Tiotropium / Respimat One-Year Study

Sponsor

Boehringer Ingelheim (Industry)

Overall Status

Completed

CT.gov ID

NCT00168831

Collaborator

(none)

1,007

Enrollment

Locations

Arms

12.9

Patients Per Site

Study Details

Study Description

Brief Summary

To evaluate the long term effects of treatment with two doses of Tiotropium delivered by the Respimat inhaler in patients with COPD.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: Tiotropium Inhalation Solution Other: Placebo	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

1007 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double

Primary Purpose:

Treatment

Official Title:

A Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Comparison of One-Year Treatment of Two Doses (5mg and 10mg) of Tiotropium Inhalation Solution Delivered by the Respimat Device in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Study Start Date :

Feb 1, 2003

Actual Primary Completion Date :

Jun 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Other: Tiotropium Respimat 5mcg (Tio R5)	Drug: Tiotropium Inhalation Solution
Other: Tiotropium Respimat 10mcg (Tio R10)	Drug: Tiotropium Inhalation Solution
Other: Placebo	Other: Placebo

Arm

Intervention/Treatment

Other: Tiotropium Respimat 5mcg (Tio R5)

Drug: Tiotropium Inhalation Solution

Other: Tiotropium Respimat 10mcg (Tio R10)

Drug: Tiotropium Inhalation Solution

Other: Placebo

Other: Placebo

Outcome Measures

Primary Outcome Measures

Change From Baseline in Trough FEV1 After 48 Weeks [10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication]
Change From Baseline in Trough Forced Expiratory Volume in 1 second (FEV1) after 48 weeks
Saint George's Respiratory Questionnaire (SGRQ) Total Score, Full Analysis Set - Saint George's Respiratory Questionnaire (FAS-QOL) [Week 48]
Rating scale of 3 domains - symptoms, activities and impact (weighted). Worst score = 100, best score = 0
TDI Focal Score, Full Analysis Set - Transitional Dyspnoea Index (FAS-TDI) (Combined Studies) [Week 48]
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.
COPD Exacerbation Rate, Safety Set (SS) (Combined Studies) [48 weeks]
Number of Chronic Obstructive Pulmonary Disease (COPD) exacerbations per patient year For this endpoint data of the twin studies NCT00168844 and NCT00168831 was combined.

Secondary Outcome Measures

Change From Baseline in Heart Rate [Baseline to Week 40 pre-dose]
Week 40 pre-dose - baseline
Change From Baseline in PR Interval [Baseline to Week 40 pre-dose]
Change From Baseline in QRS Interval [Baseline to Week 40 pre-dose]
Week 40 pre-dose - baseline
Change From Baseline in QT Interval [Baseline to Week 40 pre-dose]
Week 40 pre-dose - baseline
Change From Baseline in QT Interval (Bazett) [Baseline to Week 40 pre-dose]
Week 40 pre-dose - baseline
Change From Baseline in QT Interval (Fridericia) [Baseline to Week 40 pre-dose]
Week 40 pre-dose - baseline
Change From Baseline in Heart Rate [Baseline to Week 40]
Week 40 - baseline
Change From Baseline in Supraventricular Premature Beat (SVPB) Total [Baseline to Week 40]
Week 40 - baseline
Change From Baseline in SVPB Run Events [Baseline to Week 40]
Week 40 - baseline
Change From Baseline in SVPB Pairs [Baseline to Week 40]
Week 40 - baseline
Change From Baseline in Ventricular Premature Beat (VPB) Total [Baseline to Week 40]
Week 40 - baseline
Change From Baseline in Ventricular Premature Beat (VPB) Run Events [Baseline to Week 40]
Week 40 - baseline
Change From Baseline in VPB Pairs [Baseline to Week 40]
Week 40 - baseline
Change From Baseline in Haematocrit, Packed Cell Volume (PCV) [Baseline to Week 48 or at premature discontinuation if before Week 48]
Change From Baseline in Haemoglobin [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Red Blood Cell Count [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in White Blood Cell Count [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Platelets [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Neutrophils [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Eosinophils [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Basophils [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Lymphocytes [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Monocytes [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Neutrophils (Absolute) [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Eosinophils (Absolute) [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Basophils (Absolute) [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Lymphocytes (Absolute) [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Monocytes (Absolute) [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Calcium [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Phosphate [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Aspartate Transaminase/Glutamic-oxaloacetic Transaminase (AST/GOT), Serum Glutamic-oxaloacetic Transaminase (SGOT) [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Alanine Transaminase/Glutamic Pyruvate Transaminase (ALT/GPT), Serum Glutamate Pyruvate Transaminase (SGPT) [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Alkaline Phosphatase [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Lactic Dehyrogenase (LDH) [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Glucose [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Urea [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Blood Urea Nitrogen [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Creatinine [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Bilirubin, Total [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Uric Acid [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Protein, Total [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Albumin [Baseline to Week 48 or at premature discontinuation if before Week 48]
Week 48 - baseline
Change From Baseline in Trough FEV1 After 2, 8, 16, 24, 32 and 40 Weeks [10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication]
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.
Change From Baseline in Trough FVC After 2, 8, 16, 24, 32, 40 and 48 Weeks [10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication]
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.
Change From Baseline in FEV1 AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks [10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication]
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.
Change From Baseline in FVC AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks [10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication]
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.
Weekly Mean Morning Pre-dose PEFRs [Weeks 2, 8, 16, 24, 32, 40, 48]
Weekly mean morning pre-dose peak expiratory flow rates (PEFRs). The means are adjusted for centre, smoking status at entry, and baseline value.
Weekly Mean Morning Evening PEFRs [Weeks 2, 8, 16, 24, 32, 40, 48]
Weekly mean evening peak expiratory flow rates (PEFRs). The means are adjusted for centre, smoking status at entry, and baseline value.
Weekly Mean Number of Puffs of Rescue Medication Per Day [Weeks 2, 8, 16, 24, 32, 40, 48]
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.
Mahler TDI Scores [Week 48]
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
Saint George's Respiratory Questionnaire (SGRQ) Scores [Week 48]
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.
COPD Symptoms Scores [Week 48]
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.
PGE Scores [Week 48]
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.
PGR Scores [Week 48]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Criteria

Patients with stable moderate to severe COPD and a smoking history of at least 10 pack years were eligible for inclusion in the study. Patients with significant diseases other than COPD were excluded as were patients with a recent history of myocardial infarction, history of malignancy, unstable or life-threatening cardiac arrhythmia, narrow-angle glaucoma, asthma or other allergic conditions. Patients treated with cromolyn, nedocromil, oral beta-adrenergics or unstable doses of oral corticosteroids were ineligible for inclusion in the study as were patients who had received previous treatment with tiotropium.

Contacts and Locations

Locations

	Site	City	State	Country
1	Boehringer Ingelheim Investigational Site	Birmingham	Alabama	United States
2	Boehringer Ingelheim Investigational Site	La Jolla	California	United States
3	Boehringer Ingelheim Investigational Site	Long Beach	California	United States
4	Boehringer Ingelheim Investigational Site	San Luis Obispo	California	United States
5	Boehringer Ingelheim Investigational Site	Gainesville	Florida	United States
6	Boehringer Ingelheim Investigational Site	Hallandale	Florida	United States
7	Boehringer Ingelheim Investigational Site	Hines	Illinois	United States
8	Boehringer Ingelheim Investigational Site	Chesterfield	Missouri	United States
9	Boehringer Ingelheim Investigational Site	Bay Shore	New York	United States
10	Boehringer Ingelheim Investigational Site	Charleston	South Carolina	United States
11	Boehringer Ingelheim Investigational Site	Houston	Texas	United States
12	Boehringer Ingelheim Investigational Site	Richmond	Virginia	United States
13	Boehringer Ingelheim Investigational Site	Garran	Australian Capital Territory	Australia
14	Boehringer Ingelheim Investigational Site	Adelaide	South Australia	Australia
15	Boehringer Ingelheim Investigational Site	Nedlands	Western Australia	Australia
16	Boehringer Ingelheim Investigational Site	Innsbruck		Austria
17	Boehringer Ingelheim Investigational Site	Mittersill		Austria
18	Boehringer Ingelheim Investigational Site	Schwechat		Austria
19	Boehringer Ingelheim Investigational Site	Wels		Austria
20	Baumgartner Hohe Otto Wagner Spital Wien	Wien		Austria
21	Boehringer Ingelheim Investigational Site	Wien		Austria
22	Boehringer Ingelheim Investigational Site	Winnipeg	Manitoba	Canada
23	Boehringer Ingelheim Investigational Site	Hamilton	Ontario	Canada
24	Boehringer Ingelheim Investigational Site	Toronto	Ontario	Canada
25	Boehringer Ingelheim Investigational Site	Montreal	Quebec	Canada
26	Boehringer Ingelheim Investigational Site	Sherbrooke	Quebec	Canada
27	Boehringer Ingelheim Investigational Site	Espoo		Finland
28	Boehringer Ingelheim Investigational Site	Helsinki		Finland
29	Boehringer Ingelheim Investigational Site	Lahti		Finland
30	Boehringer Ingelheim Investigational Site	Lappeenranta		Finland
31	Boehringer Ingelheim Investigational Site	Lohja		Finland
32	Boehringer Ingelheim Investigational Site	Amboise cedex		France
33	Boehringer Ingelheim Investigational Site	Chauny		France
34	Boehringer Ingelheim Investigational Site	Marseille cedex 06		France
35	Boehringer Ingelheim Investigational Site	Metz cedex 01		France
36	Boehringer Ingelheim Investigational Site	Montpellier		France
37	Boehringer Ingelheim Investigational Site	Nantes		France
38	Boehringer Ingelheim Investigational Site	Alexandroupolis		Greece
39	Boehringer Ingelheim Investigational Site	Athens		Greece
40	Boehringer Ingelheim Investigational Site	Mournies-Chania		Greece
41	Boehringer Ingelheim Investigational Site	Trikala		Greece
42	Boehringer Ingelheim Investigational Site	Dublin 4		Ireland
43	Boehringer Ingelheim Investigational Site	Dublin 7		Ireland
44	Boehringer Ingelheim Investigational Site	Dublin		Ireland
45	Boehringer Ingelheim Investigational Site	Bologna		Italy
46	Boehringer Ingelheim Investigational Site	Bussolengo (vr)		Italy
47	Boehringer Ingelheim Investigational Site	Cava dei tirreni (SA)		Italy
48	Boehringer Ingelheim Investigational Site	Crema (CR)		Italy
49	Boehringer Ingelheim Investigational Site	Genova		Italy
50	Boehringer Ingelheim Investigational Site	Milano		Italy
51	Boehringer Ingelheim Investigational Site	Pistoia		Italy
52	Boehringer Ingelheim Investigational Site	Roma		Italy
53	Boehringer Ingelheim Investigational Site	Salerno		Italy
54	Boehringer Ingelheim Investigational Site	Sesto San Giovanni (Milano)		Italy
55	Boehringer Ingelheim Investigational Site	Arnhem		Netherlands
56	Boehringer Ingelheim Investigational Site	Eindhoven		Netherlands
57	Boehringer Ingelheim Investigational Site	Heerenveen		Netherlands
58	Boehringer Ingelheim Investigational Site	Hoorn		Netherlands
59	Boehringer Ingelheim Investigational Site	Leeuwarden		Netherlands
60	Boehringer Ingelheim Investigational Site	Rotterdam		Netherlands
61	Boehringer Ingelheim Investigational Site	Auckland		New Zealand
62	Boehringer Ingelheim Investigational Site	Hamilton		New Zealand
63	Boehringer Ingelheim Investigational Site	St. Petersburg		Russian Federation
64	Boehringer Ingelheim Investigational Site	Bellville		South Africa
65	Boehringer Ingelheim Investigational Site	Cape Town		South Africa
66	Boehringer Ingelheim Investigational Site	George		South Africa
67	Boehringer Ingelheim Investigational Site	Johannesburg		South Africa
68	Boehringer Ingelheim Investigational Site	Vanderbijlpark		South Africa
69	Boehringer Ingelheim Investigational Site	Barcelona		Spain
70	Boehringer Ingelheim Investigational Site	Centelles		Spain
71	Boehringer Ingelheim Investigational Site	Murcia		Spain
72	Boehringer Ingelheim Investigational Site	Sant Boi de Llobregat (Barcelona)		Spain
73	Boehringer Ingelheim Investigational Site	Babbacombe		United Kingdom
74	Boehringer Ingelheim Investigational Site	Cottingham		United Kingdom
75	Boehringer Ingelheim Investigational Site	Isleworth		United Kingdom
76	Boehringer Ingelheim Investigational Site	Manchester		United Kingdom
77	Boehringer Ingelheim Investigational Site	Plymouth		United Kingdom
78	Boehringer Ingelheim Investigational Site	Sunderland		United Kingdom

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

Study Chair: Boehringer Ingelheim Study Coordinator, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.

Responsible Party:

, ,

ClinicalTrials.gov Identifier:

NCT00168831

Other Study ID Numbers:

205.255

First Posted:

Sep 15, 2005

Last Update Posted:

May 20, 2014

Last Verified:

Sep 1, 2013

Additional relevant MeSH terms:

Lung Diseases

Pulmonary Disease, Chronic Obstructive

Tiotropium Bromide

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail

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

Baseline Characteristics

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo	Total
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)	Total of all reporting groups
Overall Participants	338	335	334	1007
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.4 (8.9)	65.6 (8.6)	65.7 (8.4)	65.2 (8.7)
Sex: Female, Male (Count of Participants)
Female	90 26.6%	89 26.6%	99 29.6%	278 27.6%
Male	248 73.4%	246 73.4%	235 70.4%	729 72.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Trough FEV1 After 48 Weeks
Description	Change From Baseline in Trough Forced Expiratory Volume in 1 second (FEV1) after 48 weeks
Time Frame	10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	324	324	307
Mean (Standard Error) [Litres]	0.077 (0.012)	0.105 (0.012)	-0.036 (0.012)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 5mcg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA analysis with terms for treatment, smoking status at entry, centre and baseline value

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.113
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.017
	Estimation Comments	Tiotropium Respimat 5mcg - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 10mcg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA analysis with terms for treatment, smoking status at entry,centre and baseline value

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.140
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.017
	Estimation Comments	Tiotropium Respimat 10mcg - Placebo

2. Primary Outcome

Title	Saint George's Respiratory Questionnaire (SGRQ) Total Score, Full Analysis Set - Saint George's Respiratory Questionnaire (FAS-QOL)
Description	Rating scale of 3 domains - symptoms, activities and impact (weighted). Worst score = 100, best score = 0
Time Frame	Week 48

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	310	304	276
Mean (Standard Error) [Points on a scale]	39.771 (0.718)	40.038 (0.726)	43.484 (0.763)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 5mcg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	ANCOVA
	Comments	The means are adjusted for centre, smoking status at entry and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.713
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.052
	Estimation Comments	Tiotropium Respimat 5mcg - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 10mcg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0012
	Comments
	Method	ANCOVA
	Comments	The means are adjusted for centre, smoking status at entry and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.445
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.059
	Estimation Comments	Tiotropium Respimat 10mcg - Placebo

3. Primary Outcome

Title	TDI Focal Score, Full Analysis Set - Transitional Dyspnoea Index (FAS-TDI) (Combined Studies)
Description	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.
Time Frame	Week 48

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	628	618	552
Mean (Standard Error) [Points on a scale]	1.890 (0.112)	1.913 (0.113)	0.837 (0.120)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 5mcg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The means are adjusted for centre, smoking status at entry and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.053
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.165
	Estimation Comments	Tiotropium Respimat 5mcg - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 10mcg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The means are adjusted for centre, smoking status at entry and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.075
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.166
	Estimation Comments	Tiotropium Respimat 10mcg - Placebo

4. Primary Outcome

Title	COPD Exacerbation Rate, Safety Set (SS) (Combined Studies)
Description	Number of Chronic Obstructive Pulmonary Disease (COPD) exacerbations per patient year For this endpoint data of the twin studies NCT00168844 and NCT00168831 was combined.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description
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.

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	670	667	653
Mean (Standard Deviation) [Number of exacerbations per patient year]	0.93 (2.02)	1.02 (3.05)	1.91 (8.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 5mcg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Poisson regression
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.782
	Confidence Interval	(2-Sided) 95% 0.687 to 0.890
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tiotropium Respimat 5mcg vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 10mcg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Poisson regression
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.725
	Confidence Interval	(2-Sided) 95% 0.635 to 0.828
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tiotropium Respimat 10mcg vs. Placebo

5. Secondary Outcome

Title	Change From Baseline in Heart Rate
Description	Week 40 pre-dose - baseline
Time Frame	Baseline to Week 40 pre-dose

Outcome Measure Data

Analysis Population Description
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)

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	155	135	109
Mean (Standard Deviation) [beats per minute (bpm)]	2.1 (12.4)	3.6 (10.5)	1.8 (9.7)

6. Secondary Outcome

Title	Change From Baseline in PR Interval
Description
Time Frame	Baseline to Week 40 pre-dose

Outcome Measure Data

Analysis Population Description
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)

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	150	131	105
Mean (Standard Deviation) [milliseconds (msec)]	-0.8 (20.2)	-2.5 (15.1)	-0.5 (15.3)

7. Secondary Outcome

Title	Change From Baseline in QRS Interval
Description	Week 40 pre-dose - baseline
Time Frame	Baseline to Week 40 pre-dose

Outcome Measure Data

Analysis Population Description
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)

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	155	135	109
Mean (Standard Deviation) [msec]	0.9 (9.4)	1.7 (12.1)	-1.1 (10.3)

8. Secondary Outcome

Title	Change From Baseline in QT Interval
Description	Week 40 pre-dose - baseline
Time Frame	Baseline to Week 40 pre-dose

Outcome Measure Data

Analysis Population Description
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)

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	155	135	109
Mean (Standard Deviation) [msec]	-4.6 (26.5)	-3.5 (25.2)	-3.2 (22.3)

9. Secondary Outcome

Title	Change From Baseline in QT Interval (Bazett)
Description	Week 40 pre-dose - baseline
Time Frame	Baseline to Week 40 pre-dose

Outcome Measure Data

Analysis Population Description
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)

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	155	135	109
Mean (Standard Deviation) [msec]	-0.5 (29.9)	5.4 (24.0)	2.5 (23.4)

10. Secondary Outcome

Title	Change From Baseline in QT Interval (Fridericia)
Description	Week 40 pre-dose - baseline
Time Frame	Baseline to Week 40 pre-dose

Outcome Measure Data

Analysis Population Description
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)

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	155	135	109
Mean (Standard Deviation) [msec]	-2.0 (24.3)	2.2 (21.3)	0.5 (19.5)

11. Secondary Outcome

Title	Change From Baseline in Heart Rate
Description	Week 40 - baseline
Time Frame	Baseline to Week 40

Outcome Measure Data

Analysis Population Description
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)

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	77	66	56
Mean (Standard Deviation) [bpm]	0.3 (5.4)	1.2 (6.4)	0.3 (6.6)

12. Secondary Outcome

Title	Change From Baseline in Supraventricular Premature Beat (SVPB) Total
Description	Week 40 - baseline
Time Frame	Baseline to Week 40

Outcome Measure Data

Analysis Population Description
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)

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	77	66	56
Mean (Standard Deviation) [premature beats per 24 hours]	-3.4 (94.2)	6.8 (87.4)	20.9 (125.8)

13. Secondary Outcome

Title	Change From Baseline in SVPB Run Events
Description	Week 40 - baseline
Time Frame	Baseline to Week 40

Outcome Measure Data

Analysis Population Description
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)

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	77	66	56
Mean (Standard Deviation) [events per 24 hours]	0.0 (0.6)	-0.1 (0.5)	-0.1 (1.6)

14. Secondary Outcome

Title	Change From Baseline in SVPB Pairs
Description	Week 40 - baseline
Time Frame	Baseline to Week 40

Outcome Measure Data

Analysis Population Description
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)

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	77	66	56
Mean (Standard Deviation) [pairs per 24 hours]	-0.4 (4.0)	-0.2 (2.3)	2.0 (16.4)

15. Secondary Outcome

Title	Change From Baseline in Ventricular Premature Beat (VPB) Total
Description	Week 40 - baseline
Time Frame	Baseline to Week 40

Outcome Measure Data

Analysis Population Description
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)

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	77	66	56
Mean (Standard Deviation) [premature beats per 24 hours]	-14.3 (105.9)	4.6 (68.8)	-24.1 (182.3)

16. Secondary Outcome

Title	Change From Baseline in Ventricular Premature Beat (VPB) Run Events
Description	Week 40 - baseline
Time Frame	Baseline to Week 40

Outcome Measure Data

Analysis Population Description
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)

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	77	66	56
Mean (Standard Deviation) [events per 24 hours]	0.0 (0.1)	0.0 (0.1)	0.0 (0.0)

17. Secondary Outcome

Title	Change From Baseline in VPB Pairs
Description	Week 40 - baseline
Time Frame	Baseline to Week 40

Outcome Measure Data

Analysis Population Description
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)

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	77	66	56
Mean (Standard Deviation) [pairs per 24 hours]	-0.2 (1.6)	-0.1 (3.8)	-0.9 (5.7)

18. Secondary Outcome

Title	Change From Baseline in Haematocrit, Packed Cell Volume (PCV)
Description
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	289	274	268
Mean (Standard Deviation) [Percentage of erythrocytes]	0 (4)	0 (4)	0 (4)

19. Secondary Outcome

Title	Change From Baseline in Haemoglobin
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	299	280	276
Mean (Standard Deviation) [grams per litre (g/L)]	0 (11)	-1 (10)	-1 (12)

20. Secondary Outcome

Title	Change From Baseline in Red Blood Cell Count
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	298	279	275
Mean (Standard Deviation) [10^12/Litre (L)]	0.0 (0.3)	0.0 (0.3)	0.0 (0.3)

21. Secondary Outcome

Title	Change From Baseline in White Blood Cell Count
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	299	280	276
Mean (Standard Deviation) [10^9/Litre (L)]	0.2 (1.7)	0.3 (1.5)	0.2 (1.5)

22. Secondary Outcome

Title	Change From Baseline in Platelets
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	292	274	272
Mean (Standard Deviation) [10^9/L]	5 (31)	3 (29)	0 (35)

23. Secondary Outcome

Title	Change From Baseline in Neutrophils
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	296	276	274
Mean (Standard Deviation) [percentage of white blood cell count]	1 (8)	1 (8)	0 (8)

24. Secondary Outcome

Title	Change From Baseline in Eosinophils
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	296	276	274
Mean (Standard Deviation) [percentage of white blood cell count]	0 (2)	0 (2)	0 (2)

25. Secondary Outcome

Title	Change From Baseline in Basophils
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	296	276	274
Mean (Standard Deviation) [percentage of white blood cell count]	0 (0)	0 (0)	0 (0)

26. Secondary Outcome

Title	Change From Baseline in Lymphocytes
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	296	276	274
Mean (Standard Deviation) [percentage of white blood cell count]	-1 (4)	-1 (4)	0 (4)

27. Secondary Outcome

Title	Change From Baseline in Monocytes
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	296	276	274
Mean (Standard Deviation) [percentage of white blood cell count]	0 (4)	0 (4)	0 (4)

28. Secondary Outcome

Title	Change From Baseline in Neutrophils (Absolute)
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	296	276	274
Mean (Standard Deviation) [10^9/L]	0.2 (1.9)	0.3 (1.6)	0.2 (1.6)

29. Secondary Outcome

Title	Change From Baseline in Eosinophils (Absolute)
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	296	276	274
Mean (Standard Deviation) [10^9/L]	0.0 (0.1)	0.0 (0.1)	0.0 (0.1)

30. Secondary Outcome

Title	Change From Baseline in Basophils (Absolute)
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	296	276	274
Mean (Standard Deviation) [10^9/L]	0.0 (0.1)	0.0 (0.1)	0.0 (0.1)

31. Secondary Outcome

Title	Change From Baseline in Lymphocytes (Absolute)
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	296	276	274
Mean (Standard Deviation) [10^9/L]	-0.1 (0.6)	0.0 (0.7)	0.0 (0.7)

32. Secondary Outcome

Title	Change From Baseline in Monocytes (Absolute)
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	296	276	274
Mean (Standard Deviation) [10^9/L]	0.0 (0.3)	0.0 (0.3)	0.0 (0.3)

33. Secondary Outcome

Title	Change From Baseline in Calcium
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	304	284	277
Mean (Standard Deviation) [millimoles per litre (mmol/L)]	0.0 (0.1)	0.0 (0.1)	0.0 (0.2)

34. Secondary Outcome

Title	Change From Baseline in Phosphate
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	304	284	277
Mean (Standard Deviation) [mmol/L]	0.01 (0.23)	0.00 (0.24)	0.02 (0.26)

35. Secondary Outcome

Title	Change From Baseline in Aspartate Transaminase/Glutamic-oxaloacetic Transaminase (AST/GOT), Serum Glutamic-oxaloacetic Transaminase (SGOT)
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	304	284	277
Mean (Standard Deviation) [Units per litre (U/L)]	-1 (20)	-1 (25)	-2 (13)

36. Secondary Outcome

Title	Change From Baseline in Alanine Transaminase/Glutamic Pyruvate Transaminase (ALT/GPT), Serum Glutamate Pyruvate Transaminase (SGPT)
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	304	284	277
Mean (Standard Deviation) [U/L]	-1 (18)	-1 (18)	-1 (13)

37. Secondary Outcome

Title	Change From Baseline in Alkaline Phosphatase
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	304	284	277
Mean (Standard Deviation) [U/L]	-4 (19)	-5 (23)	-3 (27)

38. Secondary Outcome

Title	Change From Baseline in Lactic Dehyrogenase (LDH)
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	302	282	276
Mean (Standard Deviation) [U/L]	1 (40)	3 (44)	5 (42)

39. Secondary Outcome

Title	Change From Baseline in Glucose
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	303	280	276
Mean (Standard Deviation) [mmol/L]	0.02 (2.11)	0.26 (2.17)	0.10 (2.34)

40. Secondary Outcome

Title	Change From Baseline in Urea
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	304	284	277
Mean (Standard Deviation) [mmol/L]	-0.2 (1.9)	0.0 (2.1)	0.1 (2.2)

41. Secondary Outcome

Title	Change From Baseline in Blood Urea Nitrogen
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	304	284	277
Mean (Standard Deviation) [milligrams per decilitre (mg/dL)]	-0.3 (3.0)	0.0 (3.3)	0.2 (3.5)

42. Secondary Outcome

Title	Change From Baseline in Creatinine
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	304	284	277
Mean (Standard Deviation) [micromoles per litre (umol/L)]	2.2 (9.3)	1.5 (12.2)	2.1 (10.5)

43. Secondary Outcome

Title	Change From Baseline in Bilirubin, Total
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	304	284	277
Mean (Standard Deviation) [umol/L]	-0.2 (5.2)	0.4 (4.2)	-0.1 (4.6)

44. Secondary Outcome

Title	Change From Baseline in Uric Acid
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	304	284	277
Mean (Standard Deviation) [umol/L]	16.41 (80.08)	9.39 (85.92)	6.52 (76.49)

45. Secondary Outcome

Title	Change From Baseline in Protein, Total
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	304	284	277
Mean (Standard Deviation) [grams per litre (g/L)]	-1 (5)	-1 (5)	-1 (6)

46. Secondary Outcome

Title	Change From Baseline in Albumin
Description	Week 48 - baseline
Time Frame	Baseline to Week 48 or at premature discontinuation if before Week 48

Outcome Measure Data

Analysis Population Description
Safety Set

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	304	284	277
Mean (Standard Deviation) [g/L]	1 (4)	1 (4)	1 (4)

47. Secondary Outcome

Title	Change From Baseline in Trough FEV1 After 2, 8, 16, 24, 32 and 40 Weeks
Description	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.
Time Frame	10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	324	324	307
Week 2	0.111 (0.010)	0.114 (0.010)	-0.003 (0.011)
Week 8	0.099 (0.011)	0.133 (0.011)	-0.012 (0.011)
Week 16	0.118 (0.012)	0.132 (0.012)	-0.008 (0.012)
Week 24	0.104 (0.012)	0.132 (0.012)	-0.010 (0.012)
Week 32	0.095 (0.012)	0.145 (0.012)	-0.012 (0.013)
Week 40	0.091 (0.012)	0.106 (0.012)	-0.027 (0.012)

48. Secondary Outcome

Title	Change From Baseline in Trough FVC After 2, 8, 16, 24, 32, 40 and 48 Weeks
Description	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.
Time Frame	10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	324	324	307
Week 2	0.257 (0.021)	0.264 (0.022)	0.009 (0.022)
Week 8	0.207 (0.023)	0.266 (0.023)	-0.007 (0.024)
Week 16	0.259 (0.025)	0.266 (0.025)	-0.002 (0.025)
Week 24	0.236 (0.025)	0.274 (0.025)	0.008 (0.025)
Week 32	0.203 (0.026)	0.286 (0.026)	-0.008 (0.027)
Week 40	0.211 (0.025)	0.207 (0.025)	-0.028 (0.026)
Week 48	0.197 (0.026)	0.209 (0.026)	-0.043 (0.026)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 5mcg, Placebo
	Comments	Analysis for week 48
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA analysis with terms for treatment, smoking status at entry, centre and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.240
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.037
	Estimation Comments	Tiotropium Respimat 5mcg - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 10mcg
	Comments	Analysis for week 48
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.252
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.037
	Estimation Comments	Tiotropium Respimat 10mcg - Placebo

49. Secondary Outcome

Title	Change From Baseline in FEV1 AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks
Description	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.
Time Frame	10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	324	324	307
Week 2	0.246 (0.011)	0.257 (0.011)	0.044 (0.012)
Week 8	0.234 (0.012)	0.258 (0.012)	0.037 (0.013)
Week 16	0.235 (0.012)	0.242 (0.012)	0.026 (0.013)
Week 24	0.222 (0.012)	0.245 (0.012)	0.024 (0.013)
Week 32	0.198 (0.013)	0.241 (0.013)	0.018 (0.013)
Week 40	0.197 (0.012)	0.206 (0.012)	-0.000 (0.012)
Week 48	0.181 (0.013)	0.210 (0.013)	-0.002 (0.013)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 5mcg, Placebo
	Comments	Analysis for week 48
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA analysis with terms for treatment, smoking status at entry, centre and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.183
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.018
	Estimation Comments	Tiotropium Respimat 5mcg - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 10mcg, Placebo
	Comments	Analysis for week 48
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA analysis with terms for treatment, smoking status at entry, centre and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.212
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.018
	Estimation Comments	Tiotropium Respimat 10mcg - Placebo

50. Secondary Outcome

Title	Change From Baseline in FVC AUC0-3 After 2, 8, 16, 24, 32, 40 and 48 Weeks
Description	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.
Time Frame	10 minutes prior to test-drug inhalation and at 5, 30 and 60 minutes and 2 and 3 hours after inhalation of study medication

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	324	324	307
Week 2	0.513 (0.024)	0.522 (0.024)	0.140 (0.025)
Week 8	0.463 (0.026)	0.521 (0.026)	0.117 (0.027)
Week 16	0.466 (0.026)	0.488 (0.026)	0.108 (0.027)
Week 24	0.468 (0.027)	0.498 (0.027)	0.092 (0.027)
Week 32	0.438 (0.027)	0.477 (0.027)	0.075 (0.028)
Week 40	0.417 (0.027)	0.406 (0.027)	0.029 (0.028)
Week 48	0.387 (0.028)	0.411 (0.028)	0.018 (0.029)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 5mcg, Placebo
	Comments	Analysis for week 48
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA analysis with terms for treatment, smoking status at entry, centre and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.369
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.040
	Estimation Comments	Tiotropium Respimat 5mcg - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 10mcg, Placebo
	Comments	Analysis for week 48
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA analysis with terms for treatment, smoking status at entry, centre and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.393
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.040
	Estimation Comments	Tiotropium Respimat 10mcg - Placebo

51. Secondary Outcome

Title	Weekly Mean Morning Pre-dose PEFRs
Description	Weekly mean morning pre-dose peak expiratory flow rates (PEFRs). The means are adjusted for centre, smoking status at entry, and baseline value.
Time Frame	Weeks 2, 8, 16, 24, 32, 40, 48

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	322	324	308
Week 2	245.7 (1.6)	245.4 (1.6)	226.9 (1.6)
Week 8	252.4 (2.3)	253.9 (2.3)	229.4 (2.4)
Week 16	257.5 (2.8)	258.4 (2.8)	231.6 (2.9)
Week 24	260.5 (3.2)	263.8 (3.2)	230.9 (3.2)
Week 32	261.5 (3.2)	264.6 (3.2)	232.6 (3.3)
Week 40	260.7 (3.2)	264.7 (3.2)	231.1 (3.3)
Week 48	260.3 (3.4)	264.1 (3.4)	232.4 (3.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 5mcg, Placebo
	Comments	Analysis for week 48
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA analysis with terms for treatment, centre,smoking status at entry and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	27.9
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.9
	Estimation Comments	Tiotropium Respimat 5mcg - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 10mcg, Placebo
	Comments	Analysis for week 48
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA analysis with terms for treatment, centre,smoking status at entry and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	31.7
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.9
	Estimation Comments	Tiotropium Respimat 10mcg - Placebo

52. Secondary Outcome

Title	Weekly Mean Morning Evening PEFRs
Description	Weekly mean evening peak expiratory flow rates (PEFRs). The means are adjusted for centre, smoking status at entry, and baseline value.
Time Frame	Weeks 2, 8, 16, 24, 32, 40, 48

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	319	322	309
Week 2	262.7 (1.7)	265.0 (1.7)	237.5 (1.7)
Week 8	267.9 (2.5)	273.5 (2.5)	240.6 (2.5)
Week 16	272.7 (3.0)	276.3 (3.0)	240.8 (3.1)
Week 24	275.5 (3.2)	280.3 (3.2)	241.9 (3.3)
Week 32	276.6 (3.3)	279.7 (3.2)	241.0 (3.3)
Week 40	274.0 (3.3)	280.5 (3.2)	240.5 (3.2)
Week 48	274.0 (3.4)	281.0 (3.4)	241.9 (3.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 5mcg, Placebo
	Comments	Analysis for week 48
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA analysis with terms for treatment, centre,smoking status at entry and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	32.0
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.9
	Estimation Comments	Tiotropium Respimat 5mcg - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 10mcg, Placebo
	Comments	Analysis for week 48
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA analysis with terms for treatment, centre,smoking status at entry and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	39.1
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.9
	Estimation Comments	Tiotropium Respimat 10mcg - Placebo

53. Secondary Outcome

Title	Weekly Mean Number of Puffs of Rescue Medication Per Day
Description	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.
Time Frame	Weeks 2, 8, 16, 24, 32, 40, 48

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	321	324	311
Week 2	2.0 (0.1)	2.0 (0.1)	2.8 (0.1)
Week 8	2.3 (0.1)	2.0 (0.1)	3.0 (0.1)
Week 16	2.5 (0.1)	2.1 (0.1)	3.0 (0.1)
Week 24	2.5 (0.1)	2.3 (0.1)	3.0 (0.1)
Week 32	2.7 (0.1)	2.3 (0.1)	3.1 (0.1)
Week 40	2.7 (0.1)	2.4 (0.1)	3.2 (0.1)
Week 48	2.8 (0.1)	2.5 (0.1)	3.2 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 5mcg, Placebo
	Comments	Analysis for week 48
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0169
	Comments
	Method	ANCOVA
	Comments	ANCOVA analysis with terms for treatment, centre,smoking status at entry and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.4
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.2
	Estimation Comments	Tiotropium Respimat 5mcg - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Tiotropium Respimat 10mcg, Placebo
	Comments	Analysis for week 48
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	ANCOVA analysis with terms for treatment, centre,smoking status at entry and baseline value.

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.7
	Confidence Interval	() 95% to
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.2
	Estimation Comments	Tiotropium Respimat 10mcg - Placebo

54. Secondary Outcome

Title	Mahler TDI Scores
Description	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
Time Frame	Week 48

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	310	305	279
Functional Impairment	0.630 (0.057)	0.577 (0.057)	0.318 (0.060)
Magnitude of Task	0.654 (0.057)	0.621 (0.057)	0.275 (0.060)
Magnitude of Effort	0.604 (0.061)	0.594 (0.062)	0.264 (0.065)

55. Secondary Outcome

Title	Saint George's Respiratory Questionnaire (SGRQ) Scores
Description	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.
Time Frame	Week 48

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	310	304	276
Symptoms	40.680 (1.116)	42.108 (1.128)	48.244 (1.185)
Activities	58.529 (0.897)	57.045 (0.906)	60.921 (0.953)
Impacts	28.858 (0.783)	29.532 (0.791)	32.239 (0.832)

56. Secondary Outcome

Title	COPD Symptoms Scores
Description	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.
Time Frame	Week 48

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	325	324	304
Wheezing	0.66 (0.04)	0.72 (0.04)	0.85 (0.04)
Shortness of Breath	1.42 (0.04)	1.41 (0.04)	1.61 (0.04)
Coughing	0.96 (0.04)	1.05 (0.04)	1.06 (0.04)
Tightness of Chest	0.51 (0.04)	0.55 (0.04)	0.64 (0.04)

57. Secondary Outcome

Title	PGE Scores
Description	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.
Time Frame	Week 48

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	324	325	305
Mean (Standard Error) [Points on a scale]	4.90 (0.06)	4.84 (0.06)	4.44 (0.06)

58. Secondary Outcome

Title	PGR Scores
Description	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.
Time Frame	Week 48

Outcome Measure Data

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

Arm/Group Title	Tiotropium Respimat 5mcg	Tiotropium Respimat 10mcg	Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)	Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
Measure Participants	312	307	281
Mean (Standard Error) [Points on a scale]	2.88 (0.08)	2.94 (0.08)	3.42 (0.08)

Adverse Events

	Tiotropium Respimat 5mcg		Tiotropium Respimat 10mcg		Placebo
Time Frame	From first drug administration until 30 days after last drug administration.
Adverse Event Reporting Description

Arm/Group Title	Tiotropium Respimat 5mcg		Tiotropium Respimat 10mcg		Placebo
Arm/Group Description	Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (5 mcg)		Tiotropium Bromide inhalation solution delivered from Respimat Inhaler (10 mcg)		Placebo inhalation solution delivered from Respimat Inhaler (matching placebo)
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Tiotropium Respimat 5mcg		Tiotropium Respimat 10mcg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/ (NaN)		72/ (NaN)		56/ (NaN)
Cardiac disorders
Acute coronary syndrome	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Angina pectoris	0/338 (0%)		2/335 (0.6%)		0/334 (0%)
Angina unstable	1/338 (0.3%)		3/335 (0.9%)		0/334 (0%)
Arrhythmia	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Atrial fibrillation	3/338 (0.9%)		0/335 (0%)		0/334 (0%)
Atrial flutter	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Atrioventricular block	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Cardiac failure	1/338 (0.3%)		1/335 (0.3%)		3/334 (0.9%)
Cardiac failure congestive	1/338 (0.3%)		1/335 (0.3%)		0/334 (0%)
Coronary artery disease	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Myocardial infarction	1/338 (0.3%)		1/335 (0.3%)		2/334 (0.6%)
Myocardial ischaemia	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Pericardial effusion	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Right ventricular failure	1/338 (0.3%)		0/335 (0%)		1/334 (0.3%)
Sick sinus syndrome	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Silent myocardial infarction	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Supraventricular tachycardia	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Ear and labyrinth disorders
Vertigo	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Gastrointestinal disorders
Abdominal pain	3/338 (0.9%)		0/335 (0%)		0/334 (0%)
Abdominal pain upper	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Constipation	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Diverticulum	1/338 (0.3%)		1/335 (0.3%)		0/334 (0%)
Duodenitis	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Gastric ulcer	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Gastritis	0/338 (0%)		0/335 (0%)		2/334 (0.6%)
Gastrointestinal haemorrhage	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Hernial eventration	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Inguinal hernia	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Intestinal obstruction	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Intestinal perforation	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Jejunal ulcer	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Nausea	2/338 (0.6%)		0/335 (0%)		0/334 (0%)
Neurogenic bowel	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Oesophageal stenosis	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Peritonitis	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Umbilical hernia	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Vomiting	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
General disorders
Chest pain	4/338 (1.2%)		0/335 (0%)		0/334 (0%)
Death	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Malaise	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Pyrexia	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Hepatobiliary disorders
Cholecystitis	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Cholecystitis acute	2/338 (0.6%)		1/335 (0.3%)		0/334 (0%)
Infections and infestations
Biliary sepsis	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Bronchitis acute	0/338 (0%)		2/335 (0.6%)		1/334 (0.3%)
Bronchopneumonia	1/338 (0.3%)		1/335 (0.3%)		0/334 (0%)
Gastroenteritis	1/338 (0.3%)		0/335 (0%)		1/334 (0.3%)
Influenza	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Lobar pneumonia	0/338 (0%)		1/335 (0.3%)		1/334 (0.3%)
Lower respiratory tract infection	1/338 (0.3%)		1/335 (0.3%)		0/334 (0%)
Pneumonia	6/338 (1.8%)		4/335 (1.2%)		3/334 (0.9%)
Pneumonia pneumococcal	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Pyelonephritis acute	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Rectal abscess	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Respiratory tract infection	1/338 (0.3%)		0/335 (0%)		1/334 (0.3%)
Sepsis	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Sinusitis	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Tracheobronchitis	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Urinary tract infection	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Viral infection	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Viral upper respiratory tract infection	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Wound infection	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Injury, poisoning and procedural complications
Ankle fracture	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Clavicle fracture	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Concussion	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Contusion	0/338 (0%)		2/335 (0.6%)		0/334 (0%)
Excoriation	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Fall	1/338 (0.3%)		1/335 (0.3%)		0/334 (0%)
Graft thrombosis	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Humerus fracture	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Pubic rami fracture	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Road traffic accident	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Tendon rupture	1/338 (0.3%)		1/335 (0.3%)		0/334 (0%)
Upper limb fracture	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Investigations
Heart rate irregular	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Liver function test abnormal	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Chest wall pain	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Compartment syndrome	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Osteoarthritis	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Spinal column stenosis	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Bladder cancer	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Breast cancer	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Bronchial carcinoma	2/338 (0.6%)		2/335 (0.6%)		2/334 (0.6%)
Bronchial neoplasm	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Colon cancer	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Gastric cancer	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Lung neoplasm	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Lung neoplasm malignant	2/338 (0.6%)		2/335 (0.6%)		1/334 (0.3%)
Lung squamous cell carcinoma stage unspecified	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Metastases to liver	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Neoplasm malignant	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Non-small cell lung cancer	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Non-small cell lung cancer metastatic	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Oesophageal carcinoma	1/338 (0.3%)		1/335 (0.3%)		0/334 (0%)
Pancreatic neoplasm	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Prostate cancer	1/338 (0.3%)		1/335 (0.3%)		1/334 (0.3%)
Rectal cancer	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Renal neoplasm	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Squamous cell carcinoma	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Nervous system disorders
Amnesia	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Cerebrovascular accident	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Ischaemic cerebral infarction	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Ischaemic stroke	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Loss of consciousness	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Paraplegia	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Sciatica	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Temporal lobe epilepsy	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Transient ischaemic attack	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Psychiatric disorders
Alcoholism	2/338 (0.6%)		0/335 (0%)		0/334 (0%)
Completed suicide	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Depression	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Drug dependence	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Tension	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Renal and urinary disorders
Azotaemia	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Calculus ureteric	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Calculus urinary	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Dysuria	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Nephropathy toxic	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Neurogenic bladder	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Renal failure	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Renal failure acute	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Urethral meatus stenosis	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Chronic obstructive airways disease exacerbated	19/338 (5.6%)		29/335 (8.7%)		20/334 (6%)
Chronic obstructive pulmonary disease	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Dyspnoea	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Dyspnoea exacerbated	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Haemoptysis	0/338 (0%)		0/335 (0%)		2/334 (0.6%)
Hypoxia	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Pleural effusion	0/338 (0%)		0/335 (0%)		2/334 (0.6%)
Pneumothorax	3/338 (0.9%)		0/335 (0%)		1/334 (0.3%)
Pulmonary embolism	2/338 (0.6%)		1/335 (0.3%)		2/334 (0.6%)
Pulmonary hypertension	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Pulmonary infarction	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Pulmonary oedema	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Respiratory arrest	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Respiratory disorder	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Respiratory failure	1/338 (0.3%)		0/335 (0%)		1/334 (0.3%)
Snoring	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Vocal cord polyp	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Skin and subcutaneous tissue disorders
Pigmentation disorder	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Surgical and medical procedures
Postoperative care	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Transurethral prostatectomy	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Vascular disorders
Aortic aneurysm	0/338 (0%)		1/335 (0.3%)		1/334 (0.3%)
Aortic aneurysm rupture	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Aortic rupture	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Deep vein thrombosis	0/338 (0%)		0/335 (0%)		1/334 (0.3%)
Femoral arterial stenosis	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Hypotension	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Iliac artery stenosis	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Peripheral ischaemia	0/338 (0%)		1/335 (0.3%)		0/334 (0%)
Peripheral vascular disorder	1/338 (0.3%)		0/335 (0%)		0/334 (0%)
Other (Not Including Serious) Adverse Events
	Tiotropium Respimat 5mcg		Tiotropium Respimat 10mcg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	177/ (NaN)		174/ (NaN)		182/ (NaN)
Gastrointestinal disorders
Dry mouth	25/338 (7.4%)		44/335 (13.1%)		7/334 (2.1%)
Infections and infestations
Influenza	13/338 (3.8%)		15/335 (4.5%)		17/334 (5.1%)
Nasopharyngitis	53/338 (15.7%)		33/335 (9.9%)		24/334 (7.2%)
Upper respiratory tract infection	17/338 (5%)		17/335 (5.1%)		19/334 (5.7%)
Nervous system disorders
Headache	19/338 (5.6%)		16/335 (4.8%)		15/334 (4.5%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive airways disease exacerbated	103/338 (30.5%)		96/335 (28.7%)		141/334 (42.2%)
Cough	19/338 (5.6%)		25/335 (7.5%)		11/334 (3.3%)
Pharyngeal pain	19/338 (5.6%)		17/335 (5.1%)		9/334 (2.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.

Results Point of Contact

Name/Title	Boehringer Ingelheim Pharmaceuticals
Organization	Boehringer Ingelheim Pharmaceuticals
Phone	1-800-243-0127
Email	clintriage.rdg@boehringer-ingelheim.com

Responsible Party:

, ,

ClinicalTrials.gov Identifier:

NCT00168831

Other Study ID Numbers:

205.255

First Posted:

Sep 15, 2005

Last Update Posted:

May 20, 2014

Last Verified:

Sep 1, 2013