Trial Outcomes & Findings for Study to Evaluate the Effect on Lung Function and ECG When a Combination of Tiotropium Plus Olodaterol is Administered to Patients With COPD Either From a Single Inhaler or Each Compound is Administered After Each Other From Two Different Inhalers (NCT NCT02030535)

NCT ID: NCT02030535

Last Updated: 2015-07-16

Results Overview

The response was defined as the change from patient baseline. Patient baseline was the average of the mean pre-dose values (period baseline) on each test day (Visit 2 (Day 1), Visit 3 (Day 22 (±7days)), and Visit 4 (Day 43±7days)). For patients who did not complete all periods, patient baseline was the average of the available period baselines. The means presented are the adjusted means.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 53 participants
• Primary outcome timeframe: 1 hour (h) and 10 min pre-dose and at 15 min, 30 min, 1 h, 2 h and 3 h post-dose
• Results posted on: 2015-07-16

Participant Flow

Participant milestones

Measure	Overall Study Total number of patients randomised and treated in the study. (This is a cross-over trial consisting of a minimum two-week screening period. After screening, eligible patients were randomly assigned to one of 12 treatment sequences. Each patient received all three treatments as single doses on the three test days. Between test days with single dose administration there are 3-week washout periods.)
Treatment Period 1 (1 Day) STARTED	53
Treatment Period 1 (1 Day) COMPLETED	53
Treatment Period 1 (1 Day) NOT COMPLETED	0
Washout Period 1 (21 Days) STARTED	53
Washout Period 1 (21 Days) COMPLETED	52
Washout Period 1 (21 Days) NOT COMPLETED	1
Treatment Period 2 (1 Day) STARTED	52
Treatment Period 2 (1 Day) COMPLETED	52
Treatment Period 2 (1 Day) NOT COMPLETED	0
Washout Period 2 (21 Days) STARTED	52
Washout Period 2 (21 Days) COMPLETED	52
Washout Period 2 (21 Days) NOT COMPLETED	0
Treatment Period 3 (1 Day) STARTED	52
Treatment Period 3 (1 Day) COMPLETED	52
Treatment Period 3 (1 Day) NOT COMPLETED	0

Reasons for withdrawal

Measure

Overall Study Total number of patients randomised and treated in the study. (This is a cross-over trial consisting of a minimum two-week screening period. After screening, eligible patients were randomly assigned to one of 12 treatment sequences. Each patient received all three treatments as single doses on the three test days. Between test days with single dose administration there are 3-week washout periods.)

Washout Period 1 (21 Days) Adverse Event

1

Baseline Characteristics

Study to Evaluate the Effect on Lung Function and ECG When a Combination of Tiotropium Plus Olodaterol is Administered to Patients With COPD Either From a Single Inhaler or Each Compound is Administered After Each Other From Two Different Inhalers

Baseline characteristics by cohort

Measure	Overall Study n=53 Participants Total number of patients randomised and treated in the study.
Age, Continuous	64.4 years STANDARD_DEVIATION 6.8 • n=5 Participants
Sex: Female, Male Female	22 Participants n=5 Participants
Sex: Female, Male Male	31 Participants n=5 Participants

PRIMARY outcome

Timeframe: 1 hour (h) and 10 min pre-dose and at 15 min, 30 min, 1 h, 2 h and 3 h post-dose

Population: Full Analysis Set (FAS): This patient set included all patients in the TS who had at least 1 visit (Visit 2(Day1), Visit 3(Day22), or Visit 4(Day43)) with both the period baseline value plus any evaluable post-dose spirometry measurement from the same visit.

The response was defined as the change from patient baseline. Patient baseline was the average of the mean pre-dose values (period baseline) on each test day (Visit 2 (Day 1), Visit 3 (Day 22 (±7days)), and Visit 4 (Day 43±7days)).

For patients who did not complete all periods, patient baseline was the average of the available period baselines.

The means presented are the adjusted means.

Outcome measures

Measure	Placebo n=53 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3hours) Response After Single-dose Administration	0.014 Litres Standard Error 0.016	0.233 Litres Standard Error 0.016	0.266 Litres Standard Error 0.016

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Mean QTcF interval change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Mean (Heart Rate Corrected QT Interval (Using Fredericia Adjustment)) QTcF Interval Change From Patient Baseline Over All Post-dose Time Points	1.3 ms Standard Deviation 7.1	2.2 ms Standard Deviation 6.9	1.9 ms Standard Deviation 6.9

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Peak QTcF interval change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Peak QTcF Interval Change From Patient Baseline Over All Post-dose Time Points	5.2 ms Standard Deviation 8.3	5.7 ms Standard Deviation 7.6	5.7 ms Standard Deviation 7.3

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Mean heart rate change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Mean Heart Rate Change From Patient Baseline Over All Post-dose Time Points	-3.0 bpm Standard Deviation 5.2	-2.5 bpm Standard Deviation 5.5	-3.6 bpm Standard Deviation 4.3

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Peak heart rate change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Peak Heart Rate Change From Patient Baseline Over All Post-dose Time Points	-0.7 bpm Standard Deviation 5.5	-0.3 bpm Standard Deviation 5.7	-1.2 bpm Standard Deviation 4.4

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Heart rate change from patient baseline at individual post-dose time points

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Heart Rate Change From Patient Baseline at Individual Post-dose Time Points 5 min	-2.3 bpm Standard Deviation 5.2	-2.5 bpm Standard Deviation 5.5	-2.9 bpm Standard Deviation 4.6
Heart Rate Change From Patient Baseline at Individual Post-dose Time Points 10 min	-2.7 bpm Standard Deviation 5.9	-2.4 bpm Standard Deviation 5.5	-3.1 bpm Standard Deviation 4.6
Heart Rate Change From Patient Baseline at Individual Post-dose Time Points 25 min	-3.1 bpm Standard Deviation 5.5	-2.6 bpm Standard Deviation 6.0	-4.5 bpm Standard Deviation 5.0
Heart Rate Change From Patient Baseline at Individual Post-dose Time Points 50 min	-4.1 bpm Standard Deviation 5.6	-2.4 bpm Standard Deviation 6.0	-3.9 bpm Standard Deviation 4.7

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Mean RR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Mean RR (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	40.4 ms Standard Deviation 57.7	29.3 ms Standard Deviation 57.1	39.5 ms Standard Deviation 51.5

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Peak RR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Peak RR Change From Patient Baseline Over All Post-dose Time Points	68.8 ms Standard Deviation 64.3	55.5 ms Standard Deviation 59.5	68.0 ms Standard Deviation 52.7

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

RR change from patient baseline at individual post-dose time points

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
RR Change From Patient Baseline at Individual Post-dose Time Points 5 min	29.9 ms Standard Deviation 62.5	29.7 ms Standard Deviation 58.5	31.9 ms Standard Deviation 55.5
RR Change From Patient Baseline at Individual Post-dose Time Points 10 min	38.8 ms Standard Deviation 68.9	28.1 ms Standard Deviation 57.4	33.5 ms Standard Deviation 56.1
RR Change From Patient Baseline at Individual Post-dose Time Points 25 min	40.4 ms Standard Deviation 59.4	33.0 ms Standard Deviation 65.7	50.0 ms Standard Deviation 59.9
RR Change From Patient Baseline at Individual Post-dose Time Points 50 min	52.3 ms Standard Deviation 62.7	25.2 ms Standard Deviation 64.9	44.0 ms Standard Deviation 57.0

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Mean QT change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Mean QT (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	7.2 ms Standard Deviation 10.7	6.5 ms Standard Deviation 11.1	7.9 ms Standard Deviation 9.9

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Peak QT change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Peak QT (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	12.4 ms Standard Deviation 11.5	11.5 ms Standard Deviation 11.1	13.4 ms Standard Deviation 10.6

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

QT change from patient baseline at individual post-dose time points

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
QT Change From Patient Baseline at Individual Post-dose Time Points 5 min	4.3 ms Standard Deviation 10.7	5.5 ms Standard Deviation 11.2	4.9 ms Standard Deviation 10.4
QT Change From Patient Baseline at Individual Post-dose Time Points 10 min	7.1 ms Standard Deviation 12.6	6.3 ms Standard Deviation 11.8	7.9 ms Standard Deviation 11.3
QT Change From Patient Baseline at Individual Post-dose Time Points 25 min	7.9 ms Standard Deviation 11.4	7.4 ms Standard Deviation 12.0	9.6 ms Standard Deviation 11.1
QT Change From Patient Baseline at Individual Post-dose Time Points 50 min	9.4 ms Standard Deviation 12.1	6.7 ms Standard Deviation 12.6	9.4 ms Standard Deviation 10.9

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Mean QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment))change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Mean QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment)) Change From Patient Baseline Over All Post-dose Time Points	-1.9 ms Standard Deviation 9.0	-0.2 ms Standard Deviation 8.6	-1.4 ms Standard Deviation 8.1

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Peak QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment))change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Peak QTcB (Heart Rate Corrected QT Interval (Using Bazett Adjustment)) Change From Patient Baseline Over All Post-dose Time Points	3.0 ms Standard Deviation 10.7	4.2 ms Standard Deviation 9.7	3.5 ms Standard Deviation 8.5

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

QTcB change from patient baseline at individual post-dose time points

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
QTcB Change From Patient Baseline at Individual Post-dose Time Points 5 min	-2.5 ms Standard Deviation 9.0	-1.4 ms Standard Deviation 8.8	-2.6 ms Standard Deviation 8.7
QTcB Change From Patient Baseline at Individual Post-dose Time Points 10 min	-1.4 ms Standard Deviation 9.9	-0.2 ms Standard Deviation 8.7	-0.0 ms Standard Deviation 9.0
QTcB Change From Patient Baseline at Individual Post-dose Time Points 25 min	-1.0 ms Standard Deviation 11.3	0.1 ms Standard Deviation 10.3	-2.2 ms Standard Deviation 9.3
QTcB Change From Patient Baseline at Individual Post-dose Time Points 50 min	-2.6 ms Standard Deviation 9.9	0.7 ms Standard Deviation 9.8	-0.7 ms Standard Deviation 9.4

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Mean PR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Mean PR (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	0.6 ms Standard Deviation 4.9	1.6 ms Standard Deviation 6.3	1.4 ms Standard Deviation 6.4

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Peak PR change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Peak PR (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	3.9 ms Standard Deviation 4.8	4.6 ms Standard Deviation 5.9	4.7 ms Standard Deviation 7.2

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

PR change from patient baseline at individual post-dose time points

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
PR Change From Patient Baseline at Individual Post-dose Time Points 5 min	0.1 ms Standard Deviation 5.9	1.2 ms Standard Deviation 7.3	-0.2 ms Standard Deviation 6.6
PR Change From Patient Baseline at Individual Post-dose Time Points 10 min	0.1 ms Standard Deviation 6.0	2.5 ms Standard Deviation 8.4	1.4 ms Standard Deviation 7.1
PR Change From Patient Baseline at Individual Post-dose Time Points 25 min	0.1 ms Standard Deviation 6.5	0.8 ms Standard Deviation 6.3	1.9 ms Standard Deviation 7.8
PR Change From Patient Baseline at Individual Post-dose Time Points 50 min	2.2 ms Standard Deviation 5.4	1.9 ms Standard Deviation 5.4	2.7 ms Standard Deviation 7.7

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Mean QRS change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Mean QRS (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	-0.3 ms Standard Deviation 1.3	0.1 ms Standard Deviation 1.5	0.1 ms Standard Deviation 1.3

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

Peak QRS change from patient baseline over all post-dose time points (5min, 10min, 25min and 50min)

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
Peak QRS (Time Interval of ECG) Change From Patient Baseline Over All Post-dose Time Points	0.6 ms Standard Deviation 1.5	0.9 ms Standard Deviation 1.5	1.0 ms Standard Deviation 1.3

SECONDARY outcome

Timeframe: 40 min pre-dose and at 5 min, 10 min, 25 min and 50 min post-dose

Population: Treated set (observed cases)

QRS change from patient baseline at individual post-dose time points

Outcome measures

Measure	Placebo n=52 Participants Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo 5/5μg n=52 Participants Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation. 2 inhalations a.m. dosing via RESPIMAT® inhaler	Tiotropium 5μg + Olodaterol 5μg n=52 Participants Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination (FC) (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing via RESPIMAT® inhaler
QRS Change From Patient Baseline at Individual Post-dose Time Points 5 min	-0.3 ms Standard Deviation 1.5	-0.2 ms Standard Deviation 1.8	-0.0 ms Standard Deviation 1.6
QRS Change From Patient Baseline at Individual Post-dose Time Points 10 min	-0.3 ms Standard Deviation 1.6	0.1 ms Standard Deviation 1.6	0.1 ms Standard Deviation 1.6
QRS Change From Patient Baseline at Individual Post-dose Time Points 25 min	-0.3 ms Standard Deviation 1.4	0.1 ms Standard Deviation 1.6	0.0 ms Standard Deviation 1.4
QRS Change From Patient Baseline at Individual Post-dose Time Points 50 min	-0.4 ms Standard Deviation 1.7	0.2 ms Standard Deviation 1.7	0.2 ms Standard Deviation 1.6

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Tio+Olo FDC

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Tiotropium and Olodaterol FC

Serious events: 2 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=53 participants at risk Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo FDC n=52 participants at risk Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tiotropium and Olodaterol FC n=52 participants at risk Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination FC (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing.
Cardiac disorders Prinzmetal angina	0.00% 0/53 • Adverse events (AEs) occurring up to the minimum of 21 days after drug stop date or the start of the next treatment period were considered on treatment; Up to 64 days.	0.00% 0/52 • Adverse events (AEs) occurring up to the minimum of 21 days after drug stop date or the start of the next treatment period were considered on treatment; Up to 64 days.	1.9% 1/52 • Adverse events (AEs) occurring up to the minimum of 21 days after drug stop date or the start of the next treatment period were considered on treatment; Up to 64 days.
Reproductive system and breast disorders Cystocele	0.00% 0/53 • Adverse events (AEs) occurring up to the minimum of 21 days after drug stop date or the start of the next treatment period were considered on treatment; Up to 64 days.	0.00% 0/52 • Adverse events (AEs) occurring up to the minimum of 21 days after drug stop date or the start of the next treatment period were considered on treatment; Up to 64 days.	1.9% 1/52 • Adverse events (AEs) occurring up to the minimum of 21 days after drug stop date or the start of the next treatment period were considered on treatment; Up to 64 days.

Other adverse events

Measure	Placebo n=53 participants at risk Single test dose of oral inhalation of Placebo via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tio+Olo FDC n=52 participants at risk Single test dose of oral inhalation of Tio+Olo FDC(fixed dose combination) (5/5 μg) inhalation solution as fixed dose inhalation solution (Tio+Olo FDC) 2.5 μg each per actuation via RESPIMAT inhaler. 2 inhalations a.m. dosing.	Tiotropium and Olodaterol FC n=52 participants at risk Single test dose of oral inhalation of tiotropium (5 μg) and olodaterol (5 μg) free combination FC (Tio/Olo free combination) Olodaterol: 5 μg (2.5 μg per actuation) Tiotropium: 5 μg (2.5 μg per actuation) 2 inhalations a.m. dosing.
Infections and infestations Nasopharyngitis	5.7% 3/53 • Adverse events (AEs) occurring up to the minimum of 21 days after drug stop date or the start of the next treatment period were considered on treatment; Up to 64 days.	1.9% 1/52 • Adverse events (AEs) occurring up to the minimum of 21 days after drug stop date or the start of the next treatment period were considered on treatment; Up to 64 days.	3.8% 2/52 • Adverse events (AEs) occurring up to the minimum of 21 days after drug stop date or the start of the next treatment period were considered on treatment; Up to 64 days.

Additional Information

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