Trial Outcomes & Findings for 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 (NCT NCT01696071)

NCT ID: NCT01696071

Last Updated: 2014-08-13

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 98 participants
• Primary outcome timeframe: 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
• Results posted on: 2014-08-13

Participant Flow

Participant milestones

Measure	Tio R2.5 Twice Daily (BID) / Tio R5 Once Daily (QD) 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)	Tio R5 QD / Tio R2.5 BID 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)
Treatment Period 1: 4 Weeks STARTED	51	47
Treatment Period 1: 4 Weeks COMPLETED	51	47
Treatment Period 1: 4 Weeks NOT COMPLETED	0	0
Treatment Period 2: 4 Weeks STARTED	51	47
Treatment Period 2: 4 Weeks COMPLETED	50	47
Treatment Period 2: 4 Weeks NOT COMPLETED	1	0

Reasons for withdrawal

Measure	Tio R2.5 Twice Daily (BID) / Tio R5 Once Daily (QD) 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)	Tio R5 QD / Tio R2.5 BID 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)
Treatment Period 2: 4 Weeks Adverse Event	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Baseline Total n=98 Participants Total number of patients randomised and treated in the study.
Age, Continuous	43.8 years STANDARD_DEVIATION 12.1 • n=5 Participants
Sex: Female, Male Female	44 Participants n=5 Participants
Sex: Female, Male Male	54 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure	Tio R2.5 BID n=98 Participants Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with inhaled corticosteroid (iCS).	Tio R5 QD n=97 Participants 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.
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve From 0 - 24h (AUC 0-24) Response.	0.219 Liters Standard Error 0.031	0.217 Liters Standard Error 0.031

SECONDARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure	Tio R2.5 BID n=98 Participants Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with inhaled corticosteroid (iCS).	Tio R5 QD n=97 Participants 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.
FEV1 AUC0-12h Response	0.182 Litres Standard Error 0.031 • Interval -0.032 to 0.052	0.192 Litres Standard Error 0.031 • Interval -0.032 to 0.052

SECONDARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure	Tio R2.5 BID n=98 Participants Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with inhaled corticosteroid (iCS).	Tio R5 QD n=97 Participants 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.
FEV1 AUC12-24h Response	0.256 Litres Standard Error 0.033	0.243 Litres Standard Error 0.033

SECONDARY outcome

Timeframe: 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.

Population: 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.

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.

Outcome measures

Measure	Tio R2.5 BID n=98 Participants Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with inhaled corticosteroid (iCS).	Tio R5 QD n=97 Participants 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.
Peak FEV1 Response.	0.465 Litres Standard Error 0.031	0.451 Litres Standard Error 0.031

SECONDARY outcome

Timeframe: 10 minutes (min) prior to dose after 4 weeks

Population: 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.

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.

Outcome measures

Measure	Tio R2.5 BID n=98 Participants Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with inhaled corticosteroid (iCS).	Tio R5 QD n=97 Participants 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.
Trough FEV1 (L) Response.	0.203 Litres Standard Error 0.033	0.207 Litres Standard Error 0.034

SECONDARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure	Tio R2.5 BID n=98 Participants Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with inhaled corticosteroid (iCS).	Tio R5 QD n=97 Participants 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.
Forced Vital Capacity (FVC) AUC0-24h Response	0.079 Litres Standard Error 0.032	0.075 Litres Standard Error 0.032

SECONDARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure	Tio R2.5 BID n=98 Participants Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with inhaled corticosteroid (iCS).	Tio R5 QD n=97 Participants 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.
FVC AUC0-12h Response	0.056 Litres Standard Error 0.031	0.053 Litres Standard Error 0.031

SECONDARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure	Tio R2.5 BID n=98 Participants Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with inhaled corticosteroid (iCS).	Tio R5 QD n=97 Participants 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.
FVC AUC12-24h Response	0.102 Litres Standard Error 0.034	0.096 Litres Standard Error 0.034

SECONDARY outcome

Timeframe: 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

Population: 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.

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).

Outcome measures

Measure	Tio R2.5 BID n=98 Participants Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with inhaled corticosteroid (iCS).	Tio R5 QD n=97 Participants 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.
Peak FVC Response	0.328 Litres Standard Error 0.033	0.309 Litres Standard Error 0.033

SECONDARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure	Tio R2.5 BID n=98 Participants Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with inhaled corticosteroid (iCS).	Tio R5 QD n=97 Participants 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.
Trough FVC Responses	0.077 Litres Standard Error 0.034	0.118 Litres Standard Error 0.034

SECONDARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure	Tio R2.5 BID n=98 Participants Tiotropium 2.5 mcg BID morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with inhaled corticosteroid (iCS).	Tio R5 QD n=97 Participants 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.
Peak Expiratory Flow (PEF) AUC0-24h Response	42.788 Litres/min Standard Error 5.923	41.399 Litres/min Standard Error 5.933

Adverse Events

Tio R2.5 Bid

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Tio R5 qd

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Measure	Tio R2.5 Bid n=98 participants at risk Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top of maintenance therapy with iCS.	Tio R5 qd n=98 participants at risk 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cervix carcinoma stage 0	1.0% 1/98 • From baseline visit to end of study drug administration, plus 30 days, up to 82 days.	0.00% 0/98 • From baseline visit to end of study drug administration, plus 30 days, up to 82 days.
Reproductive system and breast disorders Cervical dysplasia	1.0% 1/98 • From baseline visit to end of study drug administration, plus 30 days, up to 82 days.	0.00% 0/98 • From baseline visit to end of study drug administration, plus 30 days, up to 82 days.

Other adverse events

Adverse event data not reported

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER