Trial Outcomes & Findings for Tiotropium / Respimat One-Year Study (NCT NCT00168831)

NCT ID: NCT00168831

Last Updated: 2014-05-20

Results Overview

Change From Baseline in Trough Forced Expiratory Volume in 1 second (FEV1) after 48 weeks

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1007 participants
• Primary outcome timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication
• Results posted on: 2014-05-20

Participant Flow

Participant milestones

Measure	Tiotropium Respimat 5mcg (Tio R5) Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg (Tio R10) Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Overall Study STARTED	338	335	334
Overall Study COMPLETED	278	254	220
Overall Study NOT COMPLETED	60	81	114

Reasons for withdrawal

Measure	Tiotropium Respimat 5mcg (Tio R5) Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg (Tio R10) Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Overall Study Adverse Event	36	47	74
Overall Study Lost to Follow-up	5	6	4
Overall Study Withdrawal by Subject	7	14	19
Overall Study Protocol Violation	6	11	11
Overall Study Other	6	3	6

Baseline Characteristics

Tiotropium / Respimat One-Year Study

Baseline characteristics by cohort

Measure	Tiotropium Respimat 5mcg n=338 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=335 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=334 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)	Total n=1007 Participants Total of all reporting groups
Age, Continuous	64.4 years STANDARD_DEVIATION 8.9 • n=93 Participants	65.6 years STANDARD_DEVIATION 8.6 • n=4 Participants	65.7 years STANDARD_DEVIATION 8.4 • n=27 Participants	65.2 years STANDARD_DEVIATION 8.7 • n=483 Participants
Sex: Female, Male Female	90 Participants n=93 Participants	89 Participants n=4 Participants	99 Participants n=27 Participants	278 Participants n=483 Participants
Sex: Female, Male Male	248 Participants n=93 Participants	246 Participants n=4 Participants	235 Participants n=27 Participants	729 Participants n=483 Participants

PRIMARY outcome

Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication

Population: Full Analysis Set - Clinic Spirometry (FAS-PFT)

Change From Baseline in Trough Forced Expiratory Volume in 1 second (FEV1) after 48 weeks

Outcome measures

Measure	Tiotropium Respimat 5mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=307 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Trough FEV1 After 48 Weeks	0.077 Litres Standard Error 0.012	0.105 Litres Standard Error 0.012	-0.036 Litres Standard Error 0.012

PRIMARY outcome

Timeframe: Week 48

Population: Full Analysis Set - Saint George's Respiratory Questionnaire (FAS-QOL)

Rating scale of 3 domains - symptoms, activities and impact (weighted). Worst score = 100, best score = 0

Outcome measures

Measure	Tiotropium Respimat 5mcg n=310 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=276 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Saint George's Respiratory Questionnaire (SGRQ) Total Score, Full Analysis Set - Saint George's Respiratory Questionnaire (FAS-QOL)	39.771 Points on a scale Standard Error 0.718	40.038 Points on a scale Standard Error 0.726	43.484 Points on a scale Standard Error 0.763

PRIMARY outcome

Timeframe: Week 48

Population: Full Analysis Set - Transitional Dyspnoea Index (FAS-TDI)

Rating scale of 3 components - change in functional impairment, change in magnitude of tasks, change in magnitude of efforts. Worst score = -9, best score = +9

For this endpoint data of twin studies NCT00168844 and NCT00168831 was combined.

Outcome measures

Measure	Tiotropium Respimat 5mcg n=628 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=618 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=552 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
TDI Focal Score, Full Analysis Set - Transitional Dyspnoea Index (FAS-TDI) (Combined Studies)	1.890 Points on a scale Standard Error 0.112	1.913 Points on a scale Standard Error 0.113	0.837 Points on a scale Standard Error 0.120

PRIMARY outcome

Timeframe: 48 weeks

Population: Safety Set. Combined analysis of studies NCT00168844 and NCT00168831. 670 patients analysed in total comprises 338 patients from NCT00168831 and 332 patients from study NCT00168844, 667 patients - 335 and 332, 653 patients - 334 and 319 respectively.

Number of Chronic Obstructive Pulmonary Disease (COPD) exacerbations per patient year

For this endpoint data of the twin studies NCT00168844 and NCT00168831 was combined.

Outcome measures

Measure	Tiotropium Respimat 5mcg n=670 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=667 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=653 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
COPD Exacerbation Rate, Safety Set (SS) (Combined Studies)	0.93 Number of exacerbations per patient year Standard Deviation 2.02	1.02 Number of exacerbations per patient year Standard Deviation 3.05	1.91 Number of exacerbations per patient year Standard Deviation 8.17

SECONDARY outcome

Timeframe: Baseline to Week 40 pre-dose

Population: Combined analysis of studies NCT00168844 and NCT00168831 in subset of patients who had additional 12-lead electrocardiogram (ECG) and 24-hour Holter monitoring performed (see protocol and clinical trial report)

Week 40 pre-dose - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=155 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=135 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=109 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Heart Rate	2.1 beats per minute (bpm) Standard Deviation 12.4	3.6 beats per minute (bpm) Standard Deviation 10.5	1.8 beats per minute (bpm) Standard Deviation 9.7

SECONDARY outcome

Timeframe: Baseline to Week 40 pre-dose

Population: Combined analysis of studies NCT00168844 and NCT00168831 in subset of patients who had additional 12-lead electrocardiogram (ECG) and 24-hour Holter monitoring performed (see protocol and clinical trial report)

Outcome measures

Measure	Tiotropium Respimat 5mcg n=150 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=131 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=105 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in PR Interval	-0.8 milliseconds (msec) Standard Deviation 20.2	-2.5 milliseconds (msec) Standard Deviation 15.1	-0.5 milliseconds (msec) Standard Deviation 15.3

SECONDARY outcome

Timeframe: Baseline to Week 40 pre-dose

Population: Combined analysis of studies NCT00168844 and NCT00168831 in subset of patients who had additional 12-lead ECG and 24-hour Holter monitoring performed (see protocol and clinical trial report)

Week 40 pre-dose - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=155 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=135 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=109 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in QRS Interval	0.9 msec Standard Deviation 9.4	1.7 msec Standard Deviation 12.1	-1.1 msec Standard Deviation 10.3

SECONDARY outcome

Timeframe: Baseline to Week 40 pre-dose

Population: Combined analysis of studies NCT00168844 and NCT00168831 in subset of patients who had additional 12-lead ECG and 24-hour Holter monitoring performed (see protocol and clinical trial report)

Week 40 pre-dose - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=155 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=135 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=109 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in QT Interval	-4.6 msec Standard Deviation 26.5	-3.5 msec Standard Deviation 25.2	-3.2 msec Standard Deviation 22.3

SECONDARY outcome

Timeframe: Baseline to Week 40 pre-dose

Population: Combined analysis of studies NCT00168844 and NCT00168831 in subset of patients who had additional 12-lead ECG and 24-hour Holter monitoring performed (see protocol and clinical trial report)

Week 40 pre-dose - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=155 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=135 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=109 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in QT Interval (Bazett)	-0.5 msec Standard Deviation 29.9	5.4 msec Standard Deviation 24.0	2.5 msec Standard Deviation 23.4

SECONDARY outcome

Timeframe: Baseline to Week 40 pre-dose

Population: Combined analysis of studies NCT00168844 and NCT00168831 in subset of patients who had additional 12-lead ECG and 24-hour Holter monitoring performed (see protocol and clinical trial report)

Week 40 pre-dose - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=155 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=135 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=109 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in QT Interval (Fridericia)	-2.0 msec Standard Deviation 24.3	2.2 msec Standard Deviation 21.3	0.5 msec Standard Deviation 19.5

SECONDARY outcome

Timeframe: Baseline to Week 40

Population: Combined analysis of studies NCT00168844 and NCT00168831 in subset of patients who had additional 12-lead ECG and 24-hour Holter monitoring performed (see protocol and clinical trial report)

Week 40 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=77 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=66 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=56 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Heart Rate	0.3 bpm Standard Deviation 5.4	1.2 bpm Standard Deviation 6.4	0.3 bpm Standard Deviation 6.6

SECONDARY outcome

Timeframe: Baseline to Week 40

Population: Combined analysis of studies NCT00168844 and NCT00168831 in subset of patients who had additional 12-lead ECG and 24-hour Holter monitoring performed (see protocol and clinical trial report)

Week 40 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=77 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=66 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=56 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Supraventricular Premature Beat (SVPB) Total	-3.4 premature beats per 24 hours Standard Deviation 94.2	6.8 premature beats per 24 hours Standard Deviation 87.4	20.9 premature beats per 24 hours Standard Deviation 125.8

SECONDARY outcome

Timeframe: Baseline to Week 40

Population: Combined analysis of studies NCT00168844 and NCT00168831 in subset of patients who had additional 12-lead ECG and 24-hour Holter monitoring performed (see protocol and clinical trial report)

Week 40 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=77 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=66 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=56 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in SVPB Run Events	0.0 events per 24 hours Standard Deviation 0.6	-0.1 events per 24 hours Standard Deviation 0.5	-0.1 events per 24 hours Standard Deviation 1.6

SECONDARY outcome

Timeframe: Baseline to Week 40

Population: Combined analysis of studies NCT00168844 and NCT00168831 in subset of patients who had additional 12-lead ECG and 24-hour Holter monitoring performed (see protocol and clinical trial report)

Week 40 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=77 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=66 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=56 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in SVPB Pairs	-0.4 pairs per 24 hours Standard Deviation 4.0	-0.2 pairs per 24 hours Standard Deviation 2.3	2.0 pairs per 24 hours Standard Deviation 16.4

SECONDARY outcome

Timeframe: Baseline to Week 40

Population: Combined analysis of studies NCT00168844 and NCT00168831 in subset of patients who had additional 12-lead ECG and 24-hour Holter monitoring performed (see protocol and clinical trial report)

Week 40 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=77 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=66 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=56 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Ventricular Premature Beat (VPB) Total	-14.3 premature beats per 24 hours Standard Deviation 105.9	4.6 premature beats per 24 hours Standard Deviation 68.8	-24.1 premature beats per 24 hours Standard Deviation 182.3

SECONDARY outcome

Timeframe: Baseline to Week 40

Population: Combined analysis of studies NCT00168844 and NCT00168831 in subset of patients who had additional 12-lead ECG and 24-hour Holter monitoring performed (see protocol and clinical trial report)

Week 40 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=77 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=66 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=56 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Ventricular Premature Beat (VPB) Run Events	0.0 events per 24 hours Standard Deviation 0.1	0.0 events per 24 hours Standard Deviation 0.1	0.0 events per 24 hours Standard Deviation 0.0

SECONDARY outcome

Timeframe: Baseline to Week 40

Population: Combined analysis of studies NCT00168844 and NCT00168831 in subset of patients who had additional 12-lead ECG and 24-hour Holter monitoring performed (see protocol and clinical trial report)

Week 40 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=77 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=66 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=56 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in VPB Pairs	-0.2 pairs per 24 hours Standard Deviation 1.6	-0.1 pairs per 24 hours Standard Deviation 3.8	-0.9 pairs per 24 hours Standard Deviation 5.7

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Outcome measures

Measure	Tiotropium Respimat 5mcg n=289 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=274 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=268 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Haematocrit, Packed Cell Volume (PCV)	0 Percentage of erythrocytes Standard Deviation 4	0 Percentage of erythrocytes Standard Deviation 4	0 Percentage of erythrocytes Standard Deviation 4

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=299 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=280 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=276 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Haemoglobin	0 grams per litre (g/L) Standard Deviation 11	-1 grams per litre (g/L) Standard Deviation 10	-1 grams per litre (g/L) Standard Deviation 12

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=298 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=279 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=275 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Red Blood Cell Count	0.0 10^12/Litre (L) Standard Deviation 0.3	0.0 10^12/Litre (L) Standard Deviation 0.3	0.0 10^12/Litre (L) Standard Deviation 0.3

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=299 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=280 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=276 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in White Blood Cell Count	0.2 10^9/Litre (L) Standard Deviation 1.7	0.3 10^9/Litre (L) Standard Deviation 1.5	0.2 10^9/Litre (L) Standard Deviation 1.5

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=292 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=274 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=272 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Platelets	5 10^9/L Standard Deviation 31	3 10^9/L Standard Deviation 29	0 10^9/L Standard Deviation 35

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=296 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=276 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=274 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Neutrophils	1 percentage of white blood cell count Standard Deviation 8	1 percentage of white blood cell count Standard Deviation 8	0 percentage of white blood cell count Standard Deviation 8

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=296 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=276 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=274 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Eosinophils	0 percentage of white blood cell count Standard Deviation 2	0 percentage of white blood cell count Standard Deviation 2	0 percentage of white blood cell count Standard Deviation 2

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=296 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=276 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=274 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Basophils	0 percentage of white blood cell count Standard Deviation 0	0 percentage of white blood cell count Standard Deviation 0	0 percentage of white blood cell count Standard Deviation 0

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=296 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=276 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=274 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Lymphocytes	-1 percentage of white blood cell count Standard Deviation 4	-1 percentage of white blood cell count Standard Deviation 4	0 percentage of white blood cell count Standard Deviation 4

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=296 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=276 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=274 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Monocytes	0 percentage of white blood cell count Standard Deviation 4	0 percentage of white blood cell count Standard Deviation 4	0 percentage of white blood cell count Standard Deviation 4

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=296 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=276 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=274 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Neutrophils (Absolute)	0.2 10^9/L Standard Deviation 1.9	0.3 10^9/L Standard Deviation 1.6	0.2 10^9/L Standard Deviation 1.6

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=296 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=276 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=274 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Eosinophils (Absolute)	0.0 10^9/L Standard Deviation 0.1	0.0 10^9/L Standard Deviation 0.1	0.0 10^9/L Standard Deviation 0.1

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=296 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=276 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=274 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Basophils (Absolute)	0.0 10^9/L Standard Deviation 0.1	0.0 10^9/L Standard Deviation 0.1	0.0 10^9/L Standard Deviation 0.1

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=296 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=276 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=274 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Lymphocytes (Absolute)	-0.1 10^9/L Standard Deviation 0.6	0.0 10^9/L Standard Deviation 0.7	0.0 10^9/L Standard Deviation 0.7

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=296 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=276 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=274 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Monocytes (Absolute)	0.0 10^9/L Standard Deviation 0.3	0.0 10^9/L Standard Deviation 0.3	0.0 10^9/L Standard Deviation 0.3

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=284 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=277 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Calcium	0.0 millimoles per litre (mmol/L) Standard Deviation 0.1	0.0 millimoles per litre (mmol/L) Standard Deviation 0.1	0.0 millimoles per litre (mmol/L) Standard Deviation 0.2

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=284 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=277 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Phosphate	0.01 mmol/L Standard Deviation 0.23	0.00 mmol/L Standard Deviation 0.24	0.02 mmol/L Standard Deviation 0.26

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=284 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=277 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Aspartate Transaminase/Glutamic-oxaloacetic Transaminase (AST/GOT), Serum Glutamic-oxaloacetic Transaminase (SGOT)	-1 Units per litre (U/L) Standard Deviation 20	-1 Units per litre (U/L) Standard Deviation 25	-2 Units per litre (U/L) Standard Deviation 13

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=284 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=277 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Alanine Transaminase/Glutamic Pyruvate Transaminase (ALT/GPT), Serum Glutamate Pyruvate Transaminase (SGPT)	-1 U/L Standard Deviation 18	-1 U/L Standard Deviation 18	-1 U/L Standard Deviation 13

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=284 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=277 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Alkaline Phosphatase	-4 U/L Standard Deviation 19	-5 U/L Standard Deviation 23	-3 U/L Standard Deviation 27

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=302 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=282 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=276 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Lactic Dehyrogenase (LDH)	1 U/L Standard Deviation 40	3 U/L Standard Deviation 44	5 U/L Standard Deviation 42

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=303 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=280 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=276 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Glucose	0.02 mmol/L Standard Deviation 2.11	0.26 mmol/L Standard Deviation 2.17	0.10 mmol/L Standard Deviation 2.34

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=284 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=277 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Urea	-0.2 mmol/L Standard Deviation 1.9	0.0 mmol/L Standard Deviation 2.1	0.1 mmol/L Standard Deviation 2.2

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=284 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=277 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Blood Urea Nitrogen	-0.3 milligrams per decilitre (mg/dL) Standard Deviation 3.0	0.0 milligrams per decilitre (mg/dL) Standard Deviation 3.3	0.2 milligrams per decilitre (mg/dL) Standard Deviation 3.5

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=284 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=277 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Creatinine	2.2 micromoles per litre (umol/L) Standard Deviation 9.3	1.5 micromoles per litre (umol/L) Standard Deviation 12.2	2.1 micromoles per litre (umol/L) Standard Deviation 10.5

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=284 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=277 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Bilirubin, Total	-0.2 umol/L Standard Deviation 5.2	0.4 umol/L Standard Deviation 4.2	-0.1 umol/L Standard Deviation 4.6

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=284 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=277 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Uric Acid	16.41 umol/L Standard Deviation 80.08	9.39 umol/L Standard Deviation 85.92	6.52 umol/L Standard Deviation 76.49

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=284 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=277 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Protein, Total	-1 grams per litre (g/L) Standard Deviation 5	-1 grams per litre (g/L) Standard Deviation 5	-1 grams per litre (g/L) Standard Deviation 6

SECONDARY outcome

Timeframe: Baseline to Week 48 or at premature discontinuation if before Week 48

Population: Safety Set

Week 48 - baseline

Outcome measures

Measure	Tiotropium Respimat 5mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=284 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=277 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Albumin	1 g/L Standard Deviation 4	1 g/L Standard Deviation 4	1 g/L Standard Deviation 4

SECONDARY outcome

Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication

Population: Full Analysis Set - Clinic Spirometry (FAS-PFT)

Change From Baseline in Trough Forced Expiratory Volume in 1 second (FEV1) after 2, 8, 16, 24, 32 and 40 weeks. The means are adjusted for centre, smoking status at entry and baseline value.

Outcome measures

Measure	Tiotropium Respimat 5mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=307 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Trough FEV1 After 2, 8, 16, 24, 32 and 40 Weeks Week 2	0.111 Litres Standard Error 0.010	0.114 Litres Standard Error 0.010	-0.003 Litres Standard Error 0.011
Change From Baseline in Trough FEV1 After 2, 8, 16, 24, 32 and 40 Weeks Week 8	0.099 Litres Standard Error 0.011	0.133 Litres Standard Error 0.011	-0.012 Litres Standard Error 0.011
Change From Baseline in Trough FEV1 After 2, 8, 16, 24, 32 and 40 Weeks Week 16	0.118 Litres Standard Error 0.012	0.132 Litres Standard Error 0.012	-0.008 Litres Standard Error 0.012
Change From Baseline in Trough FEV1 After 2, 8, 16, 24, 32 and 40 Weeks Week 24	0.104 Litres Standard Error 0.012	0.132 Litres Standard Error 0.012	-0.010 Litres Standard Error 0.012
Change From Baseline in Trough FEV1 After 2, 8, 16, 24, 32 and 40 Weeks Week 32	0.095 Litres Standard Error 0.012	0.145 Litres Standard Error 0.012	-0.012 Litres Standard Error 0.013
Change From Baseline in Trough FEV1 After 2, 8, 16, 24, 32 and 40 Weeks Week 40	0.091 Litres Standard Error 0.012	0.106 Litres Standard Error 0.012	-0.027 Litres Standard Error 0.012

SECONDARY outcome

Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication

Population: Full Analysis Set - Clinic Spirometry (FAS-PFT)

Change From Baseline in Trough Forced vital capacity (FVC) after 2, 8, 16, 24, 32, 40 and 48 weeks. The means are adjusted for centre, smoking status at entry and baseline value.

Outcome measures

Measure	Tiotropium Respimat 5mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=307 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in Trough FVC After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 16	0.259 Litres Standard Error 0.025	0.266 Litres Standard Error 0.025	-0.002 Litres Standard Error 0.025
Change From Baseline in Trough FVC After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 2	0.257 Litres Standard Error 0.021	0.264 Litres Standard Error 0.022	0.009 Litres Standard Error 0.022
Change From Baseline in Trough FVC After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 8	0.207 Litres Standard Error 0.023	0.266 Litres Standard Error 0.023	-0.007 Litres Standard Error 0.024
Change From Baseline in Trough FVC After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 24	0.236 Litres Standard Error 0.025	0.274 Litres Standard Error 0.025	0.008 Litres Standard Error 0.025
Change From Baseline in Trough FVC After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 32	0.203 Litres Standard Error 0.026	0.286 Litres Standard Error 0.026	-0.008 Litres Standard Error 0.027
Change From Baseline in Trough FVC After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 40	0.211 Litres Standard Error 0.025	0.207 Litres Standard Error 0.025	-0.028 Litres Standard Error 0.026
Change From Baseline in Trough FVC After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 48	0.197 Litres Standard Error 0.026	0.209 Litres Standard Error 0.026	-0.043 Litres Standard Error 0.026

SECONDARY outcome

Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication

Population: Full Analysis Set - Clinic Spirometry (FAS-PFT)

FEV1 AUC0-3 represents the Area under Curve over the time interval from 0 to 3 hours after 2, 8, 16, 24, 32, 40 and 48 weeks. The means are adjusted for centre, smoking status at entry and baseline value.

Outcome measures

Measure	Tiotropium Respimat 5mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=307 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in FEV1 AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 2	0.246 Litres Standard Error 0.011	0.257 Litres Standard Error 0.011	0.044 Litres Standard Error 0.012
Change From Baseline in FEV1 AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 8	0.234 Litres Standard Error 0.012	0.258 Litres Standard Error 0.012	0.037 Litres Standard Error 0.013
Change From Baseline in FEV1 AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 16	0.235 Litres Standard Error 0.012	0.242 Litres Standard Error 0.012	0.026 Litres Standard Error 0.013
Change From Baseline in FEV1 AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 24	0.222 Litres Standard Error 0.012	0.245 Litres Standard Error 0.012	0.024 Litres Standard Error 0.013
Change From Baseline in FEV1 AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 32	0.198 Litres Standard Error 0.013	0.241 Litres Standard Error 0.013	0.018 Litres Standard Error 0.013
Change From Baseline in FEV1 AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 40	0.197 Litres Standard Error 0.012	0.206 Litres Standard Error 0.012	-0.000 Litres Standard Error 0.012
Change From Baseline in FEV1 AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 48	0.181 Litres Standard Error 0.013	0.210 Litres Standard Error 0.013	-0.002 Litres Standard Error 0.013

SECONDARY outcome

Timeframe: 10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication

Population: Full Analysis Set - Clinic Spirometry (FAS-PFT)

FVC AUC0-3 represents the Area under Curve over the time interval from 0 to 3 hours after 2, 8, 16, 24, 32, 40 and 48 weeks. The means are adjusted for centre, smoking status at entry and baseline value.

Outcome measures

Measure	Tiotropium Respimat 5mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=307 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Change From Baseline in FVC AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 2	0.513 Litres Standard Error 0.024	0.522 Litres Standard Error 0.024	0.140 Litres Standard Error 0.025
Change From Baseline in FVC AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 8	0.463 Litres Standard Error 0.026	0.521 Litres Standard Error 0.026	0.117 Litres Standard Error 0.027
Change From Baseline in FVC AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 16	0.466 Litres Standard Error 0.026	0.488 Litres Standard Error 0.026	0.108 Litres Standard Error 0.027
Change From Baseline in FVC AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 24	0.468 Litres Standard Error 0.027	0.498 Litres Standard Error 0.027	0.092 Litres Standard Error 0.027
Change From Baseline in FVC AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 32	0.438 Litres Standard Error 0.027	0.477 Litres Standard Error 0.027	0.075 Litres Standard Error 0.028
Change From Baseline in FVC AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 40	0.417 Litres Standard Error 0.027	0.406 Litres Standard Error 0.027	0.029 Litres Standard Error 0.028
Change From Baseline in FVC AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks Week 48	0.387 Litres Standard Error 0.028	0.411 Litres Standard Error 0.028	0.018 Litres Standard Error 0.029

SECONDARY outcome

Timeframe: Weeks 2, 8, 16, 24, 32, 40, 48

Population: Full Analysis Set - Diary (FAS-DRY)

Weekly mean morning pre-dose peak expiratory flow rates (PEFRs). The means are adjusted for centre, smoking status at entry, and baseline value.

Outcome measures

Measure	Tiotropium Respimat 5mcg n=322 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=308 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Weekly Mean Morning Pre-dose PEFRs Week 24	260.5 Litres/minute Standard Error 3.2	263.8 Litres/minute Standard Error 3.2	230.9 Litres/minute Standard Error 3.2
Weekly Mean Morning Pre-dose PEFRs Week 2	245.7 Litres/minute Standard Error 1.6	245.4 Litres/minute Standard Error 1.6	226.9 Litres/minute Standard Error 1.6
Weekly Mean Morning Pre-dose PEFRs Week 8	252.4 Litres/minute Standard Error 2.3	253.9 Litres/minute Standard Error 2.3	229.4 Litres/minute Standard Error 2.4
Weekly Mean Morning Pre-dose PEFRs Week 16	257.5 Litres/minute Standard Error 2.8	258.4 Litres/minute Standard Error 2.8	231.6 Litres/minute Standard Error 2.9
Weekly Mean Morning Pre-dose PEFRs Week 32	261.5 Litres/minute Standard Error 3.2	264.6 Litres/minute Standard Error 3.2	232.6 Litres/minute Standard Error 3.3
Weekly Mean Morning Pre-dose PEFRs Week 40	260.7 Litres/minute Standard Error 3.2	264.7 Litres/minute Standard Error 3.2	231.1 Litres/minute Standard Error 3.3
Weekly Mean Morning Pre-dose PEFRs Week 48	260.3 Litres/minute Standard Error 3.4	264.1 Litres/minute Standard Error 3.4	232.4 Litres/minute Standard Error 3.5

SECONDARY outcome

Timeframe: Weeks 2, 8, 16, 24, 32, 40, 48

Population: Full Analysis Set - Diary (FAS-DRY)

Weekly mean evening peak expiratory flow rates (PEFRs). The means are adjusted for centre, smoking status at entry, and baseline value.

Outcome measures

Measure	Tiotropium Respimat 5mcg n=319 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=322 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=309 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Weekly Mean Morning Evening PEFRs Week 2	262.7 Litres/minute Standard Error 1.7	265.0 Litres/minute Standard Error 1.7	237.5 Litres/minute Standard Error 1.7
Weekly Mean Morning Evening PEFRs Week 8	267.9 Litres/minute Standard Error 2.5	273.5 Litres/minute Standard Error 2.5	240.6 Litres/minute Standard Error 2.5
Weekly Mean Morning Evening PEFRs Week 16	272.7 Litres/minute Standard Error 3.0	276.3 Litres/minute Standard Error 3.0	240.8 Litres/minute Standard Error 3.1
Weekly Mean Morning Evening PEFRs Week 24	275.5 Litres/minute Standard Error 3.2	280.3 Litres/minute Standard Error 3.2	241.9 Litres/minute Standard Error 3.3
Weekly Mean Morning Evening PEFRs Week 32	276.6 Litres/minute Standard Error 3.3	279.7 Litres/minute Standard Error 3.2	241.0 Litres/minute Standard Error 3.3
Weekly Mean Morning Evening PEFRs Week 40	274.0 Litres/minute Standard Error 3.3	280.5 Litres/minute Standard Error 3.2	240.5 Litres/minute Standard Error 3.2
Weekly Mean Morning Evening PEFRs Week 48	274.0 Litres/minute Standard Error 3.4	281.0 Litres/minute Standard Error 3.4	241.9 Litres/minute Standard Error 3.5

SECONDARY outcome

Timeframe: Weeks 2, 8, 16, 24, 32, 40, 48

Population: Full Analysis Set - Diary (FAS-DRY)

Weekly mean number of puffs of rescue medication used per day as required (PRN salbutamol). The means are adjusted for centre, smoking status at entry, and baseline value.

Outcome measures

Measure	Tiotropium Respimat 5mcg n=321 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=311 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Weekly Mean Number of Puffs of Rescue Medication Per Day Week 2	2.0 Puffs Standard Error 0.1	2.0 Puffs Standard Error 0.1	2.8 Puffs Standard Error 0.1
Weekly Mean Number of Puffs of Rescue Medication Per Day Week 8	2.3 Puffs Standard Error 0.1	2.0 Puffs Standard Error 0.1	3.0 Puffs Standard Error 0.1
Weekly Mean Number of Puffs of Rescue Medication Per Day Week 16	2.5 Puffs Standard Error 0.1	2.1 Puffs Standard Error 0.1	3.0 Puffs Standard Error 0.1
Weekly Mean Number of Puffs of Rescue Medication Per Day Week 24	2.5 Puffs Standard Error 0.1	2.3 Puffs Standard Error 0.1	3.0 Puffs Standard Error 0.1
Weekly Mean Number of Puffs of Rescue Medication Per Day Week 32	2.7 Puffs Standard Error 0.1	2.3 Puffs Standard Error 0.1	3.1 Puffs Standard Error 0.1
Weekly Mean Number of Puffs of Rescue Medication Per Day Week 40	2.7 Puffs Standard Error 0.1	2.4 Puffs Standard Error 0.1	3.2 Puffs Standard Error 0.1
Weekly Mean Number of Puffs of Rescue Medication Per Day Week 48	2.8 Puffs Standard Error 0.1	2.5 Puffs Standard Error 0.1	3.2 Puffs Standard Error 0.1

SECONDARY outcome

Timeframe: Week 48

Population: Full Analysis Set - Transitional Dyspnoea Index (FAS-TDI)

Mahler Transitional Dyspnoea Index (TDI) scores measured as change in functional impairment, change in magnitude of tasks and change in magnitude of efforts over the treatment period. The means are adjusted for centre, smoking status at entry and baseline value.

Worst score = -3, best score = +3

Outcome measures

Measure	Tiotropium Respimat 5mcg n=310 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=305 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=279 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Mahler TDI Scores Functional Impairment	0.630 Points on a scale Standard Error 0.057	0.577 Points on a scale Standard Error 0.057	0.318 Points on a scale Standard Error 0.060
Mahler TDI Scores Magnitude of Task	0.654 Points on a scale Standard Error 0.057	0.621 Points on a scale Standard Error 0.057	0.275 Points on a scale Standard Error 0.060
Mahler TDI Scores Magnitude of Effort	0.604 Points on a scale Standard Error 0.061	0.594 Points on a scale Standard Error 0.062	0.264 Points on a scale Standard Error 0.065

SECONDARY outcome

Timeframe: Week 48

Population: Full Analysis Set - Saint George's Respiratory Questionnaire (FAS-QOL)

Saint George's Respiratory Questionnaire (SGRQ) Scores impacts, activities and symptoms. Worst score = 100, best score = 0.

The means are adjusted for centre, smoking status at entry and baseline value.

Outcome measures

Measure	Tiotropium Respimat 5mcg n=310 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=304 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=276 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Saint George's Respiratory Questionnaire (SGRQ) Scores Symptoms	40.680 Points on a scale Standard Error 1.116	42.108 Points on a scale Standard Error 1.128	48.244 Points on a scale Standard Error 1.185
Saint George's Respiratory Questionnaire (SGRQ) Scores Activities	58.529 Points on a scale Standard Error 0.897	57.045 Points on a scale Standard Error 0.906	60.921 Points on a scale Standard Error 0.953
Saint George's Respiratory Questionnaire (SGRQ) Scores Impacts	28.858 Points on a scale Standard Error 0.783	29.532 Points on a scale Standard Error 0.791	32.239 Points on a scale Standard Error 0.832

SECONDARY outcome

Timeframe: Week 48

Population: Full Analysis Set - COPD symptoms (FAS-SYM)

COPD symptoms Scores - wheezing, shortness of breath, coughing and tightness of chest over the treatment period.

Scale: 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe The means are adjusted for centre, smoking status at entry and baseline value.

Outcome measures

Measure	Tiotropium Respimat 5mcg n=325 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=304 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
COPD Symptoms Scores Wheezing	0.66 Points on a scale Standard Error 0.04	0.72 Points on a scale Standard Error 0.04	0.85 Points on a scale Standard Error 0.04
COPD Symptoms Scores Shortness of Breath	1.42 Points on a scale Standard Error 0.04	1.41 Points on a scale Standard Error 0.04	1.61 Points on a scale Standard Error 0.04
COPD Symptoms Scores Coughing	0.96 Points on a scale Standard Error 0.04	1.05 Points on a scale Standard Error 0.04	1.06 Points on a scale Standard Error 0.04
COPD Symptoms Scores Tightness of Chest	0.51 Points on a scale Standard Error 0.04	0.55 Points on a scale Standard Error 0.04	0.64 Points on a scale Standard Error 0.04

SECONDARY outcome

Timeframe: Week 48

Population: Full Analysis Set - Physician's Global Evaluation (FAS-PGE)

Physician's Global evaluation (PGE) scores over the treatment period. Scale: 1-2 = Poor, 3-4 = Fair, 5-6 = Good, 7-8 = Excellent The means are adjusted for centre, smoking status at entry and baseline value.

Outcome measures

Measure	Tiotropium Respimat 5mcg n=324 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=325 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=305 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
PGE Scores	4.90 Points on a scale Standard Error 0.06	4.84 Points on a scale Standard Error 0.06	4.44 Points on a scale Standard Error 0.06

SECONDARY outcome

Timeframe: Week 48

Population: Full Analysis Set - Patient's Global Rating (FAS-PGR)

Patient's Global rating (PGR) scores over the treatment period. Scale: 1=much better to 7=much worse The means are adjusted for centre, smoking status at entry and baseline value.

Outcome measures

Measure	Tiotropium Respimat 5mcg n=312 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg n=307 Participants Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo n=281 Participants Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
PGR Scores	2.88 Points on a scale Standard Error 0.08	2.94 Points on a scale Standard Error 0.08	3.42 Points on a scale Standard Error 0.08

Adverse Events

Tiotropium Respimat 5mcg

Serious events: 63 serious events

Other events: 177 other events

Deaths: 0 deaths

Tiotropium Respimat 10mcg

Serious events: 72 serious events

Other events: 174 other events

Deaths: 0 deaths

Placebo

Serious events: 56 serious events

Other events: 182 other events

Deaths: 0 deaths

Serious adverse events

Measure	Tiotropium Respimat 5mcg Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Gastrointestinal disorders Oesophageal stenosis	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Peritonitis	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Umbilical hernia	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Acute coronary syndrome	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Angina pectoris	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.60% 2/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Angina unstable	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.90% 3/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Arrhythmia	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Atrial fibrillation	0.89% 3/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Atrial flutter	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Atrioventricular block	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Cardiac failure	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.90% 3/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Cardiac failure congestive	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Coronary artery disease	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Myocardial infarction	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.60% 2/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Myocardial ischaemia	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Pericardial effusion	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Right ventricular failure	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Sick sinus syndrome	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Silent myocardial infarction	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Cardiac disorders Supraventricular tachycardia	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Ear and labyrinth disorders Vertigo	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Abdominal pain	0.89% 3/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Abdominal pain upper	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Constipation	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Diverticulum	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Duodenitis	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Gastric ulcer	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Gastritis	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.60% 2/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Hernial eventration	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Inguinal hernia	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Intestinal perforation	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Jejunal ulcer	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Nausea	0.59% 2/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Neurogenic bowel	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Gastrointestinal disorders Vomiting	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
General disorders Chest pain	1.2% 4/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
General disorders Death	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
General disorders Malaise	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
General disorders Pyrexia	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Hepatobiliary disorders Cholecystitis	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Hepatobiliary disorders Cholecystitis acute	0.59% 2/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Biliary sepsis	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Bronchitis acute	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.60% 2/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Bronchopneumonia	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Gastroenteritis	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Influenza	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Lobar pneumonia	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Lower respiratory tract infection	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Pneumonia	1.8% 6/338 • From first drug administration until 30 days after last drug administration.	1.2% 4/335 • From first drug administration until 30 days after last drug administration.	0.90% 3/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Pneumonia pneumococcal	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Pyelonephritis acute	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Rectal abscess	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Respiratory tract infection	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Sepsis	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Sinusitis	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Tracheobronchitis	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Urinary tract infection	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Viral infection	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Viral upper respiratory tract infection	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Wound infection	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Injury, poisoning and procedural complications Ankle fracture	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Injury, poisoning and procedural complications Clavicle fracture	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Injury, poisoning and procedural complications Concussion	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Injury, poisoning and procedural complications Contusion	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.60% 2/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Injury, poisoning and procedural complications Excoriation	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Injury, poisoning and procedural complications Fall	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Injury, poisoning and procedural complications Graft thrombosis	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Injury, poisoning and procedural complications Pubic rami fracture	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Injury, poisoning and procedural complications Tendon rupture	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Injury, poisoning and procedural complications Upper limb fracture	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Investigations Heart rate irregular	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Investigations Liver function test abnormal	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Musculoskeletal and connective tissue disorders Chest wall pain	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Musculoskeletal and connective tissue disorders Compartment syndrome	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Musculoskeletal and connective tissue disorders Spinal column stenosis	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bronchial carcinoma	0.59% 2/338 • From first drug administration until 30 days after last drug administration.	0.60% 2/335 • From first drug administration until 30 days after last drug administration.	0.60% 2/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bronchial neoplasm	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric cancer	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.59% 2/338 • From first drug administration until 30 days after last drug administration.	0.60% 2/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung squamous cell carcinoma stage unspecified	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to liver	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm malignant	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer metastatic	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oesophageal carcinoma	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic neoplasm	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal cancer	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal neoplasm	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Nervous system disorders Amnesia	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Nervous system disorders Cerebrovascular accident	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Nervous system disorders Ischaemic cerebral infarction	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Nervous system disorders Ischaemic stroke	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Nervous system disorders Loss of consciousness	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Nervous system disorders Paraplegia	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Nervous system disorders Sciatica	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Nervous system disorders Temporal lobe epilepsy	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Nervous system disorders Transient ischaemic attack	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Psychiatric disorders Alcoholism	0.59% 2/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Psychiatric disorders Completed suicide	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Psychiatric disorders Depression	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Psychiatric disorders Drug dependence	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Psychiatric disorders Tension	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Renal and urinary disorders Azotaemia	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Renal and urinary disorders Calculus ureteric	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Renal and urinary disorders Calculus urinary	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Renal and urinary disorders Dysuria	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Renal and urinary disorders Nephropathy toxic	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Renal and urinary disorders Neurogenic bladder	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Renal and urinary disorders Renal failure	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Renal and urinary disorders Renal failure acute	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Renal and urinary disorders Urethral meatus stenosis	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Acute pulmonary oedema	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Chronic obstructive airways disease exacerbated	5.6% 19/338 • From first drug administration until 30 days after last drug administration.	8.7% 29/335 • From first drug administration until 30 days after last drug administration.	6.0% 20/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Dyspnoea exacerbated	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.60% 2/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.60% 2/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.89% 3/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.59% 2/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.60% 2/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Pulmonary infarction	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Respiratory arrest	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Respiratory disorder	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Snoring	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Vocal cord polyp	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Skin and subcutaneous tissue disorders Pigmentation disorder	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Surgical and medical procedures Postoperative care	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Surgical and medical procedures Transurethral prostatectomy	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Vascular disorders Aortic aneurysm	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Vascular disorders Aortic aneurysm rupture	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Vascular disorders Aortic rupture	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Vascular disorders Deep vein thrombosis	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.30% 1/334 • From first drug administration until 30 days after last drug administration.
Vascular disorders Femoral arterial stenosis	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Vascular disorders Hypotension	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Vascular disorders Iliac artery stenosis	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Vascular disorders Peripheral ischaemia	0.00% 0/338 • From first drug administration until 30 days after last drug administration.	0.30% 1/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.
Vascular disorders Peripheral vascular disorder	0.30% 1/338 • From first drug administration until 30 days after last drug administration.	0.00% 0/335 • From first drug administration until 30 days after last drug administration.	0.00% 0/334 • From first drug administration until 30 days after last drug administration.

Other adverse events

Measure	Tiotropium Respimat 5mcg Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Respimat 10mcg Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Gastrointestinal disorders Dry mouth	7.4% 25/338 • From first drug administration until 30 days after last drug administration.	13.1% 44/335 • From first drug administration until 30 days after last drug administration.	2.1% 7/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Influenza	3.8% 13/338 • From first drug administration until 30 days after last drug administration.	4.5% 15/335 • From first drug administration until 30 days after last drug administration.	5.1% 17/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Nasopharyngitis	15.7% 53/338 • From first drug administration until 30 days after last drug administration.	9.9% 33/335 • From first drug administration until 30 days after last drug administration.	7.2% 24/334 • From first drug administration until 30 days after last drug administration.
Infections and infestations Upper respiratory tract infection	5.0% 17/338 • From first drug administration until 30 days after last drug administration.	5.1% 17/335 • From first drug administration until 30 days after last drug administration.	5.7% 19/334 • From first drug administration until 30 days after last drug administration.
Nervous system disorders Headache	5.6% 19/338 • From first drug administration until 30 days after last drug administration.	4.8% 16/335 • From first drug administration until 30 days after last drug administration.	4.5% 15/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Chronic obstructive airways disease exacerbated	30.5% 103/338 • From first drug administration until 30 days after last drug administration.	28.7% 96/335 • From first drug administration until 30 days after last drug administration.	42.2% 141/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Cough	5.6% 19/338 • From first drug administration until 30 days after last drug administration.	7.5% 25/335 • From first drug administration until 30 days after last drug administration.	3.3% 11/334 • From first drug administration until 30 days after last drug administration.
Respiratory, thoracic and mediastinal disorders Pharyngeal pain	5.6% 19/338 • From first drug administration until 30 days after last drug administration.	5.1% 17/335 • From first drug administration until 30 days after last drug administration.	2.7% 9/334 • From first drug administration until 30 days after last drug administration.

Additional Information

Boehringer Ingelheim Pharmaceuticals

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 of the results of this trial are described in the investigator contract.
• Publication restrictions are in place

Restriction type: OTHER