Trial Outcomes & Findings for Tiotropium Respimat Pharmacokinetic Study in COPD (NCT NCT01222533)

NCT ID: NCT01222533

Last Updated: 2014-05-16

Results Overview

Cmax,ss is the maximum measured concentration of tiotropium in plasma at steady-state.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 154 participants
• Primary outcome timeframe: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 minutes (min) before study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 hour (h), 2 h, 4 h and 6 h post dosing.
• Results posted on: 2014-05-16

Participant Flow

Participant milestones

Measure	Study Overall Total number of patients randomised and treated in the study. This was a randomised 5-period crossover trial. 154 patients were randomised to one of 15 sequences and treated. The trial was blinded within the 4 Respimat treatments, but open for the HandiHaler treatment. Each of the 5 treatment regimens was taken for 4 weeks without washouts between treatment periods.
Overall Study STARTED	154
Overall Study Received Placebo	147
Overall Study Received Tio R1.25	147
Overall Study Received Tio R2.5	145
Overall Study Received Tio R5	150
Overall Study Received Tio HH18	146
Overall Study COMPLETED	140
Overall Study NOT COMPLETED	14

Reasons for withdrawal

Measure	Study Overall Total number of patients randomised and treated in the study. This was a randomised 5-period crossover trial. 154 patients were randomised to one of 15 sequences and treated. The trial was blinded within the 4 Respimat treatments, but open for the HandiHaler treatment. Each of the 5 treatment regimens was taken for 4 weeks without washouts between treatment periods.
Overall Study Adverse Event	5
Overall Study Withdrawal by Subject	5
Overall Study Other	4

Baseline Characteristics

Tiotropium Respimat Pharmacokinetic Study in COPD

Baseline characteristics by cohort

Measure	Study Overall n=154 Participants Total number of patients randomised and treated in the study.
Age, Continuous	63.1 years STANDARD_DEVIATION 7.8 • n=5 Participants
Sex: Female, Male Female	37 Participants n=5 Participants
Sex: Female, Male Male	117 Participants n=5 Participants

PRIMARY outcome

Timeframe: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 minutes (min) before study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 hour (h), 2 h, 4 h and 6 h post dosing.

Population: Pharmacokinetic (PK) Set. This analysis set includes all patients in the treated set who had at least one blood sample drawn or one urine sample collected for PK analysis. Patients with an important protocol violation relevant to the PK population were excluded. No PK data for placebo. All patients with analysable data.

Cmax,ss is the maximum measured concentration of tiotropium in plasma at steady-state.

Outcome measures

Measure	Placebo Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=104 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=110 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=113 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Maximum Plasma Concentration at Steady-state (Cmax,ss)	—	2.81 pg/ml Geometric Coefficient of Variation 53.0	5.07 pg/ml Geometric Coefficient of Variation 61.8	10.5 pg/ml Geometric Coefficient of Variation 66.4	12.9 pg/ml Geometric Coefficient of Variation 64.6

PRIMARY outcome

Timeframe: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 minutes (min) before study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 hour (h), 2 h, 4 h and 6 h post dosing.

Population: PK Set. No PK data for Placebo. The low number of non-missing AUC0-6h,ss results for the Tio R 1.25 and Tio R 2.5 cohorts is due to the exclusion of results below the limit of quantification.

AUC0-6h,ss is the area under the concentration time curve of tiotropium in plasma over the time interval 0 to 6 hours post-dose at steady-state. AUC0-6h,ss was calculated using the linear up/log down algorithm.

Outcome measures

Measure	Placebo Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=22 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=76 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=107 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Area Under the Curve 0 to 6 Hours at Steady-state (AUC0-6h,ss)	—	10.0 pg*h/ml Geometric Coefficient of Variation 25.3	12.8 pg*h/ml Geometric Coefficient of Variation 29.9	22.1 pg*h/ml Geometric Coefficient of Variation 47.8	28.4 pg*h/ml Geometric Coefficient of Variation 52.4

SECONDARY outcome

Timeframe: 4 weeks

Population: Full analysis set (FAS) with imputed data. FAS includes all patients in the treated set who have analysable data for at least one efficacy endpoint during the relevant crossover period.

Defined as FEV1 measured just prior to the last administration of the morning dose of the randomised treatment. Means are adjusted for sequence, patients within sequences, period and treatment.

Outcome measures

Measure	Placebo n=143 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=143 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=144 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=143 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=142 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Trough Forced Expiratory Volume in One Second (FEV1) at the End of Each Treatment Period	1.345 Liter Standard Error 0.045	1.432 Liter Standard Error 0.045	1.446 Liter Standard Error 0.045	1.466 Liter Standard Error 0.045	1.473 Liter Standard Error 0.045

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS with imputed data.

FEV1 AUC0-6h calculated from zero time to 6 hours using the trapezoidal rule divided by 6 hours. Trough FEV1 will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment.

Outcome measures

Measure	Placebo n=143 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=143 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=144 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=143 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=142 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
FEV1 Area Under the Curve 0 to 6 Hours (AUC0-6h) at the End of Each Treatment Period	1.371 Liter Standard Error 0.046	1.535 Liter Standard Error 0.046	1.556 Liter Standard Error 0.046	1.562 Liter Standard Error 0.046	1.567 Liter Standard Error 0.046

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS with imputed data.

FEV1 AUC0-3h calculated from zero time to 3 hours using the trapezoidal rule divided by 3 hours. Trough FEV1 will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment.

Outcome measures

Measure	Placebo n=143 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=143 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=144 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=143 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=142 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
FEV1 Area Under the Curve 0 to 3 Hours (AUC0-3h) at the End of Each Treatment Period	1.366 Liter Standard Error 0.046	1.521 Liter Standard Error 0.046	1.546 Liter Standard Error 0.046	1.553 Liter Standard Error 0.046	1.558 Liter Standard Error 0.046

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period.

Defined as the pre-dose FVC measured just prior to the last administration of the morning dose of the randomised treatment. Means are adjusted for sequence, patients within sequences, period and treatment.

Outcome measures

Measure	Placebo n=142 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=143 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=143 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=143 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=142 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Trough Forced Vital Capacity (FVC) at the End of Each Treatment Period	3.116 Liter Standard Error 0.077	3.254 Liter Standard Error 0.077	3.304 Liter Standard Error 0.077	3.352 Liter Standard Error 0.077	3.351 Liter Standard Error 0.077

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period.

FVC AUC0-6h calculated from zero time to 6 hours using the trapezoidal rule divided by 6 hours. Trough FVC will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment.

Outcome measures

Measure	Placebo n=142 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=143 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=143 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=143 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=142 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
FVC AUC0-6h at the End of Each Treatment Period	3.153 Liter Standard Error 0.079	3.436 Liter Standard Error 0.078	3.472 Liter Standard Error 0.078	3.488 Liter Standard Error 0.078	3.483 Liter Standard Error 0.079

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period.

FVC AUC0-3h calculated from zero time to 3 hours using the trapezoidal rule divided by 3 hours. Trough FVC will be assigned to zero time. Means are adjusted for sequence, patients within sequences, period and treatment.

Outcome measures

Measure	Placebo n=142 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=143 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=143 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=143 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=142 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
FVC AUC0-3h at the End of Each Treatment Period	3.140 Liter Standard Error 0.078	3.421 Liter Standard Error 0.078	3.465 Liter Standard Error 0.078	3.479 Liter Standard Error 0.078	3.480 Liter Standard Error 0.078

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS with imputed data.

Means are adjusted for period, planned time, period*planned time, patient*planned time and patient*treatment*planned time.

Outcome measures

Measure	Placebo n=143 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=143 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=144 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=143 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=142 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
FEV1 at Each Planned Time at the End of Each Treatment Period Timepoint 0:00 (trough)	1.349 Liter Standard Error 0.045	1.436 Liter Standard Error 0.045	1.450 Liter Standard Error 0.045	1.470 Liter Standard Error 0.045	1.477 Liter Standard Error 0.045
FEV1 at Each Planned Time at the End of Each Treatment Period Timepoint 0:30	1.366 Liter Standard Error 0.046	1.501 Liter Standard Error 0.046	1.522 Liter Standard Error 0.046	1.541 Liter Standard Error 0.046	1.554 Liter Standard Error 0.046
FEV1 at Each Planned Time at the End of Each Treatment Period Timepoint 1:00	1.371 Liter Standard Error 0.046	1.529 Liter Standard Error 0.046	1.552 Liter Standard Error 0.046	1.560 Liter Standard Error 0.046	1.571 Liter Standard Error 0.046
FEV1 at Each Planned Time at the End of Each Treatment Period Timepoint 2:00	1.375 Liter Standard Error 0.046	1.543 Liter Standard Error 0.046	1.573 Liter Standard Error 0.046	1.572 Liter Standard Error 0.046	1.571 Liter Standard Error 0.046
FEV1 at Each Planned Time at the End of Each Treatment Period Timepoint 3:00	1.375 Liter Standard Error 0.047	1.556 Liter Standard Error 0.047	1.582 Liter Standard Error 0.047	1.584 Liter Standard Error 0.047	1.580 Liter Standard Error 0.047
FEV1 at Each Planned Time at the End of Each Treatment Period Timepoint 4:00	1.374 Liter Standard Error 0.047	1.557 Liter Standard Error 0.047	1.575 Liter Standard Error 0.047	1.578 Liter Standard Error 0.047	1.582 Liter Standard Error 0.047
FEV1 at Each Planned Time at the End of Each Treatment Period Timepoint 5:00	1.394 Liter Standard Error 0.047	1.562 Liter Standard Error 0.047	1.571 Liter Standard Error 0.047	1.579 Liter Standard Error 0.047	1.588 Liter Standard Error 0.047
FEV1 at Each Planned Time at the End of Each Treatment Period Timepoint 6:00	1.375 Liter Standard Error 0.047	1.536 Liter Standard Error 0.048	1.551 Liter Standard Error 0.047	1.558 Liter Standard Error 0.047	1.570 Liter Standard Error 0.048

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS with imputed data. One patient with missing FVC data in Placebo and Tio R2.5 period.

Means are adjusted for period, planned time, period*planned time, patient*planned time and patient*treatment*planned time.

Outcome measures

Measure	Placebo n=142 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=143 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=143 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=143 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=142 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
FVC at Each Planned Time at the End of Each Treatment Period Timepoint 0:00 (trough)	3.118 Liter Standard Error 0.076	3.255 Liter Standard Error 0.076	3.307 Liter Standard Error 0.076	3.356 Liter Standard Error 0.076	3.351 Liter Standard Error 0.076
FVC at Each Planned Time at the End of Each Treatment Period Timepoint 0:30	3.131 Liter Standard Error 0.077	3.390 Liter Standard Error 0.077	3.435 Liter Standard Error 0.077	3.473 Liter Standard Error 0.077	3.496 Liter Standard Error 0.077
FVC at Each Planned Time at the End of Each Treatment Period Timepoint 1:00	3.152 Liter Standard Error 0.078	3.449 Liter Standard Error 0.078	3.484 Liter Standard Error 0.078	3.488 Liter Standard Error 0.078	3.499 Liter Standard Error 0.078
FVC at Each Planned Time at the End of Each Treatment Period Timepoint 2:00	3.146 Liter Standard Error 0.078	3.443 Liter Standard Error 0.078	3.489 Liter Standard Error 0.078	3.499 Liter Standard Error 0.078	3.487 Liter Standard Error 0.078
FVC at Each Planned Time at the End of Each Treatment Period Timepoint 3:00	3.156 Liter Standard Error 0.078	3.466 Liter Standard Error 0.078	3.513 Liter Standard Error 0.078	3.516 Liter Standard Error 0.078	3.497 Liter Standard Error 0.078
FVC at Each Planned Time at the End of Each Treatment Period Timepoint 4:00	3.161 Liter Standard Error 0.079	3.468 Liter Standard Error 0.079	3.495 Liter Standard Error 0.079	3.505 Liter Standard Error 0.079	3.501 Liter Standard Error 0.079
FVC at Each Planned Time at the End of Each Treatment Period Timepoint 5:00	3.191 Liter Standard Error 0.079	3.459 Liter Standard Error 0.079	3.467 Liter Standard Error 0.079	3.501 Liter Standard Error 0.079	3.488 Liter Standard Error 0.079
FVC at Each Planned Time at the End of Each Treatment Period Timepoint 6:00	3.168 Liter Standard Error 0.079	3.417 Liter Standard Error 0.079	3.470 Liter Standard Error 0.079	3.473 Liter Standard Error 0.079	3.469 Liter Standard Error 0.079

SECONDARY outcome

Timeframe: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 minutes (min) before study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 hour (h), 2 h, 4 h and 6 h post dosing.

Population: PK Set. All patients with analysable data.

AUC0-1h,ss is the area under the concentration time curve of tiotropium in plasma over the time interval 0 to 1 hour post-dose at steady-state. AUC0-1h,ss was calculated using the linear up/log down algorithm.

Outcome measures

Measure	Placebo Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=61 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=97 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=112 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Area Under the Curve 0 to 1 Hour at Steady-state (AUC0-1h,ss)	—	2.08 pg*h/mL Geometric Coefficient of Variation 32.3	3.16 pg*h/mL Geometric Coefficient of Variation 44.4	6.13 pg*h/mL Geometric Coefficient of Variation 58.3	7.79 pg*h/mL Geometric Coefficient of Variation 54.9

SECONDARY outcome

Timeframe: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 min before first dosing of study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 h, 2 h, 4 h and 6 h post dosing.

Population: PK Set. All patients with analysable data.

Tmax,ss is the time from dosing to the maximum concentration of tiotropium in plasma-venous blood at steady-state.

Outcome measures

Measure	Placebo Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=104 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=110 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=113 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Time to Maximum Plasma Concentration at Steady-state (Tmax,ss)	—	0.100 hours Interval 0.033 to 2.0	0.0830 hours Interval 0.033 to 6.0	0.117 hours Interval 0.033 to 0.333	0.117 hours Interval 0.033 to 1.0

SECONDARY outcome

Timeframe: Based on urine sampling for PK assessments done at 4 weeks in the following intervals: -1 to 0 hour (h), 0 to 2 h and 2 to 6 h post-dosing.

Population: PK Set. All patients with analysable data.

Total quantity of the analyte that is excreted in urine over the time interval 0 to 6 hours at steady state.

Outcome measures

Measure	Placebo Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=108 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=110 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=107 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=109 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Amount of Drug Eliminated in Urine at Steady-state (Ae0-6h,ss)	—	88.7 ng Geometric Coefficient of Variation 68.0	177 ng Geometric Coefficient of Variation 68.0	387 ng Geometric Coefficient of Variation 65.9	522 ng Geometric Coefficient of Variation 53.8

SECONDARY outcome

Timeframe: Based on blood sampling for PK assessments done at 4 weeks at the following time point: 5 minutes (min) before first dosing of study drug (baseline)

Population: PK Set. All patients with analysable data.

Cpre,ss is the measured concentration of tiotropium in plasma before dosing at steady-state.

Outcome measures

Measure	Placebo Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=5 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=19 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=74 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=85 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Pre-dose Plasma Concentration at Steady-state (Cpre,ss)	—	1.57 pg/mL Geometric Coefficient of Variation 43.1	1.39 pg/mL Geometric Coefficient of Variation 22.8	1.60 pg/mL Geometric Coefficient of Variation 35.8	1.71 pg/mL Geometric Coefficient of Variation 42.5

SECONDARY outcome

Timeframe: Based on blood and urine sampling for PK assessments done at 4 weeks over 6 h post dosing.

Population: PK Set. All patients with analysable data.

Renal clearance of the drug over the time interval 0 to 6 hours at steady-state. CL R,0-6h,ss was calculated as the quotient of Ae0-6h,ss and AUC0-6h,ss.

Outcome measures

Measure	Placebo Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=22 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=75 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=102 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=109 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Renal Clearance at Steady-state (CL R,0-6h,ss)	—	256 mL/min Geometric Coefficient of Variation 32.1	277 mL/min Geometric Coefficient of Variation 55.8	307 mL/min Geometric Coefficient of Variation 39.6	310 mL/min Geometric Coefficient of Variation 40.4

SECONDARY outcome

Timeframe: Based on blood sampling for PK assessments done at 4 weeks at the following time points: 5 min before first dosing of study drug (baseline) and at 2 min , 5 min, 7 min, 9 min, 12 min, 15 min, 20 min, 30 min, 40 min, 1 h, 2 h, 4 h and 6 h post dosing.

Population: PK Set. All patients with analysable data.

Cmin,ss is the minimum measured concentration of tiotropium in plasma at steady-state.

Outcome measures

Measure	Placebo Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=103 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=110 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=113 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Minimum Plasma Concentration at Steady-state (Cmin,ss)	—	1.16 pg/mL Geometric Coefficient of Variation 14.5	1.25 pg/mL Geometric Coefficient of Variation 17.7	1.57 pg/mL Geometric Coefficient of Variation 32.3	1.76 pg/mL Geometric Coefficient of Variation 42.3

OTHER_PRE_SPECIFIED outcome

Timeframe: 6.5 hours (including pre dose)

Population: ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded).

Maximum HR evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

Outcome measures

Measure	Placebo n=115 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=115 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=115 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=116 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Maximum Heart Rate (HR) Day 29 6.5 h(N=115,115,115,116,113)	109.29 bpm Standard Deviation 15.23	109.57 bpm Standard Deviation 15.29	109.93 bpm Standard Deviation 15.47	109.34 bpm Standard Deviation 14.36	108.68 bpm Standard Deviation 14.28
Maximum Heart Rate (HR) Day 29 1st h(N=114,113,115,115,111)	97.83 bpm Standard Deviation 13.65	99.20 bpm Standard Deviation 14.65	98.43 bpm Standard Deviation 14.68	97.16 bpm Standard Deviation 13.97	97.33 bpm Standard Deviation 13.00
Maximum Heart Rate (HR) Day 26 6.5 h(N=115,110,113,110,112)	108.35 bpm Standard Deviation 16.32	107.37 bpm Standard Deviation 14.04	108.90 bpm Standard Deviation 15.85	107.65 bpm Standard Deviation 16.37	109.57 bpm Standard Deviation 14.70
Maximum Heart Rate (HR) Day 26 1st h(N=115,109,113,107,109)	91.73 bpm Standard Deviation 12.44	91.51 bpm Standard Deviation 12.87	92.59 bpm Standard Deviation 15.40	91.60 bpm Standard Deviation 12.07	92.74 bpm Standard Deviation 12.75

OTHER_PRE_SPECIFIED outcome

Timeframe: 6.5 hours (including pre dose)

Population: ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)

Mean HR evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

Outcome measures

Measure	Placebo n=115 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=115 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=115 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=116 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Mean Heart Rate (HR) Day 29 6.5 h(N=115,115,115,116,113)	76.97 bpm Standard Deviation 10.39	76.37 bpm Standard Deviation 10.69	77.75 bpm Standard Deviation 10.95	76.87 bpm Standard Deviation 10.82	77.31 bpm Standard Deviation 10.45
Mean Heart Rate (HR) Day 29 1st h(N=114,113,115,115,111)	73.87 bpm Standard Deviation 10.07	73.76 bpm Standard Deviation 10.60	74.39 bpm Standard Deviation 10.82	73.82 bpm Standard Deviation 11.06	73.71 bpm Standard Deviation 9.80
Mean Heart Rate (HR) Day 26 6.5 h(N=115,110,113,110,112)	75.76 bpm Standard Deviation 10.88	75.00 bpm Standard Deviation 10.87	76.25 bpm Standard Deviation 12.00	75.35 bpm Standard Deviation 10.86	75.81 bpm Standard Deviation 10.39
Mean Heart Rate (HR) Day 26 1st h(N=115,109,113,107,109)	70.75 bpm Standard Deviation 10.20	70.33 bpm Standard Deviation 10.66	71.11 bpm Standard Deviation 11.93	70.67 bpm Standard Deviation 10.77	70.21 bpm Standard Deviation 9.58

OTHER_PRE_SPECIFIED outcome

Timeframe: 6.5 hours (including pre dose)

Population: ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)

The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) event evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

Outcome measures

Measure	Placebo n=115 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=115 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=115 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=116 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
SVPB Total Day 29 6.5 h	109 participants	112 participants	109 participants	108 participants	107 participants
SVPB Total Day 29 1st h	83 participants	79 participants	75 participants	84 participants	75 participants
SVPB Total Day 26 6.5 h	111 participants	103 participants	106 participants	98 participants	105 participants
SVPB Total Day 26 1st h	82 participants	74 participants	75 participants	62 participants	66 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 6.5 hours (including pre dose)

Population: ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)

The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) run evaluated over the entire 6.5 h Holter monitoring period. Runs were defined as at least 3 premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

Outcome measures

Measure	Placebo n=115 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=115 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=115 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=116 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
SVPB Runs Day 29 6.5 h	47 participants	36 participants	44 participants	34 participants	39 participants
SVPB Runs Day 29 1st h	9 participants	16 participants	8 participants	5 participants	6 participants
SVPB Runs Day 26 6.5 h	35 participants	34 participants	29 participants	36 participants	34 participants
SVPB Runs Day 26 1st h	12 participants	6 participants	9 participants	11 participants	10 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 6.5 hours (including pre dose)

Population: ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)

The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) pair evaluated over the entire 6.5 h Holter monitoring period. Pairs were defined as 2 consecutive premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

Outcome measures

Measure	Placebo n=115 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=115 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=115 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=116 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
SVPB Pairs Day 29 6.5 h	48 participants	52 participants	55 participants	49 participants	53 participants
SVPB Pairs Day 29 1st h	17 participants	20 participants	19 participants	20 participants	16 participants
SVPB Pairs Day 26 6.5 h	41 participants	46 participants	29 participants	42 participants	45 participants
SVPB Pairs Day 26 1st h	18 participants	13 participants	10 participants	14 participants	13 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 6.5 hours (including pre dose)

Population: ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)

The outcome measure describes the number of patients with a Supraventricular Premature Beat (SVPB) single evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

Outcome measures

Measure	Placebo n=115 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=115 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=115 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=116 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
SVPB Singles Day 29 6.5 h	109 participants	112 participants	109 participants	108 participants	107 participants
SVPB Singles Day 29 1st h	82 participants	77 participants	72 participants	82 participants	73 participants
SVPB Singles Day 26 6.5 h	111 participants	102 participants	106 participants	98 participants	105 participants
SVPB Singles Day 26 1st h	78 participants	74 participants	74 participants	61 participants	64 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 6.5 hours (including pre dose)

Population: ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)

The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) event evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

Outcome measures

Measure	Placebo n=115 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=115 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=115 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=116 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
VPB Total Day 29 6.5 h	91 participants	99 participants	90 participants	96 participants	96 participants
VPB Total Day 29 1st h	59 participants	63 participants	58 participants	50 participants	59 participants
VPB Total Day 26 6.5 h	92 participants	82 participants	83 participants	89 participants	88 participants
VPB Total Day 26 1st h	59 participants	49 participants	49 participants	49 participants	56 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 6.5 hours (including pre dose)

Population: ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)

The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) run evaluated over the entire 6.5 h Holter monitoring period. Runs were defined as at least 3 premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

Outcome measures

Measure	Placebo n=115 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=115 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=115 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=116 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
VPB Runs Day 29 6.5 h	3 participants	5 participants	4 participants	10 participants	9 participants
VPB Runs Day 29 1st h	0 participants	3 participants	2 participants	2 participants	1 participants
VPB Runs Day 26 6.5 h	8 participants	7 participants	8 participants	9 participants	9 participants
VPB Runs Day 26 1st h	0 participants	2 participants	1 participants	4 participants	3 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 6.5 hours (including pre dose)

Population: ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)

The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) pair evaluated over the entire 6.5 h Holter monitoring period. Pairs were defined as 2 consecutive premature beats in a row. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

Outcome measures

Measure	Placebo n=115 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=115 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=115 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=116 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
VPB Pairs Day 29 6.5 h	24 participants	19 participants	21 participants	16 participants	22 participants
VPB Pairs Day 29 1st h	8 participants	6 participants	6 participants	6 participants	7 participants
VPB Pairs Day 26 6.5 h	24 participants	20 participants	19 participants	21 participants	22 participants
VPB Pairs Day 26 1st h	7 participants	10 participants	7 participants	6 participants	10 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 6.5 hours (including pre dose)

Population: ECGFAS - including all patients in the treated set for whom continuous 12 lead ECGs (Holter monitoring) were recorded on at least one occasion (pacemaker patients were excluded)

The outcome measure describes the number of patients with a Ventricular Premature Beat (VPB) single evaluated over the entire 6.5 h Holter monitoring period. The arrhythmia variables were pre-specified for day 29 and analysed post-hoc for day 26. The lines "Day 29 1st h" and "Day 26 1st h" are related to the interval 0 h to 1 h, i.e. the first hour after dosing.

Outcome measures

Measure	Placebo n=115 Participants Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=115 Participants Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=115 Participants Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=116 Participants Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=113 Participants Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
VPB Singles Day 29 6.5 h	91 participants	99 participants	89 participants	94 participants	96 participants
VPB Singles Day 29 1st h	59 participants	63 participants	58 participants	50 participants	58 participants
VPB Singles Day 26 6.5 h	92 participants	82 participants	81 participants	88 participants	88 participants
VPB Singles Day 26 1st h	59 participants	49 participants	48 participants	49 participants	55 participants

Adverse Events

Placebo

Serious events: 3 serious events

Other events: 20 other events

Deaths: 0 deaths

Tio R1.25

Serious events: 2 serious events

Other events: 11 other events

Deaths: 0 deaths

Tio R2.5

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Tio R5

Serious events: 3 serious events

Other events: 16 other events

Deaths: 0 deaths

Tio HH18

Serious events: 2 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=147 participants at risk Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=147 participants at risk Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=145 participants at risk Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=150 participants at risk Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=146 participants at risk Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Gastrointestinal disorders Colitis ischaemic	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/145 • 4 weeks + 30 days if in last period	0.67% 1/150 • 4 weeks + 30 days if in last period	0.00% 0/146 • 4 weeks + 30 days if in last period
Gastrointestinal disorders Haemorrhoidal haemorrhage	0.68% 1/147 • 4 weeks + 30 days if in last period	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/145 • 4 weeks + 30 days if in last period	0.00% 0/150 • 4 weeks + 30 days if in last period	0.00% 0/146 • 4 weeks + 30 days if in last period
Gastrointestinal disorders Pancreatitis	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/145 • 4 weeks + 30 days if in last period	0.67% 1/150 • 4 weeks + 30 days if in last period	0.00% 0/146 • 4 weeks + 30 days if in last period
Infections and infestations Infective exacerbation of chronic obstructive airways disease	0.68% 1/147 • 4 weeks + 30 days if in last period	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/145 • 4 weeks + 30 days if in last period	0.00% 0/150 • 4 weeks + 30 days if in last period	0.00% 0/146 • 4 weeks + 30 days if in last period
Infections and infestations Pneumonia	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/145 • 4 weeks + 30 days if in last period	0.00% 0/150 • 4 weeks + 30 days if in last period	0.68% 1/146 • 4 weeks + 30 days if in last period
Injury, poisoning and procedural complications Tendon rupture	0.68% 1/147 • 4 weeks + 30 days if in last period	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/145 • 4 weeks + 30 days if in last period	0.00% 0/150 • 4 weeks + 30 days if in last period	0.00% 0/146 • 4 weeks + 30 days if in last period
Musculoskeletal and connective tissue disorders Spinal column stenosis	0.00% 0/147 • 4 weeks + 30 days if in last period	0.68% 1/147 • 4 weeks + 30 days if in last period	0.00% 0/145 • 4 weeks + 30 days if in last period	0.00% 0/150 • 4 weeks + 30 days if in last period	0.00% 0/146 • 4 weeks + 30 days if in last period
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/147 • 4 weeks + 30 days if in last period	0.68% 1/147 • 4 weeks + 30 days if in last period	0.00% 0/145 • 4 weeks + 30 days if in last period	0.00% 0/150 • 4 weeks + 30 days if in last period	0.00% 0/146 • 4 weeks + 30 days if in last period
Nervous system disorders Cerebrovascular accident	0.00% 0/147 • 4 weeks + 30 days if in last period	0.68% 1/147 • 4 weeks + 30 days if in last period	0.00% 0/145 • 4 weeks + 30 days if in last period	0.00% 0/150 • 4 weeks + 30 days if in last period	0.00% 0/146 • 4 weeks + 30 days if in last period
Renal and urinary disorders Azotaemia	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/145 • 4 weeks + 30 days if in last period	0.67% 1/150 • 4 weeks + 30 days if in last period	0.00% 0/146 • 4 weeks + 30 days if in last period
Renal and urinary disorders Renal tubular necrosis	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/145 • 4 weeks + 30 days if in last period	0.67% 1/150 • 4 weeks + 30 days if in last period	0.00% 0/146 • 4 weeks + 30 days if in last period
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.68% 1/147 • 4 weeks + 30 days if in last period	0.00% 0/147 • 4 weeks + 30 days if in last period	0.00% 0/145 • 4 weeks + 30 days if in last period	0.00% 0/150 • 4 weeks + 30 days if in last period	0.68% 1/146 • 4 weeks + 30 days if in last period

Other adverse events

Measure	Placebo n=147 participants at risk Matching Placebo once daily (qd) delivered by the Respimat inhaler	Tio R1.25 n=147 participants at risk Tiotropium inhalation solution 1.25 mcg delivered by the Respimat inhaler qd in the morning	Tio R2.5 n=145 participants at risk Tiotropium inhalation solution 2.5 mcg delivered by the Respimat inhaler qd in the morning	Tio R5 n=150 participants at risk Tiotropium inhalation solution 5 mcg delivered by the Respimat inhaler qd in the morning	Tio HH18 n=146 participants at risk Open-label tiotropium inhalation capsule 18 mcg delivered by the HandiHaler qd in the morning
Infections and infestations Nasopharyngitis	4.1% 6/147 • 4 weeks + 30 days if in last period	6.1% 9/147 • 4 weeks + 30 days if in last period	1.4% 2/145 • 4 weeks + 30 days if in last period	9.3% 14/150 • 4 weeks + 30 days if in last period	4.8% 7/146 • 4 weeks + 30 days if in last period
Respiratory, thoracic and mediastinal disorders Dyspnoea	9.5% 14/147 • 4 weeks + 30 days if in last period	3.4% 5/147 • 4 weeks + 30 days if in last period	1.4% 2/145 • 4 weeks + 30 days if in last period	2.0% 3/150 • 4 weeks + 30 days if in last period	2.1% 3/146 • 4 weeks + 30 days if in last period

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 Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication
• Publication restrictions are in place

Restriction type: OTHER