R2.5 bid
6.Secondary Outcome
Title Forced Vital Capacity (FVC) AUC0-24h Response
Hide Description

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.

The values recorded at 11 hours 50 minutes and at 23 hours 50 minutes post dosing were assigned to 12 and 24 hours, respectively.

Time Frame Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): The full analysis set (FAS) includes all patients in the treated set who had baseline data and at least one on-treatment efficacy value after 4 weeks on treatment within a period.
Arm/Group Title Tio R2.5 BID Tio R5 QD
Hide Arm/Group Description:
Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Overall Number of Participants Analyzed 98 97
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.079  (0.032) 0.075  (0.032)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tio R2.5 BID, Tio R5 QD
Comments No p-values are presented as no formal statistical hypothesis was tested.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.005
Confidence Interval 95%
-0.044 to 0.035
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.020
Estimation Comments Tio R5 qd – Tio R2.5 bid
7.Secondary Outcome
Title FVC AUC0-12h Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time Frame Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): The full analysis set (FAS) includes all patients in the treated set who had baseline data and at least one on-treatment efficacy value after 4 weeks on treatment within a period.
Arm/Group Title Tio R2.5 BID Tio R5 QD
Hide Arm/Group Description:
Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Overall Number of Participants Analyzed 98 97
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.056  (0.031) 0.053  (0.031)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tio R2.5 BID, Tio R5 QD
Comments No p-values are presented as no formal statistical hypothesis was tested
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.003
Confidence Interval 95%
-0.048 to 0.042
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.023
Estimation Comments Tio R5 qd – Tio R2.5 bid
8.Secondary Outcome
Title FVC AUC12-24h Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC12 -24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.
Time Frame Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): The full analysis set (FAS) includes all patients in the treated set who had baseline data and at least one on-treatment efficacy value after 4 weeks on treatment within a period.
Arm/Group Title Tio R2.5 BID Tio R5 QD
Hide Arm/Group Description:
Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Overall Number of Participants Analyzed 98 97
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.102  (0.034) 0.096  (0.034)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tio R2.5 BID, Tio R5 QD
Comments No p-values are presented as no formal statistical hypothesis was tested
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.006
Confidence Interval 95%
-0.047 to 0.034
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.020
Estimation Comments Tio R5 qd – Tio R2.5 bid
9.Secondary Outcome
Title Peak FVC Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. Peak FVC was defined as the highest FVC reading observed within the 24 hour period following inhalation of the last evening dose of study medication (FVC Peak0-24h).
Time Frame Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): The full analysis set (FAS) includes all patients in the treated set who had baseline data and at least one on-treatment efficacy value after 4 weeks on treatment within a period.
Arm/Group Title Tio R2.5 BID Tio R5 QD
Hide Arm/Group Description:
Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Overall Number of Participants Analyzed 98 97
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.328  (0.033) 0.309  (0.033)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tio R2.5 BID, Tio R5 QD
Comments No p-values are presented as no formal statistical hypothesis was tested
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.019
Confidence Interval 95%
-0.070 to 0.032
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.026
Estimation Comments Tio R5 qd – Tio R2.5 bid
10.Secondary Outcome
Title Trough FVC Responses
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. Trough FVC was defined as the FVC value just prior to the last evening dose of study medication.
Time Frame Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose after 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): The full analysis set (FAS) includes all patients in the treated set who had baseline data and at least one on-treatment efficacy value after 4 weeks on treatment within a period.
Arm/Group Title Tio R2.5 BID Tio R5 QD
Hide Arm/Group Description:
Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Overall Number of Participants Analyzed 98 97
Least Squares Mean (Standard Error)
Unit of Measure: Litres
0.077  (0.034) 0.118  (0.034)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tio R2.5 BID, Tio R5 QD
Comments No p-values are presented as no formal statistical hypothesis was tested
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.041
Confidence Interval 95%
-0.030 to 0.111
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.035
Estimation Comments Tio R5 qd – Tio R2.5 bid
11.Secondary Outcome
Title Peak Expiratory Flow (PEF) AUC0-24h Response
Hide Description MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres per minute.
Time Frame Baseline taken at visit 2 prior to the first evening dose of randomised study medication. Then, 10 minutes(min) prior to dose to 30min,1hour(h),2h,3h,4h,11h50min,12h30min,13h,14h,15h,16h,18h,20h,22h and 23h,23h50min relative to dose after 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS): The full analysis set (FAS) includes all patients in the treated set who had baseline data and at least one on-treatment efficacy value after 4 weeks on treatment within a period.
Arm/Group Title Tio R2.5 BID Tio R5 QD
Hide Arm/Group Description:
Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Tiotropium 5 mcg QD in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
Overall Number of Participants Analyzed 98 97
Least Squares Mean (Standard Error)
Unit of Measure: Litres/min
42.788  (5.923) 41.399  (5.933)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tio R2.5 BID, Tio R5 QD
Comments No p-values are presented as no formal statistical hypothesis was tested
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments MMRM, adjusted for treatment, period, patient and study baseline
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.389
Confidence Interval 95%
-8.651 to 5.873
Parameter Dispersion
Type: Standard Error of the mean
Value: 3.658
Estimation Comments Tio R5 qd – Tio R2.5 bid
Time Frame From baseline visit to end of study drug administration, plus 30 days, up to 82 days.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Tio R2.5 Bid Tio R5 qd
Hide Arm/Group Description Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS. Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top of maintenance therapy with iCS.
All-Cause Mortality
Tio R2.5 Bid Tio R5 qd
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Tio R2.5 Bid Tio R5 qd
Affected / at Risk (%) Affected / at Risk (%)
Total   1/98 (1.02%)   0/98 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Cervix carcinoma stage 0  1  1/98 (1.02%)  0/98 (0.00%) 
Reproductive system and breast disorders     
Cervical dysplasia  1  1/98 (1.02%)  0/98 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 16.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Tio R2.5 Bid Tio R5 qd
Affected / at Risk (%) Affected / at Risk (%)
Total   0/98 (0.00%)   0/98 (0.00%) 
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.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific and statistical accuracy, within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Results Point of Contact
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01696071     History of Changes
Other Study ID Numbers: 205.441
2012-001873-10 ( EudraCT Number: EudraCT )
First Submitted: September 26, 2012
First Posted: September 28, 2012
Results First Submitted: June 18, 2014
Results First Posted: August 13, 2014
Last Update Posted: August 13, 2014