Trial Outcomes & Findings for Bioavailability of Tiotropium + Olodaterol Fixed-dose Combination (5 μg/ 5 μg) in Chinese COPD Patients (NCT NCT02969317)

NCT ID: NCT02969317

Last Updated: 2019-03-29

Results Overview

The descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP).

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 12 participants
• Primary outcome timeframe: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration
• Results posted on: 2019-03-29

Participant Flow

12 patients were entered to receive treatment with tiotropium+olodaterol fixed-dose combination (FDC) 5 microgram / 5 microgram (5 μg / 5 μg). All of the 12 entered patients were treated with trial medication.

All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that all patients met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met.

Participant milestones

Measure	Tiotropium+Olodaterol 5 Microgram/5 Microgram Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution and 2.5 μg per actuation of Olodaterol solution
Overall Study STARTED	12
Overall Study COMPLETED	12
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Bioavailability of Tiotropium + Olodaterol Fixed-dose Combination (5 μg/ 5 μg) in Chinese COPD Patients

Baseline characteristics by cohort

Measure	Tiotropium+Olodaterol 5 Microgram/5 Microgram n=12 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution and 2.5 μg per actuation of Olodaterol solution
Age, Continuous	59.8 Years STANDARD_DEVIATION 8.1 • n=12 Participants
Sex: Female, Male Female	0 Participants n=12 Participants
Sex: Female, Male Male	12 Participants n=12 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=12 Participants
Race (NIH/OMB) Asian	12 Participants n=12 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=12 Participants
Race (NIH/OMB) Black or African American	0 Participants n=12 Participants
Race (NIH/OMB) White	0 Participants n=12 Participants
Race (NIH/OMB) More than one race	0 Participants n=12 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=12 Participants

PRIMARY outcome

Timeframe: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration

Population: Pharmacokinetic analysis set (PKS): This set included all patients in the treated set with at least one evaluable PK parameter in the treatment period without important protocol violations related to PK

The descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP).

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Day 1, 7, 14, 18, 19 and 20

Population: PKS (evaluable cases)

Tmax, time from dosing to the maximum concentration of olodaterol in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

detailed sampling time points: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20(hours:minutes) after drug administration.

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=12 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Time From Dosing to the Maximum Concentration of Olodaterol in Plasma (Tmax)	0.167 Hour [h] Interval 0.117 to 3.0

PRIMARY outcome

Timeframe: Day 1, 7, 14, 18, 19 and 20

Population: PKS (evaluable cases)

Cmax, maximum measured concentration of olodaterol in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

detailed sampling time points: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20(hours:minutes) after drug administration.

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=12 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Maximum Measured Concentration of Olodaterol in Plasma (Cmax)	1.26 Picograms per millilitre [pg/mL] Geometric Coefficient of Variation 104

PRIMARY outcome

Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration

Population: PKS (evaluable cases)

Cmax,ss, maximum measured concentration of olodaterol in plasma at steady state of olodaterol after multiple dosing at Visit 4 (day 21) of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=12 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Maximum Measured Concentration of Olodaterol in Plasma at Steady State (Cmax,ss)	2.00 Picograms per millilitre [pg/mL] Geometric Coefficient of Variation 98.4

PRIMARY outcome

Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration

Population: PKS (evaluable cases)

Cpre,ss, pre-dose concentration of olodaterol in plasma at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=9 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Pre-dose Concentration of Olodaterol in Plasma at Steady State (Cpre,ss)	0.788 Picograms per millilitre [pg/mL] Geometric Coefficient of Variation 70.7

PRIMARY outcome

Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration

Population: PKS (evaluable cases)

AUC0-6,ss, area under the concentration time curve of olodaterol in plasma over the time interval from 0 to 6 hours at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=12 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Area Under the Concentration Time Curve of Olodaterol in Plasma Over the Time Interval From 0 to 6 Hours at Steady State (AUC0-6,ss)	7.54 Picograms*hour per millilitre [pg*h/mL] Geometric Coefficient of Variation 79.7

PRIMARY outcome

Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration

Population: PKS (evaluable cases)

AUCτ,ss, area under the concentration-time curve of olodaterol in plasma at steady state over a uniform dosing interval τ at steady state after multiple dosing at Day 21 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=10 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Area Under the Concentration-time Curve of Olodaterol in Plasma at Steady State Over a Uniform Dosing Interval τ at Steady State (AUCτ,ss)	25.5 Picograms*hour per millilitre [pg*h/mL] Geometric Coefficient of Variation 64.7

PRIMARY outcome

Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration

Population: PKS (evaluable cases)

Tmax,ss,time from dosing to the maximum concentration of olodaterol in plasma at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=12 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Time From Dosing to the Maximum Concentration of Olodaterol in Plasma at Steady State (Tmax,ss)	2.00 Hour [h] Interval 0.117 to 12.0

PRIMARY outcome

Timeframe: Day 1 and Day 21

Population: PKS (evaluable cases)

Accumulation ratios in plasma of olodaterol (RA,Cmax =Cmax,ss/Cmax) after multiple dosing at Day 21 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=12 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Accumulation Ratios in Plasma of Olodaterol (RA,Cmax =Cmax,ss/Cmax)	1.58 Ratio Geometric Coefficient of Variation 97.4

PRIMARY outcome

Timeframe: Day 1 and Day 21

Population: PKS (evaluable cases)

Regarding AUC0-6 and RA,AUC0-6, the descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP). And RA,AUC0-6 is the ratio of AUC0-6,ss to AUC0-6. So, the descriptive RA,AUC0-6 was not calculated either.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Day 1

Population: PKS (evaluable cases)

The descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP).

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Day 1, 7, 14, 18, 19, 20

Population: PKS (evaluable cases)

Tmax, time from dosing to the maximum concentration of Tiotropium in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mgis presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Detailed sampling time points:0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20 (hours:minutes) after drug administration

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=11 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Time From Dosing to the Maximum Concentration of Tiotropium in Plasma (Tmax)	0.167 Hour [h] Interval 0.033 to 2.0

PRIMARY outcome

Timeframe: Day 1, 7, 14, 18, 19, 20

Population: PKS (evaluable cases)

Cmax, maximum measured concentration of Tiotropium in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Detailed sampling time points:0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20 (hours:minutes) after drug administration

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=11 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Maximum Measured Concentration of Tiotropium in Plasma (Cmax)	6.12 Picograms per millilitre [pg/mL] Geometric Coefficient of Variation 83.5

PRIMARY outcome

Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration

Population: PKS (evaluable cases)

Cmax,ss, maximum measured concentration of olodaterol in plasma at steady state of Tiotropium after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=12 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Maximum Measured Concentration of Tiotropium in Plasma at Steady State (Cmax,ss)	7.65 Picograms per millilitre [pg/mL] Geometric Coefficient of Variation 112

PRIMARY outcome

Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration

Population: PKS (evaluable cases)

Cpre,ss, pre-dose concentration of Tiotropium in plasma at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=8 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Pre-dose Concentration of Tiotropium in Plasma at Steady State (Cpre,ss)	1.90 Picograms per millilitre [pg/mL] Geometric Coefficient of Variation 30.6

PRIMARY outcome

Timeframe: Day 21:0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration

Population: PKS (evaluable cases)

AUC0-6,ss, area under the concentration time curve of Tiotropium in plasma over the time interval from 0 to 6 hours at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=11 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Area Under the Concentration Time Curve of Tiotropium in Plasma Over the Time Interval From 0 to 6 Hours at Steady State (AUC0-6,ss)	22.0 Picograms*hour per millilitre [pg*h/mL] Geometric Coefficient of Variation 75.2

PRIMARY outcome

Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration

Population: PKS (evaluable cases)

AUCτ,ss, area under the concentration-time curve of Tiotropium in plasma at steady state over a uniform dosing interval τ at steady state after multiple dosing at Visit 4 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=11 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Area Under the Concentration-time Curve of Tiotropium in Plasma at Steady State Over a Uniform Dosing Interval τ at Steady State (AUCτ,ss)	54.8 Picograms*hour per millilitre [pg*h/mL] Geometric Coefficient of Variation 71.8

PRIMARY outcome

Timeframe: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration

Population: PKS (evaluable cases)

Tmax,ss,time from dosing to the maximum concentration of Tiotropium in plasma at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=12 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Time From Dosing to the Maximum Concentration of Tiotropium in Plasma at Steady State (Tmax,ss)	0.0830 Hour [h] Interval 0.033 to 2.0

PRIMARY outcome

Timeframe: Day 1, 7, 14, 18, 19, 20 and 21

Population: PKS (evaluable cases)

Accumulation ratios in plasma of Tiotropium (RA,Cmax =Cmax,ss/Cmax) after multiple dosing at Visit 4 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).

Outcome measures

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=11 Participants Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Accumulation Ratios in Plasma of Tiotropium (RA,Cmax =Cmax,ss/Cmax)	1.29 ratio Geometric Coefficient of Variation 127

PRIMARY outcome

Timeframe: Day 1 and Day 21

Population: PKS (evaluable cases)

Regarding AUC0-6 and RA,AUC0-6, the descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in CTP. And RA,AUC0-6 is the ratio of AUC0-6,ss to AUC0-6. So, the descriptive RA,AUC0-6 was not calculated either.

Outcome measures

Outcome data not reported

Adverse Events

Tiotropium+Olodaterol FDC 5 mg/5 mg

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Tiotropium+Olodaterol FDC 5 mg/5 mg n=12 participants at risk Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution
Gastrointestinal disorders Abdominal pain upper	8.3% 1/12 • From first drug administration through the residual effect period (REP) [[REP, defined as 21 days after last trial medication application], until individual patient's end of trial); up to 6 weeks. All treated subjects (that is, all subjects who received at least 1 dose of trial drug), were included in the safety analysis.
Nervous system disorders Dizziness	8.3% 1/12 • From first drug administration through the residual effect period (REP) [[REP, defined as 21 days after last trial medication application], until individual patient's end of trial); up to 6 weeks. All treated subjects (that is, all subjects who received at least 1 dose of trial drug), were included in the safety analysis.
Psychiatric disorders Anxiety	8.3% 1/12 • From first drug administration through the residual effect period (REP) [[REP, defined as 21 days after last trial medication application], until individual patient's end of trial); up to 6 weeks. All treated subjects (that is, all subjects who received at least 1 dose of trial drug), were included in the safety analysis.

Additional Information

Boehringer Ingelheim, Call Centre

Boehringer Ingelheim

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