Evaluation of the Long- Term Effects of Spiriva on Lung Function in COPD Patients

Sponsor

Boehringer Ingelheim (Industry)

Overall Status

Completed

CT.gov ID

NCT00144339

Collaborator

(none)

5,993

Enrollment

490

Locations

12.2

Patients Per Site

Study Details

Study Description

Brief Summary

The primary objective of this trial is to determine whether daily treatment with tiotropium (Spiriva®, Bromuro de Tiotropio®) inhalation capsule via HandiHaler® reduces the rate of decline in lung function over time in patients with COPD.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: tiotropium Drug: placebo	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

5993 participants

Intervention Model:

Parallel Assignment

Primary Purpose:

Treatment

Official Title:

A Randomized, Double-blind, Placebo-controlled, Parallel Group Trial Assessing the Rate of Decline of Lung Function With Tiotropium 18 mcg Inhalation Capsule Once Daily in Patients With Chronic Obstructive Pulmonary Disease (COPD).

Study Start Date :

Dec 1, 2002

Actual Primary Completion Date :

Feb 1, 2008

Outcome Measures

Primary Outcome Measures

Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 30 to 4 Years [From day 30 to 4 years]
Rate of decline of forced expiratory volume in one second (FEV1) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1.
Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 30 to 4 Years [From day 30 to 4 years]
Rate of decline of forced expiratory volume in one second (FEV1) measured after bronchodilation. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1.

Secondary Outcome Measures

Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment [Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days.]
Rate of decline of forced expiratory volume in one second (FEV1) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1
Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment [Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days]
Rate of decline of forced expiratory volume in one second (FEV1) measured after the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1
Pre-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 30 to 4 Years [From day 30 to 4 years]
Rate of decline of forced vital capacity (FVC) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC
Post-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 30 to 4 Years [From day 30 to 4 years]
Rate of decline of forced vital capacity (FVC) measured after bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC
Pre-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 30 to 4 Years [From day 30 to 4 years]
Rate of decline of slow vital capacity (SVC) measured before the use of bronchodilators. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC
Post-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 30 to 4 Years [From day 30 to 4 years]
Rate of decline of slow vital capacity (SVC) measured after bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC
Rate of Decline of St George's Respiratory Questionnaire (SGRQ) Total Score [From month 6 to 4 years]
SGRQ total score shows the impact of COPD on patient's health status, and expressed as a percentage of impairment with scale from 0 (best health status) to 100 (worst possible status). A negative rate of decline shows decreasing SGRQ total score (or improved health) over time, while a positive value shows increasing score (or worsen health).
Pre-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment [Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days.]
Rate of decline of forced vital capacity (FVC) before bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC
Post-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment [Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days]
Rate of decline of forced vital capacity (FVC) after bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC
Pre-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment [Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days]
Rate of decline slow vital capacity (SVC) before bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC
Post-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment [Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days]
Rate of decline of slow vital capacity (SVC) after bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC
Time to First Exacerbation [From Day 1 to 4 years]
Chronic obstructive pulmonary disease (COPD) exacerbation
Number of Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Per Patient Year [Day 1 to 4 years]
Number and Percentage of Patients With at Least One Chronic Obstructive Pulmonary Disease (COPD) Exacerbation [Day 1 to 4 years]
Number of Exacerbation Days Per Patient Year [Day 1 to 4 years]
Number of exacerbation days normalized by treatment exposure
Time to First COPD Exacerbation Leading to Hospitalization (for 25% Patients) [Day 1 to 4 years]
Number and Percentage of Patients With at Least on COPD Exacerbation Leading to Hospitalization [From Day 1 to 4 years]
Number of Exacerbation Leading to Hospitalization [From Day 1 to 4 years]
Estimated number of exacerbations leading to hospitalizations per patient year
Days of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Leading to Hospitalization [From Day 1 to 4 years]
Number of days with chronic obstructive pulmonary disease (COPD) exacerbation leading to hospitalization (normalized by treatment exposure)
Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 1 [Month 1]
Estimated FEV1 before bronchodilator at Month 1
Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 1 [Month 1]
Estimated forced expiratory volume in one second (FEV1) after bronchodilator at month 1
Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 6 [Month 6]
Estimated forced expiratory volume in one second (FEV1) before bronchodilator at month 6
Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 6 [Month 6]
Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 12 [Month 12]
Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 12 [Month 12]
Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 18 [Month 18]
Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 18 [Month 18]
Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 24 [Month 24]
Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 24 [Month 24]
Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 30 [Month 30]
Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 30 [Month 30]
Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 36 [Month 36]
Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 36 [Month 36]
Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 42 [Month 42]
Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 42 [Month 42]
Estimated FEV1 after bronchodilator at Month 42
Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 48 [Month 48]
Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 48 [Month 48]
Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 1 [Month 1]
Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 1 [Month 1]
Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 6 [Month 6]
Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 6 [Month 6]
Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 12 [Month 12]
Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 12 [Month 12]
Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 18 [Month 18]
Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 18 [Month 18]
Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 24 [Month 24]
Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 24 [Month 24]
Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 30 [Month 30]
Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 30 [Month 30]
Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 36 [Month 36]
Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 36 [Month 36]
Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 42 [Month 42]
Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 42 [Month 42]
Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 48 [Month 48]
Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 48 [Month 48]
Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 1 [Month 1]
Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 1 [Month 1]
Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 6 [Month 6]
Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 6 [Month 6]
Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 12 [Month 12]
Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 12 [Month 12]
Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 18 [Month 18]
Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 18 [Month 18]
Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 24 [Month 24]
Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 24 [Month 24]
Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 30 [Month 30]
Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 30 [Month 30]
Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 36 [Month 36]
Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 36 [Month 36]
Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 42 [Month 42]
Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 42 [Month 42]
Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 48 [Month 48]
Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 48 [Month 48]
Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 6 [Month 6]
SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 12 [Month 12]
SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 18 [Month 18]
SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 24 [Month 24]
SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 30 [Month 30]
SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 36 [Month 36]
SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 42 [Month 42]
SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 48 [Month 48]
SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Number and Percentage of Participants With All Cause Death and Time to Event Analysis (On-treatment) [Day 1 to completion of double blinded treatment plus 30 days between Day 1 and 4 years plus 30 days]
On-treatment defined as day 1 to completion of double blinded treatment plus 30 days
Number and Percentage of Participants With All Cause Death (Including Vital Status Follow-up, Cutoff at 1470 Days) [Day 1 to day 1470]
All cause mortality vital status information was followed-up after discontinuation; vital status information up to 1470 days after the start of treatment was used.
Number and Percentage of Participants With Lower Respiratory Death (On-treatment; Adjudicated Primary Cause) [Day 1 to completion of double blinded treatment plus 30 days between Day 1 and 4 years plus 30 days]
The primary cause of death was adjudicated by an external committee prior to unblinding; on-treatment defined as day 1 to completion of double blinded treatment plus 30 days
Number and Percentage of Participants With a Lower Respiratory Death (Adjudicated; Including Vital Status Follow-up, Cutoff at 1470 Days) [Day 1 to day 1470]
The primary cause of death was adjudicated by an external committee prior to unblinding; vital status was information followed-up after discontinuation; vital status information up to 1470 days after the start of treatment was used

Other Outcome Measures

Incidence Rate of Serious Adverse Event (System Organ Class = Cardiac Disorders) [Day 1 to completion of double blinded treatment plus 30 days]
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Incidence Rate of Serious Adverse Event (Preferred Term = Angina) [Day 1 to completion of double blinded treatment plus 30 days]
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Incidence Rate of Serious Adverse Event (Preferred Term = Atrial Fibrillation) [Day 1 to completion of double blinded treatment plus 30 days]
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Incidence Rate of Serious Adverse Event (Preferred Term = Cardiac Failure) [Day 1 to completion of double blinded treatment plus 30 days]
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Incidence Rate of Serious Adverse Event (Preferred Term = Cardiac Failure Congestive) [Day 1 to completion of double blinded treatment plus 30 days]
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Incidence Rate of Serious Adverse Event (Preferred Term = Coronary Artery Disease) [Day 1 to completion of double blinded treatment plus 30 days]
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Incidence Rate of Serious Adverse Event (Preferred Term = Myocardial Infarction) [Day 1 to completion of double blinded treatment plus 30 days]
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Incidence Rate of Serious Adverse Event (System Organ Class = Lower Respiratory System Disorders) [Day 1 to completion of double blinded treatment plus 30 days]
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Incidence Rate of Serious Adverse Event (Preferred Term = Bronchitis) [Day 1 to completion of double blinded treatment plus 30 days]
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Incidence Rate of Serious Adverse Event (Preferred Term = Chronic Obstructive Pulmonary Disease (COPD) Exacerbation) [Day 1 to completion of double blinded treatment plus 30 days]
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Incidence Rate of Serious Adverse Event (Preferred Term = Dyspnoea) [Day 1 to completion of double blinded treatment plus 30 days]
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Incidence Rate of Serious Adverse Event (Preferred Term = Pneumonia) [Day 1 to completion of double blinded treatment plus 30 days]
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Incidence Rate of Serious Adverse Event (Preferred Term = Respiratory Failure) [Day 1 to completion of double blinded treatment plus 30 days]
Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent.
Male or female patients 40 years of age or older.
Smoking history of at least 10 pack years.
Diagnosis of COPD with post bronchodilator FEV1 less than or equal to 70% of predicted normal and FEV1<70% of FVC and on stable respiratory medication.

Exclusion Criteria:

Significant diseases other than COPD which in the opinion of the investigator may put the patient at risk or influence the patients ability to participate.
Myocardial infarction in past 6 months.
Unstable or life threatening arrhythmia in past year.
Hospitalization for NYHA heart failure class III or IV in past year.
Active tuberculosis.
Asthma.
Pulmonary resection.
Malignancy treated with radiation or chemotherapy in past 5 years.
Respiratory infection in 4 weeks prior to screening.
Known hypersensitivity to anticholinergic drugs or components.
Known moderate to severe renal impairment.
Known narrow angle glaucoma.
Significant symptomatic BPH or bladder neck obstruction.
Need for oxygen therapy >12 hr/day.
Use of oral corticosteroids at unstable doses or >10 mg/day.

Contacts and Locations

Locations

	Site	City	State	Country
1	205.235.3779 Boehringer Ingelheim Investigational Site	Anniston	Alabama	United States
2	205.235.3785 Boehringer Ingelheim Investigational Site	Birmingham	Alabama	United States
3	205.235.3804 Boehringer Ingelheim Investigational Site	Jasper	Alabama	United States
4	205.235.3795 Boehringer Ingelheim Investigational Site	Mobile	Alabama	United States
5	205.235.3759 Boehringer Ingelheim Investigational Site	Phoenix	Arizona	United States
6	205.235.3770 Boehringer Ingelheim Investigational Site	Carmichael	California	United States
7	205.235.3778 Boehringer Ingelheim Investigational Site	Escondito	California	United States
8	205.235.3810 Boehringer Ingelheim Investigational Site	Lakewood	California	United States
9	205.235.3758 Boehringer Ingelheim Investigational Site	Long Beach	California	United States
10	205.235.3812 Boehringer Ingelheim Investigational Site	Long Beach	California	United States
11	205.235.3773 Boehringer Ingelheim Investigational Site	Los Angeles	California	United States
12	205.235.3800 Boehringer Ingelheim Investigational Site	Los Angeles	California	United States
13	205.235.3802 Boehringer Ingelheim Investigational Site	Los Angeles	California	United States
14	205.235.3786 Pulmonary and Critical Care Medicine	Orange	California	United States
15	205.235.3811 Boehringer Ingelheim Investigational Site	Palo Alto	California	United States
16	205.235.3741 Boehringer Ingelheim Investigational Site	Rancho Mirage	California	United States
17	205.235.3717 Boehringer Ingelheim Investigational Site	San Diego	California	United States
18	205.235.3781 Boehringer Ingelheim Investigational Site	San Diego	California	United States
19	205.235.3784 Boehringer Ingelheim Investigational Site	San Diego	California	United States
20	205.235.3760 Boehringer Ingelheim Investigational Site	Sepulveda	California	United States
21	205.235.3711 Boehringer Ingelheim Investigational Site	Stockton	California	United States
22	205.235.3764 Boehringer Ingelheim Investigational Site	Denver	Colorado	United States
23	205.235.3783 Boehringer Ingelheim Investigational Site	Wheat Ridge	Colorado	United States
24	205.235.3727 Boehringer Ingelheim Investigational Site	Hartford	Connecticut	United States
25	205.235.3808 Boehringer Ingelheim Investigational Site	Hartford	Connecticut	United States
26	205.235.3793 Boehringer Ingelheim Investigational Site	Norwalk	Connecticut	United States
27	205.235.3815 Boehringer Ingelheim Investigational Site	WEst Haven	Connecticut	United States
28	205.235.3706 Boehringer Ingelheim Investigational Site	Bay Pines	Florida	United States
29	205.235.3762 Boehringer Ingelheim Investigational Site	Brandon	Florida	United States
30	205.235.3707 Boehringer Ingelheim Investigational Site	Largo	Florida	United States
31	205.235.3703 Boehringer Ingelheim Investigational Site	Melbourne	Florida	United States
32	205.235.3775 Boehringer Ingelheim Investigational Site	Panama City	Florida	United States
33	205.235.3743 Boehringer Ingelheim Investigational Site	Sarasota	Florida	United States
34	205.235.3756 Boehringer Ingelheim Investigational Site	Tampa	Florida	United States
35	205.235.3739 Boehringer Ingelheim Investigational Site	West Palm Beach	Florida	United States
36	205.235.3719 Boehringer Ingelheim Investigational Site	Atlanta	Georgia	United States
37	205.235.3790 Boehringer Ingelheim Investigational Site	Atlanta	Georgia	United States
38	205.235.3716 Boehringer Ingelheim Investigational Site	Augusta	Georgia	United States
39	205.235.3794 Boehringer Ingelheim Investigational Site	Stockbridge	Georgia	United States
40	205.235.3724 Boehringer Ingelheim Investigational Site	Coeur d'Alene	Idaho	United States
41	205.235.3713 Boehringer Ingelheim Investigational Site	Normal	Illinois	United States
42	205.235.3768 Boehringer Ingelheim Investigational Site	Indianapolis	Indiana	United States
43	205.235.3749 Boehringer Ingelheim Investigational Site	Dubuque	Iowa	United States
44	205.235.3757 Boehringer Ingelheim Investigational Site	Olathe	Kansas	United States
45	205.235.3729 Boehringer Ingelheim Investigational Site	Lexington	Kentucky	United States
46	205.235.3737 Boehringer Ingelheim Investigational Site	Metairie	Louisiana	United States
47	205.235.3788 Boehringer Ingelheim Investigational Site	Shreveport	Louisiana	United States
48	205.235.3750 Boehringer Ingelheim Investigational Site	Bidderford	Maine	United States
49	205.235.3806 Boehringer Ingelheim Investigational Site	Baltimore	Maryland	United States
50	205.235.3721 Boehringer Ingelheim Investigational Site	Boston	Massachusetts	United States
51	205.235.3726 354 Birnie Ave	Springfield	Massachusetts	United States
52	205.235.3813 Boehringer Ingelheim Investigational Site	Ann Arbor	Michigan	United States
53	205.235.3732 Boehringer Ingelheim Investigational Site	Detroit	Michigan	United States
54	205.235.3809 Boehringer Ingelheim Investigational Site	Livonia	Michigan	United States
55	205.235.3751 Boehringer Ingelheim Investigational Site	Minneapolis	Minnesota	United States
56	205.235.3754 Boehringer Ingelheim Investigational Site	Minneapolis	Minnesota	United States
57	205.235.3789 Boehringer Ingelheim Investigational Site	Rochester	Minnesota	United States
58	205.235.3734 Boehringer Ingelheim Investigational Site	Chesterfield	Missouri	United States
59	205.235.3814 Boehringer Ingelheim Investigational Site	Kansas City	Missouri	United States
60	205.235.3747 Boehringer Ingelheim Investigational Site	St. Louis	Missouri	United States
61	205.235.3763 Boehringer Ingelheim Investigational Site	Lebanon	New Hampshire	United States
62	205.235.3797 Boehringer Ingelheim Investigational Site	Cherry Hill	New Jersey	United States
63	205.235.3799 Boehringer Ingelheim Investigational Site	Summit	New Jersey	United States
64	205.235.3796 Boehringer Ingelheim Investigational Site	Albany	New York	United States
65	205.235.3807 Boehringer Ingelheim Investigational Site	Bayshore	New York	United States
66	205.235.3816 Boehringer Ingelheim Investigational Site	Bronx	New York	United States
67	205.235.3765 Boehringer Ingelheim Investigational Site	Larchmont	New York	United States
68	205.235.3748 Boehringer Ingelheim Investigational Site	Mineola	New York	United States
69	205.235.3818 Boehringer Ingelheim Investigational Site	New York	New York	United States
70	205.235.3722 Boehringer Ingelheim Investigational Site	Rochester	New York	United States
71	205.235.3730 Boehringer Ingelheim Investigational Site	Burlington	North Carolina	United States
72	205.235.3731 Boehringer Ingelheim Investigational Site	Chapel Hill	North Carolina	United States
73	205.235.3736 Boehringer Ingelheim Investigational Site	Durham	North Carolina	United States
74	205.235.3745 Boehringer Ingelheim Investigational Site	Elizabath City	North Carolina	United States
75	205.235.3712 Boehringer Ingelheim Investigational Site	Winston-Salem	North Carolina	United States
76	205.235.3723 Boehringer Ingelheim Investigational Site	Cincinnati	Ohio	United States
77	205.235.3701 Boehringer Ingelheim Investigational Site	Cleveland	Ohio	United States
78	205.235.3791 Boehringer Ingelheim Investigational Site	Tulsa	Oklahoma	United States
79	205.235.3820 Boehringer Ingelheim Investigational Site	Portland	Oregon	United States
80	205.235.3725 Boehringer Ingelheim Investigational Site	Hershey	Pennsylvania	United States
81	205.235.3817 Boehringer Ingelheim Investigational Site	Philadelphia	Pennsylvania	United States
82	205.235.3715 Boehringer Ingelheim Investigational Site	Providence	Rhode Island	United States
83	205.235.3803 Boehringer Ingelheim Investigational Site	El Paso	Texas	United States
84	205.235.3742 Boehringer Ingelheim Investigational Site	Houston	Texas	United States
85	205.235.3787 Boehringer Ingelheim Investigational Site	Houston	Texas	United States
86	205.235.3704 Boehringer Ingelheim Investigational Site	San Antonio	Texas	United States
87	205.235.3752 Boehringer Ingelheim Investigational Site	Salt Lake City	Utah	United States
88	205.235.3744 Boehringer Ingelheim Investigational Site	Danville	Virginia	United States
89	205.235.3782 Boehringer Ingelheim Investigational Site	Fredericksburg	Virginia	United States
90	205.235.3771 Boehringer Ingelheim Investigational Site	Lynchburg	Virginia	United States
91	205.235.3738 Boehringer Ingelheim Investigational Site	Richmond	Virginia	United States
92	205.235.3792 Boehringer Ingelheim Investigational Site	Richmond	Virginia	United States
93	205.235.3761 Boehringer Ingelheim Investigational Site	Salem	Virginia	United States
94	205.235.3718 Boehringer Ingelheim Investigational Site	Spokane	Washington	United States
95	205.235.3780 Boehringer Ingelheim Investigational Site	La Crosse	Wisconsin	United States
96	205.235.101	Buenos Aires		Argentina
97	205.235.101 Boehringer Ingelheim Investigational Site	Capital Federal		Argentina
98	205.235.103 Hospital Alemán	Capital Federal		Argentina
99	205.235.104 Hospital de Clinicas José de San Martín	Capital Federal		Argentina
100	205.235.105 Hospital General de Agudos José María Ramos Mejía	Capital Federal		Argentina
101	205.235.107 Policlínica Bancaria	Capital Federal		Argentina
102	205.235.108 Hospital General de Agudos Dr. Enrique Tornú	Capital Federal		Argentina
103	205.235.109 Hospital Muñiz	Capital Federal		Argentina
104	205.235.110 Hospital Privado - Centro Médico de Córdoba S.A.	Parque Velez Sarlfield		Argentina
105	205.235.102 Instituto Cardiovascular de Rosario	Rosario		Argentina
106	205.235.106 Hospital Cetrángolo	Vicente López		Argentina
107	205.235.0205 Boehringer Ingelheim Investigational Site	Bankstown	New South Wales	Australia
108	205.235.0202 Boehringer Ingelheim Investigational Site	Concord	New South Wales	Australia
109	205.235.0209 Boehringer Ingelheim Investigational Site	Westmead	New South Wales	Australia
110	205.235.0204 Boehringer Ingelheim Investigational Site	Cairns	Queensland	Australia
111	205.235.0203 Boehringer Ingelheim Investigational Site	Redcliffe	Queensland	Australia
112	205.235.0207 Boehringer Ingelheim Investigational Site	Port Lincoln	South Australia	Australia
113	205.235.0206 Boehringer Ingelheim Investigational Site	Box Hill	Victoria	Australia
114	205.235.0201 Boehringer Ingelheim Investigational Site	Geelong	Victoria	Australia
115	205.235.0303 Boehringer Ingelheim Investigational Site	Graz		Austria
116	205.235.0305 Boehringer Ingelheim Investigational Site	Innsbruck		Austria
117	205.235.0304 Boehringer Ingelheim Investigational Site	Leoben		Austria
118	205.235.0301 Boehringer Ingelheim Investigational Site	Wien		Austria
119	205.235.0302 Boehringer Ingelheim Investigational Site	Wien		Austria
120	205.235.0439 Boehringer Ingelheim Investigational Site	Anderlecht		Belgium
121	205.235.0429 Boehringer Ingelheim Investigational Site	Baudour		Belgium
122	205.235.0421 Boehringer Ingelheim Investigational Site	Brugge		Belgium
123	205.235.0424 Boehringer Ingelheim Investigational Site	Brussel		Belgium
124	205.235.0432 Boehringer Ingelheim Investigational Site	Bruxelles		Belgium
125	205.235.0434 Boehringer Ingelheim Investigational Site	Bruxelles		Belgium
126	205.235.0422 Boehringer Ingelheim Investigational Site	Dendermonde		Belgium
127	205.235.0405 Boehringer Ingelheim Investigational Site	Edegem		Belgium
128	205.235.0414 Boehringer Ingelheim Investigational Site	Gent		Belgium
129	205.235.0418 U.Z. Gent	Gent		Belgium
130	205.235.0417 Boehringer Ingelheim Investigational Site	Herentals		Belgium
131	205.235.0402 Boehringer Ingelheim Investigational Site	Ieper		Belgium
132	205.235.0409 Boehringer Ingelheim Investigational Site	Kortrijk		Belgium
133	205.235.0407 Boehringer Ingelheim Investigational Site	Leuven		Belgium
134	205.235.0440 Boehringer Ingelheim Investigational Site	Luxembourg		Belgium
135	205.235.0403 Boehringer Ingelheim Investigational Site	Menen		Belgium
136	205.235.0406 Boehringer Ingelheim Investigational Site	Merksem		Belgium
137	205.235.0404 Boehringer Ingelheim Investigational Site	Middelheim		Belgium
138	205.235.0438 Boehringer Ingelheim Investigational Site	Mons		Belgium
139	205.235.0437 Boehringer Ingelheim Investigational Site	Namur		Belgium
140	205.235.0420 Boehringer Ingelheim Investigational Site	Neerpelt		Belgium
141	205.235.0435 Boehringer Ingelheim Investigational Site	Nobressart (ATTERT)		Belgium
142	205.235.0423 Boehringer Ingelheim Investigational Site	Oostende		Belgium
143	205.235.0433 Boehringer Ingelheim Investigational Site	Tournai		Belgium
144	205.235.0412 Boehringer Ingelheim Investigational Site	Turnhout		Belgium
145	205.235.0413 Boehringer Ingelheim Investigational Site	Turnhout		Belgium
146	205.235.0428 Boehringer Ingelheim Investigational Site	Yvoir		Belgium
147	205.235.510 Servico de Pneumologia	Florianópolis - SC		Brazil
148	205.235.508	Juiz de Fora - MG		Brazil
149	205.235.501	Porto Alegre - RS		Brazil
150	205.235.503	Porto Alegre - RS		Brazil
151	205.235.506	Porto Alegre - RS		Brazil
152	205.235.507 Depto.de Medicina Interna-Servico de pneumologia	Porto Alegre - RS		Brazil
153	205.235.502	Rio de Janeiro - RJ		Brazil
154	205.235.505 Dep.Medicina Especializada (DEMESP)	Rio de Janeiro - RJ		Brazil
155	205.235.511 Departamento de Pneumologia	Salvador - BA		Brazil
156	205.235.504 ANEXO 2-Laboratório de Funcao Pulmonar	Santo André - SP		Brazil
157	205.235.512	São Paulo - SP		Brazil
158	205.235.513	São Paulo - SP		Brazil
159	205.235.514 Unidade de Coracao e Pulmao do Dto. de Medicina	São Paulo - SP		Brazil
160	205.235.515 Lar Escola São Francisco / Setor de Pneumologia	São Paulo - SP		Brazil
161	205.235.0712 Boehringer Ingelheim Investigational Site	Benesov		Czech Republic
162	205.235.0711 Boehringer Ingelheim Investigational Site	Beroun		Czech Republic
163	205.235.0718 Clinic of Functional Diagnostics and Rehabilitation	Brno		Czech Republic
164	205.235.0725 University Hospital Brno	Brno		Czech Republic
165	205.235.0720 Office of Pulmonology and Respiratory Diseases	Cesky Tesin		Czech Republic
166	205.235.0717 Pulmonary Clinic	Hradec Kralove		Czech Republic
167	205.235.0705 Boehringer Ingelheim Investigational Site	Jablonec nad Nisou		Czech Republic
168	205.235.0726 Private Office of Pulmonary Diseases	Jaromer		Czech Republic
169	205.235.0722 Hospital Kromeriz	Kromeriz		Czech Republic
170	205.235.0724 District Hospital Kyjov	Kyjov		Czech Republic
171	205.235.0704 Boehringer Ingelheim Investigational Site	Lovosice		Czech Republic
172	205.235.0702 Boehringer Ingelheim Investigational Site	Marianske Lazne		Czech Republic
173	205.235.0701 Boehringer Ingelheim Investigational Site	Plzen		Czech Republic
174	205.235.0703 Boehringer Ingelheim Investigational Site	Plzen		Czech Republic
175	205.235.0710 Boehringer Ingelheim Investigational Site	Prague 5		Czech Republic
176	205.235.0706 Boehringer Ingelheim Investigational Site	Praha 4		Czech Republic
177	205.235.0709 Boehringer Ingelheim Investigational Site	Praha 4		Czech Republic
178	205.235.0708 Boehringer Ingelheim Investigational Site	Praha 5 - Nove Butovice		Czech Republic
179	205.235.0715 Boehringer Ingelheim Investigational Site	Praha 5		Czech Republic
180	205.235.0707 Boehringer Ingelheim Investigational Site	Praha 8		Czech Republic
181	205.235.0723 Office of Pulmonary and Respiratory Diseases	Prerov		Czech Republic
182	205.235.0721 Office of Pulmonary Diseases	Pribor		Czech Republic
183	205.235.0713 Boehringer Ingelheim Investigational Site	Strakonice		Czech Republic
184	205.235.0714 Boehringer Ingelheim Investigational Site	Tabor		Czech Republic
185	205.235.0719 Office of Pulmonology and Respiratory Diseases	Usti nad Orlici		Czech Republic
186	205.235.0716 Boehringer Ingelheim Investigational Site	Znojmo		Czech Republic
187	205.235.0826 Boehringer Ingelheim Investigational Site	Aalborg SV		Denmark
188	205.235.0804 Boehringer Ingelheim Investigational Site	Aalborg		Denmark
189	205.235.0803 Boehringer Ingelheim Investigational Site	Aarhus		Denmark
190	205.235.0828 Boehringer Ingelheim Investigational Site	Copenhagen K		Denmark
191	205.235.0802 Boehringer Ingelheim Investigational Site	Copenhagen NV		Denmark
192	205.235.0831 Boehringer Ingelheim Investigational Site	Copenhagen		Denmark
193	205.235.0821 Boehringer Ingelheim Investigational Site	Frederikshavn		Denmark
194	205.235.0832 Boehringer Ingelheim Investigational Site	Frederikssund		Denmark
195	205.235.0807 Boehringer Ingelheim Investigational Site	Fåborg		Denmark
196	205.235.0805 Boehringer Ingelheim Investigational Site	Hellerup		Denmark
197	205.235.0835 Boehringer Ingelheim Investigational Site	Hellerup		Denmark
198	205.235.0816 Boehringer Ingelheim Investigational Site	Helsingor		Denmark
199	205.235.0811 Boehringer Ingelheim Investigational Site	Hillerød		Denmark
200	205.235.0834 Boehringer Ingelheim Investigational Site	Hobro		Denmark
201	205.235.0806 Boehringer Ingelheim Investigational Site	Holbæk		Denmark
202	205.235.0814 Boehringer Ingelheim Investigational Site	Holstebro		Denmark
203	205.235.0801 Boehringer Ingelheim Investigational Site	Hvidovre		Denmark
204	205.235.0833 Boehringer Ingelheim Investigational Site	Kalundborg		Denmark
205	205.235.0830 Boehringer Ingelheim Investigational Site	Kolding		Denmark
206	205.235.0819 Boehringer Ingelheim Investigational Site	Nykobing F.		Denmark
207	205.235.0810 Boehringer Ingelheim Investigational Site	Næstved		Denmark
208	205.235.0809 Boehringer Ingelheim Investigational Site	Odense C		Denmark
209	205.235.0815 Boehringer Ingelheim Investigational Site	Randers		Denmark
210	205.235.0824 Boehringer Ingelheim Investigational Site	Silkeborg		Denmark
211	205.235.0813 Boehringer Ingelheim Investigational Site	Skive		Denmark
212	205.235.0822 Boehringer Ingelheim Investigational Site	Skive		Denmark
213	205.235.0820 Boehringer Ingelheim Investigational Site	Slagelse		Denmark
214	205.235.0808 Boehringer Ingelheim Investigational Site	Svendborg		Denmark
215	205.235.0827 Boehringer Ingelheim Investigational Site	Værløse		Denmark
216	205.235.0903 Boehringer Ingelheim Investigational Site	Helsinki		Finland
217	205.235.0901 Boehringer Ingelheim Investigational Site	Jyväskylä		Finland
218	205.235.0905 Boehringer Ingelheim Investigational Site	Kotka		Finland
219	205.235.0904 Boehringer Ingelheim Investigational Site	Lahti		Finland
220	205.235.0902 Boehringer Ingelheim Investigational Site	Pori		Finland
221	205.235.1004 Clinique Toulouse Lautrec	Albi cedex 9		France
222	205.235.1007 Cabinet Médical	Albi		France
223	205.235.1015 Centre Hospitalier	Barbezieux St Hilaire		France
224	205.235.1012 Cabinet Médical	Bourges		France
225	205.235.1024 Cabinet Médical	Chamalières		France
226	205.235.1006 Centre Hospitalier de Chauny	Chauny cedex		France
227	205.235.1005 Polyclinique	Cholet		France
228	205.235.1013 Cabinet Médical	La Teste		France
229	205.235.1020 Cabinet Médical	Marseille		France
230	205.235.1023 Cabinet Médical	Montauban		France
231	205.235.1025 Centre Médical Erdre Saint Augustin	Nantes		France
232	205.235.1002 Cabinet médical	Nice		France
233	205.235.1001 Hôpital Bichat	Paris		France
234	205.235.1016 Cabinet Médical	Provins		France
235	205.235.1019 Cabinet Médical	Strasbourg		France
236	205.235.1009 Centre Hospitalier de Bigorre	Tarbes cedex 9		France
237	205.235.1021 Clinique Pasteur	Toulouse		France
238	205.235.1113 Boehringer Ingelheim Investigational Site	Berlin		Germany
239	205.235.1114 Boehringer Ingelheim Investigational Site	Berlin		Germany
240	205.235.1103 Boehringer Ingelheim Investigational Site	Brake		Germany
241	205.235.1105 Boehringer Ingelheim Investigational Site	Braunschweig		Germany
242	205.235.1104 Boehringer Ingelheim Investigational Site	Bruchsal		Germany
243	205.235.1115 Boehringer Ingelheim Investigational Site	Hannover		Germany
244	205.235.1109 Boehringer Ingelheim Investigational Site	Kaufbeuren		Germany
245	205.235.1108 Boehringer Ingelheim Investigational Site	Lörrach		Germany
246	205.235.1102 Boehringer Ingelheim Investigational Site	Lübeck		Germany
247	205.235.1106 Boehringer Ingelheim Investigational Site	München		Germany
248	205.235.1110 Boehringer Ingelheim Investigational Site	München		Germany
249	205.235.1101 Boehringer Ingelheim Investigational Site	Ulm		Germany
250	205.235.1107 Boehringer Ingelheim Investigational Site	Weyhe		Germany
251	205.235.1112 Boehringer Ingelheim Investigational Site	Wiesloch		Germany
252	205.235.1202 8th Pulmonology Clinic "Sotiria" Athens Chest Hospital	Athens		Greece
253	205.235.1203 Boehringer Ingelheim Investigational Site	Athens		Greece
254	205.235.1201 Boehringer Ingelheim Investigational Site	Heraklion		Greece
255	205.235.1211 Boehringer Ingelheim Investigational Site	Kavala		Greece
256	205.235.1204 Boehringer Ingelheim Investigational Site	Larissa		Greece
257	205.235.1209 Boehringer Ingelheim Investigational Site	Patra		Greece
258	205.235.1210 Boehringer Ingelheim Investigational Site	Patra		Greece
259	205.235.1205 Boehringer Ingelheim Investigational Site	Thessaloniki		Greece
260	205.235.1206 Boehringer Ingelheim Investigational Site	Thessaloniki		Greece
261	205.235.1207 Boehringer Ingelheim Investigational Site	Thessaloniki		Greece
262	205.235.1401 Boehringer Ingelheim Investigational Site	Hong Kong		Hong Kong
263	205.235.1403 Boehringer Ingelheim Investigational Site	Hong Kong		Hong Kong
264	205.235.1402 Boehringer Ingelheim Investigational Site	Kowloon		Hong Kong
265	205.235.1404 Boehringer Ingelheim Investigational Site	Kowloon		Hong Kong
266	205.235.1303 Boehringer Ingelheim Investigational Site	Budapest		Hungary
267	205.235.1308 Boehringer Ingelheim Investigational Site	Budapest		Hungary
268	205.235.1309 Boehringer Ingelheim Investigational Site	Budapest		Hungary
269	205.235.1310 Boehringer Ingelheim Investigational Site	Budapest		Hungary
270	205.235.1311 Boehringer Ingelheim Investigational Site	Budapest		Hungary
271	205.235.1318 Boehringer Ingelheim Investigational Site	Debrecen		Hungary
272	205.235.1314 Boehringer Ingelheim Investigational Site	Deszk		Hungary
273	205.235.1306 Boehringer Ingelheim Investigational Site	Erd		Hungary
274	205.235.1315 Boehringer Ingelheim Investigational Site	Farkasgyepü		Hungary
275	205.235.1320 Boehringer Ingelheim Investigational Site	Gyula		Hungary
276	205.235.1307 Boehringer Ingelheim Investigational Site	Kiskunhalas		Hungary
277	205.235.1304 Boehringer Ingelheim Investigational Site	Miskolc		Hungary
278	205.235.1317 Boehringer Ingelheim Investigational Site	Mosonmagyarovar		Hungary
279	205.235.1301 Boehringer Ingelheim Investigational Site	Pecs		Hungary
280	205.235.1313 Boehringer Ingelheim Investigational Site	Solymar		Hungary
281	205.235.1305 Boehringer Ingelheim Investigational Site	Sopron		Hungary
282	205.235.1319 Boehringer Ingelheim Investigational Site	Szombathely		Hungary
283	205.235.1302 Boehringer Ingelheim Investigational Site	Tatabanya		Hungary
284	205.235.1316 Boehringer Ingelheim Investigational Site	Törökbalint		Hungary
285	205.235.1312 Boehringer Ingelheim Investigational Site	Veszprem		Hungary
286	205.235.1505 Boehringer Ingelheim Investigational Site	Dublin 15		Ireland
287	205.235.1503 Boehringer Ingelheim Investigational Site	Dublin 4		Ireland
288	205.235.1501 Boehringer Ingelheim Investigational Site	Dublin 9		Ireland
289	205.235.1631 A. O. SS. Antonio e Biagio e Arrigo	Alessandria		Italy
290	205.235.1613 A. O. S. Giuseppe Moscati	Avellino		Italy
291	205.235.1618 Ospedale Bellaria	Bologna		Italy
292	205.235.1649 Ospedale di Circolo di Busto Arsizio	Busto Arsizio (VA)		Italy
293	205.235.1635 P. O. Roberto Binaghi	Cagliari		Italy
294	205.235.1623 A. O. di Carrara	Carrara (Massa)		Italy
295	205.235.1645 Ospedale Civile "Zappatoni"	CASSANO D'ADDA (Milano)		Italy
296	205.235.1617 Ospedale S. Camillo De Lellis	Chieti		Italy
297	205.235.1612 A. O. S. Antonio Abate	Erice (Trapani)		Italy
298	205.235.1622 A. O. S. Anna	Ferrara		Italy
299	205.235.1646 A. O. di Careggi	Firenze		Italy
300	205.235.1647 A. O. Careggi	Firenze		Italy
301	205.235.1615 Ospedale S. Martino	Genova		Italy
302	205.235.1603 P. O. di Gubbio	Gubbio (Perugia)		Italy
303	205.235.1619 A. O. Fratelli Crobu	Iglesias (Cagliari)		Italy
304	205.235.1648 Ospedale "S. Maria di Collemaggio"	L'Aquila		Italy
305	205.235.1624 Ospedale di Macerata	Macerata		Italy
306	205.235.1634 P. O. Luigi Sacco	Milano		Italy
307	205.235.1639 Ospedale Maggiore	Modica (Ragusa)		Italy
308	205.235.1629 A. O. S. Luigi Gonzaga	Orbassano (Torino)		Italy
309	205.235.1604 P. O. R. Silvestrini	Perugia		Italy
310	205.235.1601 Presidio Ospedaliero di Cisanello	Pisa		Italy
311	205.235.1643 A. O. Santa Maria degli Angeli	Pordenone		Italy
312	205.235.1614 Ospedale Misericordia e Dolce	Prato		Italy
313	205.235.1607 Università degli Studi di Sassari	Sassari		Italy
314	205.235.1608 ASL 1 di Sassari	Sassari		Italy
315	205.235.1606 ASL 4 di Terni	Terni		Italy
316	205.235.1632 ASL 4 - Distretto 2	Torino		Italy
317	205.235.1633 A. O. Umberto I	Torrette di Ancona (Ancona)		Italy
318	205.235.1640 P. O. Cà Foncello	Treviso		Italy
319	205.235.1602 Ospedale di Voghera	Voghera (Pavia)		Italy
320	205.235.1706 Juntendo University Hospital	Bunkyo-ku, Tokyo		Japan
321	205.235.1705 Kameda Medical Center	Kamogawa, Chiba		Japan
322	205.235.1713 Komaki City Hospital	Komaki, Aichi		Japan
323	205.235.1712 Kurume University Hospital	Kurume, Fukuoka		Japan
324	205.235.1708 Shinshu University	Matsumoto, Nagano		Japan
325	205.235.1702 Iwate Medical University Hospital	Morioka, Iwate		Japan
326	205.235.1710 Osaka City University Hospital	Osaka, Osaka		Japan
327	205.235.1711 Kinki University Hospital	Osakasayama, Osaka		Japan
328	205.235.1701 Hokkaido University	Sapporo, Hokkaido		Japan
329	205.235.1703 Tohoku University Hospital	Sendai, Miyagi		Japan
330	205.235.1709 Tosei General Hospital	Seto, Aichi		Japan
331	205.235.1704 Hiraka General Hospital	Yokote, Akita		Japan
332	205.235.1801 Boehringer Ingelheim Investigational Site	Kaunas		Lithuania
333	205.235.1802 Boehringer Ingelheim Investigational Site	Kaunas		Lithuania
334	205.235.1803 Boehringer Ingelheim Investigational Site	Vilnius		Lithuania
335	205.235.1901 Boehringer Ingelheim Investigational Site	Kuala Lumpur		Malaysia
336	205.235.1902 Boehringer Ingelheim Investigational Site	Kuala Lumpur		Malaysia
337	205.235.1903 Boehringer Ingelheim Investigational Site	Kuala Lumpur		Malaysia
338	205.235.2005	Ciudad de Mexico		Mexico
339	205.235.2006 Tlalpan 4000, Pabellón 5, EPOC	Ciudad de Mexico		Mexico
340	205.235.2004 Edif. Dr. Rodrigo F. Barragan, P.B.	Col. Mitras Centro, Monterrey, N.L.		Mexico
341	205.235.2002	Guadalajara, Jal.		Mexico
342	205.235.2009	Puebla		Mexico
343	205.235.2010 Depto. De Ivestigación	Toluca		Mexico
344	205.235.2003	Zapopan, jalisco		Mexico
345	205.235.2110 Poli Longziekten	Almelo		Netherlands
346	205.235.2105 Lokatie De Lichtenberg	Amersfoort		Netherlands
347	205.235.2107 Poli Longziekten	Delft		Netherlands
348	205.235.2106 Lokatie Dordwijk	Dordrecht		Netherlands
349	205.235.2104 Poli longziekten	Eindhoven		Netherlands
350	205.235.2102 Martini Ziekenhuis Groningen	Groningen		Netherlands
351	205.235.2112 Poli Longziekten	Harderwijk		Netherlands
352	205.235.2115 Poli Longziekten	Heerenveen		Netherlands
353	205.235.2101 Atrium medisch centrum	Heerlen		Netherlands
354	205.235.2114 Poli Longziekten	Hengelo		Netherlands
355	205.235.2108 Poli Longziekten	Leeuwarden		Netherlands
356	205.235.2109 Poli Longziekten	Rotterdam		Netherlands
357	205.235.2111 Antonius Ziekenhuis	Sneek		Netherlands
358	205.235.0211 Boehringer Ingelheim Investigational Site	Auckland		New Zealand
359	205.235.0212 Boehringer Ingelheim Investigational Site	Christchurch, New Zealand		New Zealand
360	205.235.2202 Boehringer Ingelheim Investigational Site	Arendal		Norway
361	205.235.2201 Boehringer Ingelheim Investigational Site	Fredrikstad		Norway
362	205.235.2205 Boehringer Ingelheim Investigational Site	Sandvika		Norway
363	205.235.2204 Boehringer Ingelheim Investigational Site	Straume		Norway
364	205.235.2301 Philippine General Hospital	Manila		Philippines
365	205.235.2305 University of Santo Tomas Hospital	Manila		Philippines
366	205.235.2302 Philippine Heart Center	Quezon City		Philippines
367	205.235.2303 Veterans Memorial Medical Center	Quezon City		Philippines
368	205.235.2304 Lung Center of the Philippines	Quezon City		Philippines
369	205.235.2410 Boehringer Ingelheim Investigational Site	Gdansk		Poland
370	205.235.2407 Boehringer Ingelheim Investigational Site	Katowice		Poland
371	205.235.2408 Boehringer Ingelheim Investigational Site	Krakow		Poland
372	205.235.2405 Boehringer Ingelheim Investigational Site	Lodz		Poland
373	205.235.2409 Boehringer Ingelheim Investigational Site	Lodz		Poland
374	205.235.2401 Boehringer Ingelheim Investigational Site	Warsaw		Poland
375	205.235.2402 Boehringer Ingelheim Investigational Site	Warsaw		Poland
376	205.235.2403 Boehringer Ingelheim Investigational Site	Warsaw		Poland
377	205.235.2404 Boehringer Ingelheim Investigational Site	Wroclaw		Poland
378	205.235.2406 Boehringer Ingelheim Investigational Site	Zabrze		Poland
379	205.235.2504 Centro Hospitalar de Coimbra	Coimbra		Portugal
380	205.235.2503 Hospital Pulido Valente	Lisboa		Portugal
381	205.235.2505 Hospital de Santa Marta	Lisboa		Portugal
382	205.235.2501 Hospital de São João	Porto		Portugal
383	205.235.2502 Centro Hospitalar de Vila Nova de Gaia	Vila Nova de Gaia		Portugal
384	205.235.2601 Boehringer Ingelheim Investigational Site	Moscow		Russian Federation
385	205.235.2602 Boehringer Ingelheim Investigational Site	Moscow		Russian Federation
386	205.235.2603 Boehringer Ingelheim Investigational Site	Moscow		Russian Federation
387	205.235.2605 Boehringer Ingelheim Investigational Site	Moscow		Russian Federation
388	205.235.2604 Boehringer Ingelheim Investigational Site	St. Petersburg		Russian Federation
389	205.235.1904 Boehringer Ingelheim Investigational Site	Singapore		Singapore
390	205.235.1905 Boehringer Ingelheim Investigational Site	Singapore		Singapore
391	205.235.1906 Boehringer Ingelheim Investigational Site	Singapore		Singapore
392	205.235.2701 Boehringer Ingelheim Investigational Site	Bratislava		Slovakia
393	205.235.2702 Boehringer Ingelheim Investigational Site	Bratislava		Slovakia
394	205.235.2703 Boehringer Ingelheim Investigational Site	Martin		Slovakia
395	205.235.2704 Boehringer Ingelheim Investigational Site	Poprad		Slovakia
396	205.235.2705 Boehringer Ingelheim Investigational Site	Topolcany		Slovakia
397	205.235.2801 Boehringer Ingelheim Investigational Site	Golnik		Slovenia
398	205.235.2802 Boehringer Ingelheim Investigational Site	Golnik		Slovenia
399	205.235.2805 Boehringer Ingelheim Investigational Site	Kamnik		Slovenia
400	205.235.2803 Boehringer Ingelheim Investigational Site	Ljubljana		Slovenia
401	205.235.2804 Boehringer Ingelheim Investigational Site	Topolsica		Slovenia
402	205.235.2908	Bloemfontein		South Africa
403	205.235.2910	Cape Town		South Africa
404	205.235.2912	Cape Town		South Africa
405	205.235.2904	Durban		South Africa
406	205.235.2911	Durban		South Africa
407	205.235.2902	George		South Africa
408	205.235.2905	Paarl		South Africa
409	205.235.2901 Boehringer Ingelheim Investigational Site	Pretoria		South Africa
410	205.235.2906	Somerset West		South Africa
411	205.235.2903	Vanderbijlpark		South Africa
412	205.235.2909	Welkom		South Africa
413	205.235.3014 Complejo Hospitalario Juan Canalejo	A Coruña		Spain
414	205.235.3026 Hospital General Universitario de Alicante	Alicante		Spain
415	205.235.3011 Complejo Hospitalario Infanta Cristina	Badajoz		Spain
416	205.235.3006 Hospital Germans Trias i Pujol	Badalona (Barcelona)		Spain
417	205.235.3022 Hospital de Cruces	Barakaldo (Bilbao)		Spain
418	205.235.3003 Hospital Clínic i Provincial de Barcelona	Barcelona		Spain
419	205.235.3008 Hospital Vall d'Hebrón	Barcelona		Spain
420	205.235.3023 Hospital Dr. Josep Trueta	Girona		Spain
421	205.235.3004 Hospital General Universitario de Guadalajara	Guadalajara		Spain
422	205.235.3005 Hospital General San Jorge de Huesca	Huesca		Spain
423	205.235.3021 Hospital de Jerez de la Frontera	Jerez de la Frontera		Spain
424	205.235.3010 Hospital Severo Ochoa	Leganés, Madrid		Spain
425	205.235.3009 Hospital Clínico San Carlos	Madrid		Spain
426	205.235.3013 Clínica Puerta de Hierro	Madrid		Spain
427	205.235.3017 Hospital Ramón y Cajal	Madrid		Spain
428	205.235.3020 Hospital Universitario La Paz	Madrid		Spain
429	205.235.3028 Hospital Universitario de la Princesa	Madrid		Spain
430	205.235.3031 Hospital Gregorio Marañón	Madrid		Spain
431	205.235.3036 Hospital 12 de Octubre	Madrid		Spain
432	205.235.3033 Hospital General Carlos Haya	Málaga		Spain
433	205.235.3027 Complejo Asistencial Son Dureta	Palma de Mallorca		Spain
434	205.235.3024 Hospital de Montecelo	Pontevedra		Spain
435	205.235.3016 Hospital Universitari de Sant Joan	Reus (Tarragona)		Spain
436	205.235.3015 Corporació Sanitaria Parc Taulí de Sabadell	Sabadell (Barcelona)		Spain
437	205.235.3037 Hsopital Universitario Ntra. Sra. de la Candelaria	Santa Cruz de Tenerife		Spain
438	205.235.3039 Hospital Universitario Marqués de Valdecilla	Santander		Spain
439	205.235.3019 Hospital Vírgen de la Macarena	Sevilla		Spain
440	205.235.3035 Hospital Universitario Vírgen del Rocío	Sevilla		Spain
441	205.235.3001 Hospital Mutua Terrassa	Terrassa (Barcelona)		Spain
442	205.235.3002 Hospital Clínico Universitario de Valencia	Valencia		Spain
443	205.235.3025 Hospital Universitario Dr. Peset	Valencia		Spain
444	205.235.3032 Hospital Arnau de Vilanova	Valencia		Spain
445	205.235.3034 Hospital La Fe	Valencia		Spain
446	205.235.3018 Complejo Hospitalario Xeral - Cíes	Vigo		Spain
447	205.235.3030 Hospital Miguel Servet	Zaragoza		Spain
448	205.235.3038 Hospital Clínico Lozano Blesa	Zaragoza		Spain
449	205.235.3202 Boehringer Ingelheim Investigational Site	Basel		Switzerland
450	205.235.3203 Universitätsspital Basel	Basel		Switzerland
451	205.235.3204 Boehringer Ingelheim Investigational Site	Faltigberg		Switzerland
452	205.235.3205 Boehringer Ingelheim Investigational Site	Lugano		Switzerland
453	205.235.3206 Boehringer Ingelheim Investigational Site	Montana		Switzerland
454	205.235.3208 Boehringer Ingelheim Investigational Site	Winterthur		Switzerland
455	205.235.3201 Boehringer Ingelheim Investigational Site	Zürich		Switzerland
456	205.235.3301 Boehringer Ingelheim Investigational Site	Taipei		Taiwan
457	205.235.3302 Boehringer Ingelheim Investigational Site	Taipei		Taiwan
458	205.235.3303 Boehringer Ingelheim Investigational Site	Taipei		Taiwan
459	205.235.3402 Boehringer Ingelheim Investigational Site	Bangkok		Thailand
460	205.235.3403 Boehringer Ingelheim Investigational Site	Bangkok		Thailand
461	205.235.3404 Boehringer Ingelheim Investigational Site	Bangkok		Thailand
462	205.235.3401 Boehringer Ingelheim Investigational Site	Chiang Mai		Thailand
463	205.235.3405 Boehringer Ingelheim Investigational Site	Khon Kaen		Thailand
464	205.235.3510 Cukurova Tip Fakultesi Balcali Hastanesi	Adana		Turkey
465	205.235.3506 Hacettepe Tip Fakultesi	Ankara		Turkey
466	205.235.3507 Ankara SSK Diskapi Egitim Hastanesi	Ankara		Turkey
467	205.235.3508 Atatürk Gögüs Hastaliklari ve Gögüs Cerrahi	Ankara		Turkey
468	205.235.3509 Atatürk Üniversitesi Tip Fakultesi Aziziye	Erzurum		Turkey
469	205.235.3511 Osmangazi Universitesi Tip Fakültesi	Eskisehir		Turkey
470	205.235.3501 Istanbul Universitesi Cerrahpasa Tip Fakultesi	Istanbul		Turkey
471	205.235.3502 Yedikule Gögüs Hastaliklari Hastanesi	Istanbul		Turkey
472	205.235.3503 Tophanelioglu Cad. No: 13/15	Istanbul		Turkey
473	205.235.3504 Cevizli E5 Karayolu	Istanbul		Turkey
474	205.235.3505 Istanbul Universitesi Tip Fakültesi	Istanbul		Turkey
475	205.235.3512 DokuzEylül Universitesi Tip Fakultesi Gögüs Hastaliklari ABD	Izmir		Turkey
476	205.235.3615 Boehringer Ingelheim Investigational Site	Aberdeen		United Kingdom
477	205.235.3611 Boehringer Ingelheim Investigational Site	Chertsey		United Kingdom
478	205.235.3613 Boehringer Ingelheim Investigational Site	Chesterfield		United Kingdom
479	205.235.3608 Boehringer Ingelheim Investigational Site	Cottingham, Hull		United Kingdom
480	205.235.3605 Boehringer Ingelheim Investigational Site	Exeter		United Kingdom
481	205.235.3602 Boehringer Ingelheim Investigational Site	Glasgow		United Kingdom
482	205.235.3610 Boehringer Ingelheim Investigational Site	Leeds		United Kingdom
483	205.235.3607 Boehringer Ingelheim Investigational Site	Leicester		United Kingdom
484	205.235.3604 Boehringer Ingelheim Investigational Site	Middleton		United Kingdom
485	205.235.3612 Boehringer Ingelheim Investigational Site	Nottingham		United Kingdom
486	205.235.3616 Boehringer Ingelheim Investigational Site	Paisley		United Kingdom
487	205.235.3614 Boehringer Ingelheim Investigational Site	Penarth		United Kingdom
488	205.235.3603 Boehringer Ingelheim Investigational Site	Plymouth		United Kingdom
489	205.235.3609 Boehringer Ingelheim Investigational Site	Sheffield		United Kingdom
490	205.235.3601 Boehringer Ingelheim Investigational Site	Solihull, Birmingham		United Kingdom

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.

Responsible Party:

, ,

ClinicalTrials.gov Identifier:

NCT00144339

Other Study ID Numbers:

205.235

First Posted:

Sep 5, 2005

Last Update Posted:

May 20, 2014

Last Verified:

Apr 1, 2014

Additional relevant MeSH terms:

Lung Diseases

Pulmonary Disease, Chronic Obstructive

Tiotropium Bromide

Study Results

Participant Flow

Recruitment Details	09 Jan 2003 - 22 Feb 2008; 490 centers in 37 countries
Pre-assignment Detail

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	once daily	once daily
Period Title: Overall Study
STARTED	3006	2986
COMPLETED	1648	1887
NOT COMPLETED	1358	1099

Baseline Characteristics

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg	Total
Arm/Group Description	Once daily	Once daily	Total of all reporting groups
Overall Participants	3006	2986	5992
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.52 (8.48)	64.50 (8.41)	64.51 (8.45)
Sex: Female, Male (Count of Participants)
Female	784 26.1%	735 24.6%	1519.0 25.4%
Male	2222 73.9%	2251 75.4%	4473.0 74.6%

Outcome Measures

1. Primary Outcome

Title	Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 30 to 4 Years
Description	Rate of decline of forced expiratory volume in one second (FEV1) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1.
Time Frame	From day 30 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2413	2557
Mean (Standard Error) [ml/year]	-30 (1)	-30 (1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments	Linear random effects model
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.9524
	Comments
	Method	t-test, 2 sided
	Comments	Random-effects model

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0
	Confidence Interval	() 95% -4 to 4
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2
	Estimation Comments	Arbitrary covariance matrix; fixed treatment effect; individual patients are random; rate of decline estimated as the slope of the random effects model

2. Primary Outcome

Title	Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 30 to 4 Years
Description	Rate of decline of forced expiratory volume in one second (FEV1) measured after bronchodilation. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1.
Time Frame	From day 30 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2410	2554
Mean (Standard Error) [ml/year]	-42 (1)	-40 (1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments	Linear random effects model
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.2074
	Comments
	Method	t-test, 2 sided
	Comments	Random-effects model

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2
	Confidence Interval	() 95% -2 to 6
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2
	Estimation Comments	Arbitrary covariance matrix; fixed treatment effect; individual patients are random; rate of decline estimated as the slope of the random effects model

3. Secondary Outcome

Title	Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment
Description	Rate of decline of forced expiratory volume in one second (FEV1) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1
Time Frame	Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days.

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	1618	1803
Median (Standard Error) [ml/year]	-17 (2)	-15 (2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.2488
	Comments
	Method	Wilcoxon Rank-sum test
	Comments	Rate calculated as (measure on 30days after completion of treatment - measure on day 1 )/ years in between

4. Secondary Outcome

Title	Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment
Description	Rate of decline of forced expiratory volume in one second (FEV1) measured after the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1
Time Frame	Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	1613	1805
Median (Standard Error) [ml/year]	-32 (2)	-27 (2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0145
	Comments
	Method	Wilcoxon Rank-sum test
	Comments	Rate calculated as (measure on 30days after completion of treatment - measure on day 1 )/ years in between

5. Secondary Outcome

Title	Pre-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 30 to 4 Years
Description	Rate of decline of forced vital capacity (FVC) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC
Time Frame	From day 30 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2413	2557
Mean (Standard Error) [ml/year]	-39 (3)	-43 (3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments	Linear random effects model
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.2990
	Comments
	Method	t-test, 2 sided
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4
	Confidence Interval	() 95% -12 to 4
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4
	Estimation Comments	Arbitrary covariance matrix; fixed treatment effect; individual patients are random; rate of decline estimated as the slope of the random effects model

6. Secondary Outcome

Title	Post-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 30 to 4 Years
Description	Rate of decline of forced vital capacity (FVC) measured after bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC
Time Frame	From day 30 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2410	2554
Mean (Standard Error) [ml/year]	-61 (3)	-61 (3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments	Linear random effects model
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.8375
	Comments
	Method	t-test, 2 sided
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1
	Confidence Interval	() 95% -9 to 7
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4
	Estimation Comments	Arbitrary covariance matrix; fixed treatment effect; individual patients are random; rate of decline estimated as the slope of the random effects model

7. Secondary Outcome

Title	Pre-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 30 to 4 Years
Description	Rate of decline of slow vital capacity (SVC) measured before the use of bronchodilators. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC
Time Frame	From day 30 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2531
Mean (Standard Error) [ml/year]	-41 (3)	-47 (3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments	Linear random effects model
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1143
	Comments
	Method	t-test, 2 sided
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-6
	Confidence Interval	() 95% -14 to 2
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4
	Estimation Comments	Arbitrary covariance matrix; fixed treatment effect; individual patients are random; rate of decline estimated as the slope of the random effects model

8. Secondary Outcome

Title	Post-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 30 to 4 Years
Description	Rate of decline of slow vital capacity (SVC) measured after bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC
Time Frame	From day 30 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2383	2527
Mean (Standard Error) [ml/year]	-65 (3)	-66 (3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments	Linear random effects model
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.7870
	Comments
	Method	t-test, 2 sided
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-1
	Confidence Interval	() 95% -9 to 7
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4
	Estimation Comments	Arbitrary covariance matrix; fixed treatment effect; individual patients are random; rate of decline estimated as the slope of the random effects model

9. Secondary Outcome

Title	Rate of Decline of St George's Respiratory Questionnaire (SGRQ) Total Score
Description	SGRQ total score shows the impact of COPD on patient's health status, and expressed as a percentage of impairment with scale from 0 (best health status) to 100 (worst possible status). A negative rate of decline shows decreasing SGRQ total score (or improved health) over time, while a positive value shows increasing score (or worsen health).
Time Frame	From month 6 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2362	2505
Mean (Standard Error) [Score on scale per year]	1.21 (0.09)	1.25 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments	Linear random effects model
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.7840
	Comments
	Method	t-test, 2 sided
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.04
	Confidence Interval	() 95% -0.2 to 0.3
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.13
	Estimation Comments	Arbitrary covariance matrix; fixed treatment effect; individual patients are random; rate of decline estimated as the slope of the random effects model

10. Secondary Outcome

Title	Pre-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment
Description	Rate of decline of forced vital capacity (FVC) before bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC
Time Frame	Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days.

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	1618	1803
Median (Standard Error) [ml/year]	-12 (4)	-10 (3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.2705
	Comments
	Method	Wilcoxon Rank-sum test
	Comments	Rate calculated as (measure on 30days after completion of treatment - measure on day 1 )/ years in between

11. Secondary Outcome

Title	Post-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment
Description	Rate of decline of forced vital capacity (FVC) after bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC
Time Frame	Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	1613	1805
Median (Standard Error) [ml/year]	-40 (4)	-40 (3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.306
	Comments
	Method	Wilcoxon Rank-sum test
	Comments	Rate calculated as (measure on 30days after completion of treatment - measure on day 1 )/ years in between

12. Secondary Outcome

Title	Pre-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment
Description	Rate of decline slow vital capacity (SVC) before bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC
Time Frame	Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	1562	1706
Median (Standard Error) [ml/year]	-17 (4)	-17 (4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.8103
	Comments
	Method	Wilcoxon Rank-sum test
	Comments	Rate calculated as (measure on 30days after completion of treatment - measure on day 1 )/ years in between

13. Secondary Outcome

Title	Post-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment
Description	Rate of decline of slow vital capacity (SVC) after bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC
Time Frame	Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	1540	1711
Median (Standard Error) [ml/year]	-46 (4)	-42 (3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.9814
	Comments
	Method	Wilcoxon Rank-sum test
	Comments	Rate calculated as (measure on 30days after completion of treatment - measure on day 1 )/ years in between

14. Secondary Outcome

Title	Time to First Exacerbation
Description	Chronic obstructive pulmonary disease (COPD) exacerbation
Time Frame	From Day 1 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Median (95% Confidence Interval) [months]	12.51	16.65

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments	Cox regression
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments	Cox regression with treatment

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	() 95% 0.81 to 0.91
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.03
	Estimation Comments	Median estimated by Kaplan-Meier estimates; hazard ratio shown as tio vs. placebo

15. Secondary Outcome

Title	Number of Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Per Patient Year
Description
Time Frame	Day 1 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Mean (Standard Error) [number per patient year]	0.85 (0.02)	0.73 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments	Poisson regression adjusted for overdispersion and treatment exposure
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments

Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.86
	Confidence Interval	() 95% 0.81 to 0.91
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.03
	Estimation Comments	Ratio calculated as estimated number of events in tio/number of events in placebo

16. Secondary Outcome

Title	Number and Percentage of Patients With at Least One Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
Description
Time Frame	Day 1 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients	2049 68.2%	2001 67%
Percentage of patients	68.2 2.3%	67 2.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.3481
	Comments
	Method	Fisher Exact
	Comments

17. Secondary Outcome

Title	Number of Exacerbation Days Per Patient Year
Description	Number of exacerbation days normalized by treatment exposure
Time Frame	Day 1 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Mean (Standard Error) [days/patient year]	13.64 (0.35)	12.11 (0.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments	Poisson regression adjusted for overdispersion and treatment exposure
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	t-test, 2 sided
	Comments

Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.89
	Confidence Interval	() 95% 0.83 to 0.95
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.03
	Estimation Comments	Poisson regression adjusting for overdispersion with Pearson's method adjusting for treatment exposure. The logarithm of treatment exposure is used as offset when building the Poisson model.

18. Secondary Outcome

Title	Time to First COPD Exacerbation Leading to Hospitalization (for 25% Patients)
Description
Time Frame	Day 1 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Median (95% Confidence Interval) [months]	28.64	35.89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1766
	Comments
	Method	Fisher Exact
	Comments

19. Secondary Outcome

Title	Number and Percentage of Patients With at Least on COPD Exacerbation Leading to Hospitalization
Description
Time Frame	From Day 1 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients	811 27%	759 25.4%
Percentage of patients	27 0.9%	25.4 0.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments	Cox regression
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	() 95% 0.78 to 0.95
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.04
	Estimation Comments	Hazard ratio shown as tiotropium bromide vs. placebo

20. Secondary Outcome

Title	Number of Exacerbation Leading to Hospitalization
Description	Estimated number of exacerbations leading to hospitalizations per patient year
Time Frame	From Day 1 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number [Number per patient year]	0.16	0.15

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.3413
	Comments
	Method	t-test, 2 sided
	Comments

Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.94
	Confidence Interval	() 95% 0.82 to 1.07
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.06
	Estimation Comments	Ratio of estimated number of events between tiotropium bromide and placebo

21. Secondary Outcome

Title	Days of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Leading to Hospitalization
Description	Number of days with chronic obstructive pulmonary disease (COPD) exacerbation leading to hospitalization (normalized by treatment exposure)
Time Frame	From Day 1 to 4 years

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Mean (Standard Error) [days/patient year]	3.13 (0.17)	3.17 (0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments	Poisson regression adjusting for overdispersion with Pearson's method adjusting for treatment exposure. The logarithm of treatment exposure is used as offset when building the Poisson model.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.8624
	Comments
	Method	t-test, 2 sided
	Comments

Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	1.01
	Confidence Interval	() 95% 0.87 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of estimated number of days of chronic obstructive pulmonary disease (COPD) exacerbation leading to hospitalization between tio and placebo

22. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 1
Description	Estimated FEV1 before bronchodilator at Month 1
Time Frame	Month 1

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	1.134 (0.004)	1.221 (0.004)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.087
	Confidence Interval	() 95% 0.077 to 0.098
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 1
Description	Estimated forced expiratory volume in one second (FEV1) after bronchodilator at month 1
Time Frame	Month 1

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	1.372 (0.004)	1.418 (0.004)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.047
	Confidence Interval	() 95% 0.037 to 0.057
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 6
Description	Estimated forced expiratory volume in one second (FEV1) before bronchodilator at month 6
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	1.126 (0.004)	1.225 (0.004)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.099
	Confidence Interval	() 95% 0.087 to 0.110
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 6
Description
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Deviation) [L]	1.365 (0.004)	1.423 (0.004)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.058
	Confidence Interval	() 95% 0.047 to 0.069
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 12
Description
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	1.111 (0.004)	1.213 (0.004)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.103
	Confidence Interval	() 95% 0.091 to 0.115
	Parameter Dispersion	Type: Value:
	Estimation Comments

27. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 12
Description
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	1.345 (0.004)	1.398 (0.004)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.054
	Confidence Interval	() 95% 0.042 to 0.065
	Parameter Dispersion	Type: Value:
	Estimation Comments

28. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 18
Description
Time Frame	Month 18

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	1.101 (0.005)	1.192 (0.005)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.091
	Confidence Interval	() 95% 0.078 to 0.104
	Parameter Dispersion	Type: Value:
	Estimation Comments

29. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 18
Description
Time Frame	Month 18

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	1.326 (0.005)	1.379 (0.005)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.053
	Confidence Interval	() 95% 0.040 to 0.066
	Parameter Dispersion	Type: Value:
	Estimation Comments

30. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 24
Description
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	1.079 (0.005)	1.173 (0.005)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.094
	Confidence Interval	() 95% 0.081 to 0.107
	Parameter Dispersion	Type: Value:
	Estimation Comments

31. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 24
Description
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	1.294 (0.005)	1.356 (0.005)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.062
	Confidence Interval	() 95% 0.049 to 0.075
	Parameter Dispersion	Type: Value:
	Estimation Comments

32. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 30
Description
Time Frame	Month 30

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	1.061 (0.005)	1.156 (0.005)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.095
	Confidence Interval	() 95% 0.081 to 0.109
	Parameter Dispersion	Type: Value:
	Estimation Comments

33. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 30
Description
Time Frame	Month 30

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	1.274 (0.005)	1.335 (0.005)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.061
	Confidence Interval	() 95% 0.047 to 0.075
	Parameter Dispersion	Type: Value:
	Estimation Comments

34. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 36
Description
Time Frame	Month 36

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	1.045 (0.005)	1.144 (0.005)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.099
	Confidence Interval	() 95% 0.085 to 0.114
	Parameter Dispersion	Type: Value:
	Estimation Comments

35. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 36
Description
Time Frame	Month 36

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	1.250 (0.005)	1.315 (0.005)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.065
	Confidence Interval	() 95% 0.051 to 0.080
	Parameter Dispersion	Type: Value:
	Estimation Comments

36. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 42
Description
Time Frame	Month 42

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	1.034 (0.005)	1.129 (0.005)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.095
	Confidence Interval	() 95% 0.080 to 0.110
	Parameter Dispersion	Type: Value:
	Estimation Comments

37. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 42
Description	Estimated FEV1 after bronchodilator at Month 42
Time Frame	Month 42

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	1.236 (0.006)	1.297 (0.005)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.061
	Confidence Interval	() 95% 0.045 to 0.076
	Parameter Dispersion	Type: Value:
	Estimation Comments

38. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 48
Description
Time Frame	Month 48

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	1.024 (0.006)	1.112 (0.005)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.088
	Confidence Interval	() 95% 0.073 to 0.103
	Parameter Dispersion	Type: Value:
	Estimation Comments

39. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 48
Description
Time Frame	Month 48

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	1.219 (0.006)	1.268 (0.006)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.049
	Confidence Interval	() 95% 0.033 to 0.065
	Parameter Dispersion	Type: Value:
	Estimation Comments

40. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 1
Description
Time Frame	Month 1

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	2.667 (0.008)	2.856 (0.008)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.190
	Confidence Interval	() 95% 0.168 to 0.211
	Parameter Dispersion	Type: Value:
	Estimation Comments

41. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 1
Description
Time Frame	Month 1

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	3.149 (0.007)	3.204 (0.006)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.055
	Confidence Interval	() 95% 0.037 to 0.073
	Parameter Dispersion	Type: Value:
	Estimation Comments

42. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 6
Description
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	2.658 (0.009)	2.862 (0.008)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.204
	Confidence Interval	() 95% 0.180 to 0.228
	Parameter Dispersion	Type: Value:
	Estimation Comments

43. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 6
Description
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	3.137 (0.008)	3.193 (0.007)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.055
	Confidence Interval	() 95% 0.034 to 0.076
	Parameter Dispersion	Type: Value:
	Estimation Comments

44. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 12
Description
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	2.640 (0.009)	2.838 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.198
	Confidence Interval	() 95% 0.173 to 0.222
	Parameter Dispersion	Type: Value:
	Estimation Comments

45. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 12
Description
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	3.110 (0.008)	3.158 (0.008)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.048
	Confidence Interval	() 95% 0.026 to 0.070
	Parameter Dispersion	Type: Value:
	Estimation Comments

46. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 18
Description
Time Frame	Month 18

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	2.622 (0.010)	2.816 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.194
	Confidence Interval	() 95% 0.167 to 0.221
	Parameter Dispersion	Type: Value:
	Estimation Comments

47. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 18
Description
Time Frame	Month 18

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	3.075 (0.009)	3.126 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.050
	Confidence Interval	() 95% 0.026 to 0.074
	Parameter Dispersion	Type: Value:
	Estimation Comments

48. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 24
Description
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	2.597 (0.010)	2.785 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.189
	Confidence Interval	() 95% 0.161 to 0.216
	Parameter Dispersion	Type: Value:
	Estimation Comments

49. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 24
Description
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	3.036 (0.009)	3.095 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.059
	Confidence Interval	() 95% 0.035 to 0.084
	Parameter Dispersion	Type: Value:
	Estimation Comments

50. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 30
Description
Time Frame	Month 30

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	2.572 (0.010)	2.757 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.185
	Confidence Interval	() 95% 0.157 to 0.213
	Parameter Dispersion	Type: Value:
	Estimation Comments

51. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 30
Description
Time Frame	Month 30

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	3.010 (0.010)	3.057 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.047
	Confidence Interval	() 95% 0.021 to 0.074
	Parameter Dispersion	Type: Value:
	Estimation Comments

52. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 36
Description
Time Frame	Month 36

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	2.553 (0.011)	2.753 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.200
	Confidence Interval	() 95% 0.170 to 0.229
	Parameter Dispersion	Type: Value:
	Estimation Comments

53. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 36
Description
Time Frame	Month 36

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	2.973 (0.010)	3.038 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.065
	Confidence Interval	() 95% 0.038 to 0.093
	Parameter Dispersion	Type: Value:
	Estimation Comments

54. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 42
Description
Time Frame	Month 42

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	2.540 (0.011)	2.724 (0.011)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.184
	Confidence Interval	() 95% 0.154 to 0.215
	Parameter Dispersion	Type: Value:
	Estimation Comments

55. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 42
Description
Time Frame	Month 42

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	2.959 (0.011)	3.005 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0020
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.046
	Confidence Interval	() 95% 0.017 to 0.076
	Parameter Dispersion	Type: Value:
	Estimation Comments

56. Secondary Outcome

Title	Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 48
Description
Time Frame	Month 48

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2363	2494
Mean (Standard Error) [L]	2.532 (0.011)	2.702 (0.011)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.170
	Confidence Interval	() 95% 0.139 to 0.201
	Parameter Dispersion	Type: Value:
	Estimation Comments

57. Secondary Outcome

Title	Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 48
Description
Time Frame	Month 48

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2374	2516
Mean (Standard Error) [L]	2.929 (0.011)	2.961 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0365
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.032
	Confidence Interval	() 95% 0.002 to 0.061
	Parameter Dispersion	Type: Value:
	Estimation Comments

58. Secondary Outcome

Title	Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 1
Description
Time Frame	Month 1

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2325	2447
Mean (Standard Error) [L]	2.847 (0.008)	3.017 (0.008)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.170
	Confidence Interval	() 95% 0.147 to 0.192
	Parameter Dispersion	Type: Value:
	Estimation Comments

59. Secondary Outcome

Title	Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 1
Description
Time Frame	Month 1

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2340	2467
Mean (Standard Error) [L]	3.280 (0.007)	3.318 (0.007)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.038
	Confidence Interval	() 95% 0.018 to 0.058
	Parameter Dispersion	Type: Value:
	Estimation Comments

60. Secondary Outcome

Title	Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 6
Description
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2325	2447
Mean (Standard Error) [L]	2.841 (0.009)	3.027 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.186
	Confidence Interval	() 95% 0.161 to 0.210
	Parameter Dispersion	Type: Value:
	Estimation Comments

61. Secondary Outcome

Title	Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 6
Description
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2340	2467
Mean (Standard Error) [L]	3.268 (0.008)	3.304 (0.008)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0018
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.037
	Confidence Interval	() 95% 0.014 to 0.060
	Parameter Dispersion	Type: Value:
	Estimation Comments

62. Secondary Outcome

Title	Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 12
Description
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2325	2447
Mean (Standard Error) [L]	2.820 (0.009)	2.996 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.176
	Confidence Interval	() 95% 0.151 to 0.201
	Parameter Dispersion	Type: Value:
	Estimation Comments

63. Secondary Outcome

Title	Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 12
Description
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2340	2467
Mean (Standard Error) [L]	3.228 (0.008)	3.260 (0.008)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0069
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.032
	Confidence Interval	() 95% 0.009 to 0.055
	Parameter Dispersion	Type: Value:
	Estimation Comments

64. Secondary Outcome

Title	Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 18
Description
Time Frame	Month 18

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2325	2447
Mean (Standard Error) [L]	2.811 (0.010)	2.965 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.154
	Confidence Interval	() 95% 0.127 to 0.182
	Parameter Dispersion	Type: Value:
	Estimation Comments

65. Secondary Outcome

Title	Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 18
Description
Time Frame	Month 18

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2340	2467
Mean (Standard Error) [L]	3.195 (0.009)	3.234 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0020
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.040
	Confidence Interval	() 95% 0.015 to 0.065
	Parameter Dispersion	Type: Value:
	Estimation Comments

66. Secondary Outcome

Title	Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 24
Description
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2325	2447
Mean (Standard Error) [L]	2.775 (0.010)	2.942 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.167
	Confidence Interval	() 95% 0.139 to 0.194
	Parameter Dispersion	Type: Value:
	Estimation Comments

67. Secondary Outcome

Title	Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 24
Description
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2340	2467
Mean (Standard Error) [L]	3.157 (0.009)	3.189 (0.009)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0165
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.032
	Confidence Interval	() 95% 0.006 to 0.057
	Parameter Dispersion	Type: Value:
	Estimation Comments

68. Secondary Outcome

Title	Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 30
Description
Time Frame	Month 30

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2325	2447
Mean (Standard Error) [L]	2.738 (0.011)	2.908 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.170
	Confidence Interval	() 95% 0.141 to 0.199
	Parameter Dispersion	Type: Value:
	Estimation Comments

69. Secondary Outcome

Title	Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 30
Description
Time Frame	Month 30

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2340	2467
Mean (Standard Error) [L]	3.126 (0.010)	3.157 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0248
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.031
	Confidence Interval	() 95% 0.004 to 0.059
	Parameter Dispersion	Type: Value:
	Estimation Comments

70. Secondary Outcome

Title	Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 36
Description
Time Frame	Month 36

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2325	2447
Mean (Standard Error) [L]	2.731 (0.011)	2.897 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.166
	Confidence Interval	() 95% 0.136 to 0.196
	Parameter Dispersion	Type: Value:
	Estimation Comments

71. Secondary Outcome

Title	Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 36
Description
Time Frame	Month 36

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2340	2467
Mean (Standard Error) [L]	3.086 (0.010)	3.136 (0.010)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.050
	Confidence Interval	() 95% 0.022 to 0.078
	Parameter Dispersion	Type: Value:
	Estimation Comments

72. Secondary Outcome

Title	Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 42
Description
Time Frame	Month 42

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2325	2447
Mean (Standard Error) [L]	2.713 (0.011)	2.875 (0.011)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.161
	Confidence Interval	() 95% 0.130 to 0.192
	Parameter Dispersion	Type: Value:
	Estimation Comments

73. Secondary Outcome

Title	Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 42
Description
Time Frame	Month 42

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2340	2467
Mean (Standard Error) [L]	3.073 (0.011)	3.100 (0.011)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0809
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.027
	Confidence Interval	() 95% -0.003 to 0.057
	Parameter Dispersion	Type: Value:
	Estimation Comments

74. Secondary Outcome

Title	Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 48
Description
Time Frame	Month 48

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2325	2447
Mean (Standard Error) [L]	2.696 (0.012)	2.846 (0.011)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.150
	Confidence Interval	() 95% 0.119 to 0.182
	Parameter Dispersion	Type: Value:
	Estimation Comments

75. Secondary Outcome

Title	Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 48
Description
Time Frame	Month 48

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2340	2467
Mean (Standard Error) [L]	3.041 (0.011)	3.067 (0.011)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0915
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.026
	Confidence Interval	() 95% -0.004 to 0.057
	Parameter Dispersion	Type: Value:
	Estimation Comments

76. Secondary Outcome

Title	Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 6
Description	SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2337	2478
Mean (Standard Error) [Units on a scale]	42.289 (0.240)	39.409 (0.233)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.880
	Confidence Interval	() 95% -3.535 to -2.226
	Parameter Dispersion	Type: Value:
	Estimation Comments

77. Secondary Outcome

Title	Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 12
Description	SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2337	2478
Mean (Standard Error) [Units on a scale]	42.501 (0.253)	39.730 (0.245)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.771
	Confidence Interval	() 95% -3.461 to -2.081
	Parameter Dispersion	Type: Value:
	Estimation Comments

78. Secondary Outcome

Title	Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 18
Description	SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Time Frame	Month 18

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2337	2478
Mean (Standard Error) [Units on a scale]	43.067 (0.278)	40.474 (0.269)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.593
	Confidence Interval	() 95% -3.352 to -1.834
	Parameter Dispersion	Type: Value:
	Estimation Comments

79. Secondary Outcome

Title	Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 24
Description	SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2337	2478
Mean (Standard Error) [Units on a scale]	43.562 (0.297)	41.178 (0.286)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.384
	Confidence Interval	() 95% -3.191 to -1.576
	Parameter Dispersion	Type: Value:
	Estimation Comments

80. Secondary Outcome

Title	Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 30
Description	SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Time Frame	Month 30

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2337	2478
Mean (Standard Error) [Units on a scale]	44.342 (0.315)	41.919 (0.301)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.423
	Confidence Interval	() 95% -3.277 to -1.569
	Parameter Dispersion	Type: Value:
	Estimation Comments

81. Secondary Outcome

Title	Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 36
Description	SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Time Frame	Month 36

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2337	2478
Mean (Standard Error) [Units on a scale]	45.280 (0.326)	41.935 (0.311)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.345
	Confidence Interval	() 95% -4.229 to -2.462
	Parameter Dispersion	Type: Value:
	Estimation Comments

82. Secondary Outcome

Title	Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 42
Description	SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Time Frame	Month 42

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2337	2478
Mean (Standard Error) [Units on a scale]	45.722 (0.342)	42.905 (0.325)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.818
	Confidence Interval	() 95% -3.742 to -1.894
	Parameter Dispersion	Type: Value:
	Estimation Comments

83. Secondary Outcome

Title	Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 48
Description	SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score.
Time Frame	Month 48

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	2337	2478
Mean (Standard Error) [Units on a scale]	45.968 (0.357)	43.665 (0.338)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANOVA
	Comments	Repeated measures ANOVA

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.303
	Confidence Interval	() 95% -3.266 to -1.340
	Parameter Dispersion	Type: Value:
	Estimation Comments

84. Secondary Outcome

Title	Number and Percentage of Participants With All Cause Death and Time to Event Analysis (On-treatment)
Description	On-treatment defined as day 1 to completion of double blinded treatment plus 30 days
Time Frame	Day 1 to completion of double blinded treatment plus 30 days between Day 1 and 4 years plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with on-treatment death	402 13.4%	374 12.5%
Percentage patients with on-treatment death	13.4 0.4%	12.5 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0242
	Comments
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	() 95% 0.74 to 0.98
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.06
	Estimation Comments	Cox regression with treatment; hazard ratio shown as tiotropium bromide vs. placebo

85. Post-Hoc Outcome

Title	Number and Percentage of Participants With All Cause Death (Including Vital Status Follow-up, Cutoff at 1440 Days)
Description
Time Frame	Day 1 to day 1440

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients died from day 1 to day 1440	491 16.3%	430 14.4%
Percentage of patients died from day 1 to day 1440	16.3 0.5%	14.4 0.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments	Hazard ratio of all cause mortality vital status was information followed-up after discontinuation; vital status information up to 1440 days after the start of treatment was used
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0339
	Comments
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	() 95% 0.76 to 0.99
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.06
	Estimation Comments	Cox regression; cut-off at 4 years ; vital status form intended at 4 years; hazard ratio shown as tio vs. placebo

86. Secondary Outcome

Title	Number and Percentage of Participants With All Cause Death (Including Vital Status Follow-up, Cutoff at 1470 Days)
Description	All cause mortality vital status information was followed-up after discontinuation; vital status information up to 1470 days after the start of treatment was used.
Time Frame	Day 1 to day 1470

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients died from day 1 to day 1470	495 16.5%	446 14.9%
Percentage of patients died from day 1 to day 1470	16.5 0.5%	14.9 0.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0859
	Comments
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	() 95% 0.79 to 1.02
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.06
	Estimation Comments	Cox regression; cut-off at 4 years plus 30 days; vital status form intended at 4 years; hazard ratio shown as tio vs. placebo

87. Secondary Outcome

Title	Number and Percentage of Participants With Lower Respiratory Death (On-treatment; Adjudicated Primary Cause)
Description	The primary cause of death was adjudicated by an external committee prior to unblinding; on-treatment defined as day 1 to completion of double blinded treatment plus 30 days
Time Frame	Day 1 to completion of double blinded treatment plus 30 days between Day 1 and 4 years plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with lower respiratory	140 4.7%	131 4.4%
Percentage of patients with lower respiratory	4.7 0.2%	4.4 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1936
	Comments
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	() 95% 0.67 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox regression with treatment; hazard ratio shown as tiotropium bromide vs. placebo

88. Secondary Outcome

Title	Number and Percentage of Participants With a Lower Respiratory Death (Adjudicated; Including Vital Status Follow-up, Cutoff at 1470 Days)
Description	The primary cause of death was adjudicated by an external committee prior to unblinding; vital status was information followed-up after discontinuation; vital status information up to 1470 days after the start of treatment was used
Time Frame	Day 1 to day 1470

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with lower respiratory death	173 5.8%	153 5.1%
Percentage patients with lower respiratory death	5.8 0.2%	5.1 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.2377
	Comments
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	() 95% 0.71 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox regression; cut-off at 4 years plus 30 days; vital status form intended at 4 years; hazard ratio shown as tiotropium bromide vs. placebo

89. Other Pre-specified Outcome

Title	Incidence Rate of Serious Adverse Event (System Organ Class = Cardiac Disorders)
Description	Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Time Frame	Day 1 to completion of double blinded treatment plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with event	350	322
Incidence rate (number of events/100 patient year)	4.21	3.56

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0290
	Comments
	Method	Z-test
	Comments	incidence rate = number of patients with event/ time at risk

Method of Estimation	Estimation Parameter	Rate ratio of incidence rates
	Estimated Value	0.84
	Confidence Interval	() 95% 0.73 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio of incidence rates (tiotropium/placebo)

90. Other Pre-specified Outcome

Title	Incidence Rate of Serious Adverse Event (Preferred Term = Angina)
Description	Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Time Frame	Day 1 to completion of double blinded treatment plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with event	31	48
Incidence rate (number events/100-patient years)	0.36	0.51

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.1158
	Comments
	Method	Z-test
	Comments

Method of Estimation	Estimation Parameter	Rate ratio of incidence rates
	Estimated Value	1.44
	Confidence Interval	() 95% 0.91 to 2.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio of incidence rates (tiotropium/placebo)

91. Other Pre-specified Outcome

Title	Incidence Rate of Serious Adverse Event (Preferred Term = Atrial Fibrillation)
Description	Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Time Frame	Day 1 to completion of double blinded treatment plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with event	67	69
Incidence rate (number events/100-patient years)	0.77	0.74

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.7725
	Comments
	Method	Z-test
	Comments

Method of Estimation	Estimation Parameter	Rate ratio of incidence rates
	Estimated Value	0.95
	Confidence Interval	() 95% 0.68 to 1.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio of incidence rates (tiotropium/placebo)

92. Other Pre-specified Outcome

Title	Incidence Rate of Serious Adverse Event (Preferred Term = Cardiac Failure)
Description	Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Time Frame	Day 1 to completion of double blinded treatment plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with event	42	57
Incidence rate (number events/100-patient years)	0.48	0.61

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.2666
	Comments
	Method	Z-test
	Comments

Method of Estimation	Estimation Parameter	Rate ratio of incidence rates
	Estimated Value	1.25
	Confidence Interval	() 95% 0.84 to 1.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio of incidence rates (tiotropium/placebo)

93. Other Pre-specified Outcome

Title	Incidence Rate of Serious Adverse Event (Preferred Term = Cardiac Failure Congestive)
Description	Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Time Frame	Day 1 to completion of double blinded treatment plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with event	42	27
Incidence rate (number events/100-patient years)	0.48	0.29

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0337
	Comments
	Method	Z-test
	Comments

Method of Estimation	Estimation Parameter	Rate ratio of incidence rates
	Estimated Value	0.59
	Confidence Interval	() 95% 0.37 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio of incidence rates (tiotropium/placebo)

94. Other Pre-specified Outcome

Title	Incidence Rate of Serious Adverse Event (Preferred Term = Coronary Artery Disease)
Description	Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Time Frame	Day 1 to completion of double blinded treatment plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with event	32	20
Incidence rate (number events/100-patient years)	0.37	0.21

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0537
	Comments
	Method	Z-test
	Comments

Method of Estimation	Estimation Parameter	Rate ratio of incidence rates
	Estimated Value	0.58
	Confidence Interval	() 95% 0.33 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio of incidence rates (tiotropium/placebo)

95. Other Pre-specified Outcome

Title	Incidence Rate of Serious Adverse Event (Preferred Term = Myocardial Infarction)
Description	Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Time Frame	Day 1 to completion of double blinded treatment plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with event	84	65
Incidence rate (number events/100-patient years)	0.97	0.69

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0403
	Comments
	Method	Z-test
	Comments

Method of Estimation	Estimation Parameter	Rate ratio of incidence rates
	Estimated Value	0.71
	Confidence Interval	() 95% 0.52 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio of incidence rates (tiotropium/placebo)

96. Other Pre-specified Outcome

Title	Incidence Rate of Serious Adverse Event (System Organ Class = Lower Respiratory System Disorders)
Description	Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Time Frame	Day 1 to completion of double blinded treatment plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with event	985	911
Incidence rate (number events/100-patient years)	13.47	11.32

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Z-test
	Comments

Method of Estimation	Estimation Parameter	Rate ratio of incidence rates
	Estimated Value	0.84
	Confidence Interval	() 95% 0.77 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio of incidence rates (tiotropium/placebo)

97. Other Pre-specified Outcome

Title	Incidence Rate of Serious Adverse Event (Preferred Term = Bronchitis)
Description	Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Time Frame	Day 1 to completion of double blinded treatment plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with event	27	35
Incidence rate (number events/100-patient years)	0.31	0.37

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.4789
	Comments
	Method	Z-test
	Comments

Method of Estimation	Estimation Parameter	Rate ratio of incidence rates
	Estimated Value	1.20
	Confidence Interval	() 95% 0.73 to 1.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio of incidence rates (tiotropium/placebo)

98. Other Pre-specified Outcome

Title	Incidence Rate of Serious Adverse Event (Preferred Term = Chronic Obstructive Pulmonary Disease (COPD) Exacerbation)
Description	Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Time Frame	Day 1 to completion of double blinded treatment plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with event	742	688
Incidence rate (number events/100-patient years)	9.70	8.19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0014
	Comments
	Method	Z-test
	Comments

Method of Estimation	Estimation Parameter	Rate ratio of incidence rates
	Estimated Value	0.84
	Confidence Interval	() 95% 0.76 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio of incidence rates (tiotropium/placebo)

99. Other Pre-specified Outcome

Title	Incidence Rate of Serious Adverse Event (Preferred Term = Dyspnoea)
Description	Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Time Frame	Day 1 to completion of double blinded treatment plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with event	54	36
Incidence rate (number events/100-patient years)	0.62	0.38

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0236
	Comments
	Method	Z-test
	Comments

Method of Estimation	Estimation Parameter	Rate ratio of incidence rates
	Estimated Value	0.61
	Confidence Interval	() 95% 0.40 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio of incidence rates (tiotropium/placebo)

100. Other Pre-specified Outcome

Title	Incidence Rate of Serious Adverse Event (Preferred Term = Pneumonia)
Description	Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Time Frame	Day 1 to completion of double blinded treatment plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with event	290	296
Incidence rate (number events/100-patient years)	3.46	3.28

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.5064
	Comments
	Method	Z-test
	Comments

Method of Estimation	Estimation Parameter	Rate ratio of incidence rates
	Estimated Value	0.95
	Confidence Interval	() 95% 0.81 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio of incidence rates (tiotropium/placebo)

101. Other Pre-specified Outcome

Title	Incidence Rate of Serious Adverse Event (Preferred Term = Respiratory Failure)
Description	Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100.
Time Frame	Day 1 to completion of double blinded treatment plus 30 days

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Placebo	Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily	Once daily
Measure Participants	3006	2986
Number of patients with event	113	85
Incidence rate (number events/100-patient years)	1.31	0.90

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tiotropium Bromide Inhalation Capsules 18 mcg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0104
	Comments
	Method	Z-test
	Comments

Method of Estimation	Estimation Parameter	Rate ratio of incidence rates
	Estimated Value	0.69
	Confidence Interval	() 95% 0.52 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio of incidence rates (tiotropium/placebo)

Adverse Events

	Placebo		Tiotropium Bromide Inhalation Capsules 18 mcg
Time Frame	From first drug administration until 30 days after last drug administration
Adverse Event Reporting Description	The Dictionary used to report the adverse events is Sponsor-defined based on the MedDRA version 11.0

Arm/Group Title	Placebo		Tiotropium Bromide Inhalation Capsules 18 mcg
Arm/Group Description	Once daily		Once daily
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Tiotropium Bromide Inhalation Capsules 18 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1509/ (NaN)		1540/ (NaN)
Blood and lymphatic system disorders
Anaemia	11/3006 (0.4%)		19/2986 (0.6%)
Coagulopathy	0/3006 (0%)		2/2986 (0.1%)
Disseminated intravascular coagulation	1/3006 (0%)		0/2986 (0%)
Febrile neutropenia	2/3006 (0.1%)		1/2986 (0%)
Haemolytic anaemia	1/3006 (0%)		0/2986 (0%)
Haemorrhagic anaemia	4/3006 (0.1%)		0/2986 (0%)
Hypocoagulable state	0/3006 (0%)		1/2986 (0%)
Iron deficiency anaemia	4/3006 (0.1%)		2/2986 (0.1%)
Leukocytosis	0/3006 (0%)		1/2986 (0%)
Leukopenia	0/3006 (0%)		1/2986 (0%)
Lymphadenopathy	1/3006 (0%)		0/2986 (0%)
Microcytic anaemia	1/3006 (0%)		1/2986 (0%)
Neutropenia	0/3006 (0%)		2/2986 (0.1%)
Polycythaemia	1/3006 (0%)		2/2986 (0.1%)
Splenic haemorrhage	0/3006 (0%)		1/2986 (0%)
Splenic lesion	0/3006 (0%)		1/2986 (0%)
Splenic vein thrombosis	1/3006 (0%)		0/2986 (0%)
Splenomegaly	1/3006 (0%)		0/2986 (0%)
Thrombocytopenia	3/3006 (0.1%)		0/2986 (0%)
Cardiac disorders
Accelerated idioventricular rhythm	1/3006 (0%)		0/2986 (0%)
Acute coronary syndrome	2/3006 (0.1%)		6/2986 (0.2%)
Acute right ventricular failure	0/3006 (0%)		1/2986 (0%)
Angina	31/3006 (1%)		48/2986 (1.6%)
Aortic valve disease	1/3006 (0%)		0/2986 (0%)
Aortic valve incompetence	2/3006 (0.1%)		0/2986 (0%)
Aortic valve stenosis	0/3006 (0%)		2/2986 (0.1%)
Arrhythmia	10/3006 (0.3%)		7/2986 (0.2%)
Arrhythmia supraventricular	1/3006 (0%)		1/2986 (0%)
Arteriosclerosis coronary artery	1/3006 (0%)		1/2986 (0%)
Atrial Fibrillation	67/3006 (2.2%)		69/2986 (2.3%)
Atrial tachycardia	0/3006 (0%)		2/2986 (0.1%)
Atrial thrombosis	1/3006 (0%)		0/2986 (0%)
Atrioventricular block	1/3006 (0%)		3/2986 (0.1%)
Atrioventricular block complete	4/3006 (0.1%)		5/2986 (0.2%)
Atrioventricular block first degree	0/3006 (0%)		1/2986 (0%)
Atrioventricular block second degree	3/3006 (0.1%)		1/2986 (0%)
Bradycardia	5/3006 (0.2%)		1/2986 (0%)
Bundle branch block left	0/3006 (0%)		1/2986 (0%)
Bundle branch block right	1/3006 (0%)		0/2986 (0%)
Cardiac aneurysm	1/3006 (0%)		0/2986 (0%)
Cardiac arrest	11/3006 (0.4%)		6/2986 (0.2%)
Cardiac asthma	0/3006 (0%)		1/2986 (0%)
Cardiac disorder	2/3006 (0.1%)		0/2986 (0%)
Cardiac failure	42/3006 (1.4%)		57/2986 (1.9%)
Cardiac failure acute	3/3006 (0.1%)		4/2986 (0.1%)
Cardiac failure chronic	1/3006 (0%)		1/2986 (0%)
Cardiac failure congestive	42/3006 (1.4%)		27/2986 (0.9%)
Cardiac tamponade	0/3006 (0%)		1/2986 (0%)
Cardiac valve disease	1/3006 (0%)		0/2986 (0%)
Cardiac ventricular disorder	1/3006 (0%)		0/2986 (0%)
Cardio-respiratory arrest	7/3006 (0.2%)		6/2986 (0.2%)
Cardiogenic shock	3/3006 (0.1%)		4/2986 (0.1%)
Cardiomegaly	1/3006 (0%)		1/2986 (0%)
Cardiomyopathy	3/3006 (0.1%)		2/2986 (0.1%)
Cardiopulmonary failure	12/3006 (0.4%)		10/2986 (0.3%)
Conduction disorder	0/3006 (0%)		1/2986 (0%)
Cor pulmonale	15/3006 (0.5%)		12/2986 (0.4%)
Cor pulmonale acute	2/3006 (0.1%)		2/2986 (0.1%)
Cor pulmonale chronic	2/3006 (0.1%)		4/2986 (0.1%)
Coronary artery disease	32/3006 (1.1%)		20/2986 (0.7%)
Coronary artery embolism	0/3006 (0%)		1/2986 (0%)
Coronary artery insufficiency	1/3006 (0%)		1/2986 (0%)
Coronary artery occlusion	1/3006 (0%)		1/2986 (0%)
Coronary artery restenosis	0/3006 (0%)		1/2986 (0%)
Coronary artery stenosis	6/3006 (0.2%)		4/2986 (0.1%)
Coronary artery thrombosis	1/3006 (0%)		0/2986 (0%)
Diastolic dysfunction	0/3006 (0%)		1/2986 (0%)
Extrasystoles	0/3006 (0%)		1/2986 (0%)
Hypertensive cardiomyopathy	0/3006 (0%)		1/2986 (0%)
Hypertensive heart disease	1/3006 (0%)		0/2986 (0%)
Intracardiac thrombus	1/3006 (0%)		0/2986 (0%)
Ischaemic cardiomyopathy	3/3006 (0.1%)		2/2986 (0.1%)
Left ventricular dysfunction	2/3006 (0.1%)		1/2986 (0%)
Left ventricular failure	5/3006 (0.2%)		6/2986 (0.2%)
Mitral valve incompetence	3/3006 (0.1%)		2/2986 (0.1%)
Myocardial infarction	84/3006 (2.8%)		65/2986 (2.2%)
Myocardial ischaemia	13/3006 (0.4%)		10/2986 (0.3%)
Myocarditis	1/3006 (0%)		0/2986 (0%)
Palpitations	2/3006 (0.1%)		2/2986 (0.1%)
Pericardial haemorrhage	2/3006 (0.1%)		0/2986 (0%)
Pericarditis	1/3006 (0%)		0/2986 (0%)
Right ventricular failure	6/3006 (0.2%)		4/2986 (0.1%)
Sick sinus syndrome	1/3006 (0%)		0/2986 (0%)
Supraventricular extrasystoles	1/3006 (0%)		0/2986 (0%)
Supraventricular tachycardia	8/3006 (0.3%)		8/2986 (0.3%)
Tachyarrhythmia	2/3006 (0.1%)		5/2986 (0.2%)
Tachycardia	6/3006 (0.2%)		4/2986 (0.1%)
Torsade de pointes	1/3006 (0%)		0/2986 (0%)
Tricuspid valve incompetence	0/3006 (0%)		1/2986 (0%)
Ventricular arrhythmia	1/3006 (0%)		1/2986 (0%)
Ventricular extrasystoles	0/3006 (0%)		1/2986 (0%)
Ventricular fibrillation	9/3006 (0.3%)		3/2986 (0.1%)
Ventricular hypokinesia	1/3006 (0%)		0/2986 (0%)
Ventricular tachycardia	7/3006 (0.2%)		7/2986 (0.2%)
Congenital, familial and genetic disorders
Adenomatous polyposis coli	1/3006 (0%)		0/2986 (0%)
Arteriovenous malformation	0/3006 (0%)		1/2986 (0%)
Atrial septal defect	1/3006 (0%)		0/2986 (0%)
Congenital myopathy	1/3006 (0%)		0/2986 (0%)
Dermoid cyst	0/3006 (0%)		1/2986 (0%)
Dolichocolon	0/3006 (0%)		1/2986 (0%)
Gastrointestinal angiodysplasia	0/3006 (0%)		1/2986 (0%)
Gastrointestinal angiodysplasia haemorrhagic	1/3006 (0%)		0/2986 (0%)
Gastrointestinal arteriovenous malformation	1/3006 (0%)		1/2986 (0%)
Hydrocele	0/3006 (0%)		2/2986 (0.1%)
Neurofibromatosis	0/3006 (0%)		1/2986 (0%)
Phimosis	1/3006 (0%)		1/2986 (0%)
Pyloric stenosis	0/3006 (0%)		1/2986 (0%)
Ear and labyrinth disorders
Deafness	1/3006 (0%)		0/2986 (0%)
Hypoacusis	1/3006 (0%)		0/2986 (0%)
Otosclerosis	1/3006 (0%)		0/2986 (0%)
Sudden hearing loss	0/3006 (0%)		1/2986 (0%)
Vertigo	8/3006 (0.3%)		8/2986 (0.3%)
Vertigo positional	0/3006 (0%)		2/2986 (0.1%)
Vestibular disorder	1/3006 (0%)		0/2986 (0%)
Endocrine disorders
Adrenal insufficiency	0/3006 (0%)		1/2986 (0%)
Adrenal mass	0/3006 (0%)		1/2986 (0%)
Diabetes insipidus	1/3006 (0%)		0/2986 (0%)
Hyperparathyroidism	2/3006 (0.1%)		0/2986 (0%)
Hyperthyroidism	2/3006 (0.1%)		1/2986 (0%)
Thyroid disorder	0/3006 (0%)		1/2986 (0%)
Eye disorders
Amaurosis fugax	1/3006 (0%)		0/2986 (0%)
Blindness unilateral	0/3006 (0%)		1/2986 (0%)
Cataract	21/3006 (0.7%)		23/2986 (0.8%)
Conjunctivitis	1/3006 (0%)		0/2986 (0%)
Eye haemorrhage	0/3006 (0%)		1/2986 (0%)
Eye pain	0/3006 (0%)		1/2986 (0%)
Glaucoma	1/3006 (0%)		2/2986 (0.1%)
Iridocele	0/3006 (0%)		1/2986 (0%)
Optic ischaemic neuropathy	1/3006 (0%)		0/2986 (0%)
Retinal detachment	1/3006 (0%)		2/2986 (0.1%)
Retinal tear	1/3006 (0%)		0/2986 (0%)
Retinal vein occlusion	1/3006 (0%)		0/2986 (0%)
Vision blurred	0/3006 (0%)		1/2986 (0%)
Visual disturbance	1/3006 (0%)		0/2986 (0%)
Vitreous haemorrhage	0/3006 (0%)		1/2986 (0%)
Gastrointestinal disorders
Abdominal adhesions	2/3006 (0.1%)		2/2986 (0.1%)
Abdominal discomfort	1/3006 (0%)		0/2986 (0%)
Abdominal distension	1/3006 (0%)		0/2986 (0%)
Abdominal hernia	2/3006 (0.1%)		5/2986 (0.2%)
Abdominal pain	18/3006 (0.6%)		18/2986 (0.6%)
Abdominal strangulated hernia	1/3006 (0%)		0/2986 (0%)
Appendicitis perforated	0/3006 (0%)		2/2986 (0.1%)
Ascites	3/3006 (0.1%)		1/2986 (0%)
Coeliac disease	1/3006 (0%)		0/2986 (0%)
Colitis	3/3006 (0.1%)		0/2986 (0%)
Colitis ischaemic	1/3006 (0%)		1/2986 (0%)
Colitis ulcerative	0/3006 (0%)		1/2986 (0%)
Colonic polyp	4/3006 (0.1%)		5/2986 (0.2%)
Constipation	3/3006 (0.1%)		3/2986 (0.1%)
Crohn's disease	0/3006 (0%)		1/2986 (0%)
Dental caries	0/3006 (0%)		2/2986 (0.1%)
Diarrhoea	12/3006 (0.4%)		5/2986 (0.2%)
Diverticular perforation	2/3006 (0.1%)		1/2986 (0%)
Diverticulum	4/3006 (0.1%)		5/2986 (0.2%)
Diverticulum intestinal	0/3006 (0%)		1/2986 (0%)
Diverticulum intestinal haemorrhagic	1/3006 (0%)		3/2986 (0.1%)
Duodenal perforation	1/3006 (0%)		0/2986 (0%)
Duodenal polyp	0/3006 (0%)		1/2986 (0%)
Duodenal ulcer	4/3006 (0.1%)		3/2986 (0.1%)
Duodenal ulcer haemorrhage	1/3006 (0%)		0/2986 (0%)
Duodenitis	1/3006 (0%)		1/2986 (0%)
Dyspepsia	1/3006 (0%)		2/2986 (0.1%)
Dysphagia	3/3006 (0.1%)		2/2986 (0.1%)
Enterocolitis	1/3006 (0%)		0/2986 (0%)
Erosive duodenitis	1/3006 (0%)		0/2986 (0%)
Faecal incontinence	1/3006 (0%)		0/2986 (0%)
Faecaloma	2/3006 (0.1%)		2/2986 (0.1%)
Femoral hernia	1/3006 (0%)		0/2986 (0%)
Femoral hernia, obstructive	0/3006 (0%)		1/2986 (0%)
Flatulence	1/3006 (0%)		0/2986 (0%)
Gastric haemorrhage	3/3006 (0.1%)		2/2986 (0.1%)
Gastric polyps	1/3006 (0%)		1/2986 (0%)
Gastric ulcer	6/3006 (0.2%)		3/2986 (0.1%)
Gastric ulcer haemorrhage	0/3006 (0%)		1/2986 (0%)
Gastric varices haemorrhage	1/3006 (0%)		0/2986 (0%)
Gastric volvulus	0/3006 (0%)		1/2986 (0%)
Gastritis	5/3006 (0.2%)		9/2986 (0.3%)
Gastritis erosive	1/3006 (0%)		3/2986 (0.1%)
Gastritis haemorrhagic	2/3006 (0.1%)		1/2986 (0%)
Gastrointestinal haemorrhage	16/3006 (0.5%)		11/2986 (0.4%)
Gastrooesophageal reflux disease	2/3006 (0.1%)		2/2986 (0.1%)
Gastrooesophagitis	1/3006 (0%)		0/2986 (0%)
Haematemesis	4/3006 (0.1%)		2/2986 (0.1%)
Haematochezia	2/3006 (0.1%)		0/2986 (0%)
Haemorrhoids	5/3006 (0.2%)		2/2986 (0.1%)
Hiatus hernia	0/3006 (0%)		5/2986 (0.2%)
Ileitis	1/3006 (0%)		0/2986 (0%)
Ileus	7/3006 (0.2%)		9/2986 (0.3%)
Ileus paralytic	1/3006 (0%)		1/2986 (0%)
Inguinal hernia	21/3006 (0.7%)		20/2986 (0.7%)
Inguinal hernia, obstructive	0/3006 (0%)		1/2986 (0%)
Internal hernia	1/3006 (0%)		0/2986 (0%)
Intestinal angina	1/3006 (0%)		0/2986 (0%)
Intestinal fistula	1/3006 (0%)		0/2986 (0%)
Intestinal haemorrhage	0/3006 (0%)		2/2986 (0.1%)
Intestinal infarction	1/3006 (0%)		0/2986 (0%)
Intestinal ischaemia	2/3006 (0.1%)		1/2986 (0%)
Intestinal mucosal hypertrophy	1/3006 (0%)		0/2986 (0%)
Intestinal obstruction	2/3006 (0.1%)		9/2986 (0.3%)
Intestinal perforation	1/3006 (0%)		1/2986 (0%)
Intestinal polyp	3/3006 (0.1%)		1/2986 (0%)
Intra-abdominal haematoma	0/3006 (0%)		1/2986 (0%)
Irritable bowel syndrome	1/3006 (0%)		0/2986 (0%)
Large intestinal haemorrhage	0/3006 (0%)		1/2986 (0%)
Large intestine perforation	1/3006 (0%)		4/2986 (0.1%)
Loose tooth	1/3006 (0%)		0/2986 (0%)
Lower gastrointestinal haemorrhage	3/3006 (0.1%)		1/2986 (0%)
Malabsorption	0/3006 (0%)		1/2986 (0%)
Mallory-Weiss syndrome	0/3006 (0%)		1/2986 (0%)
Mechanical ileus	0/3006 (0%)		1/2986 (0%)
Melaena	7/3006 (0.2%)		4/2986 (0.1%)
Mouth cyst	0/3006 (0%)		1/2986 (0%)
Mouth ulceration	0/3006 (0%)		1/2986 (0%)
Nausea	0/3006 (0%)		5/2986 (0.2%)
Odynophagia	0/3006 (0%)		1/2986 (0%)
Oesophageal stenosis	1/3006 (0%)		1/2986 (0%)
Oesophageal varices haemorrhage	1/3006 (0%)		0/2986 (0%)
Oesophagitis	2/3006 (0.1%)		1/2986 (0%)
Oesophagitis ulcerative	0/3006 (0%)		1/2986 (0%)
Pancreatic duct obstruction	1/3006 (0%)		0/2986 (0%)
Pancreatitis	6/3006 (0.2%)		5/2986 (0.2%)
Pancreatitis acute	3/3006 (0.1%)		3/2986 (0.1%)
Pancreatitis chronic	0/3006 (0%)		1/2986 (0%)
Parotid lipomatosis	0/3006 (0%)		1/2986 (0%)
Peptic ulcer	1/3006 (0%)		0/2986 (0%)
Peptic ulcer haemorrhage	1/3006 (0%)		0/2986 (0%)
Peritonitis	1/3006 (0%)		4/2986 (0.1%)
Pneumoperitoneum	0/3006 (0%)		1/2986 (0%)
Polyp colorectal	2/3006 (0.1%)		0/2986 (0%)
Rectal discharge	0/3006 (0%)		1/2986 (0%)
Rectal haemorrhage	1/3006 (0%)		1/2986 (0%)
Rectal polyp	2/3006 (0.1%)		1/2986 (0%)
Reflux oesophagitis	0/3006 (0%)		3/2986 (0.1%)
Salivary gland calculus	0/3006 (0%)		1/2986 (0%)
Salivary gland mass	0/3006 (0%)		1/2986 (0%)
Small intestinal obstruction	4/3006 (0.1%)		4/2986 (0.1%)
Small intestinal perforation	0/3006 (0%)		1/2986 (0%)
Stomach discomfort	2/3006 (0.1%)		0/2986 (0%)
Stomatitis	0/3006 (0%)		1/2986 (0%)
Subileus	4/3006 (0.1%)		1/2986 (0%)
Umbilical hernia	4/3006 (0.1%)		2/2986 (0.1%)
Umbilical hernia, obstructive	1/3006 (0%)		0/2986 (0%)
Upper gastrointestinal haemorrhage	5/3006 (0.2%)		3/2986 (0.1%)
Varices oesophageal	1/3006 (0%)		1/2986 (0%)
Volvulus	0/3006 (0%)		1/2986 (0%)
Vomiting	1/3006 (0%)		5/2986 (0.2%)
General disorders
Accidental death	0/3006 (0%)		1/2986 (0%)
Adverse drug reaction	0/3006 (0%)		1/2986 (0%)
Asthenia	6/3006 (0.2%)		7/2986 (0.2%)
Cardiac death	1/3006 (0%)		0/2986 (0%)
Chest discomfort	1/3006 (0%)		1/2986 (0%)
Chest pain	19/3006 (0.6%)		23/2986 (0.8%)
Cyst rupture	1/3006 (0%)		0/2986 (0%)
Death	24/3006 (0.8%)		31/2986 (1%)
Fatigue	2/3006 (0.1%)		2/2986 (0.1%)
General physical health deterioration	5/3006 (0.2%)		3/2986 (0.1%)
Impaired healing	0/3006 (0%)		2/2986 (0.1%)
Influenza like illness	0/3006 (0%)		1/2986 (0%)
Multi-organ disorder	0/3006 (0%)		1/2986 (0%)
Multi-organ failure	10/3006 (0.3%)		6/2986 (0.2%)
Multimorbidity	1/3006 (0%)		0/2986 (0%)
Non-cardiac chest pain	20/3006 (0.7%)		18/2986 (0.6%)
Oedema	14/3006 (0.5%)		8/2986 (0.3%)
Pain	1/3006 (0%)		2/2986 (0.1%)
Perforated ulcer	1/3006 (0%)		0/2986 (0%)
Polyp	1/3006 (0%)		0/2986 (0%)
Pyrexia	6/3006 (0.2%)		9/2986 (0.3%)
Sudden cardiac death	2/3006 (0.1%)		1/2986 (0%)
Sudden death	11/3006 (0.4%)		10/2986 (0.3%)
Ulcer	0/3006 (0%)		1/2986 (0%)
Hepatobiliary disorders
Acute hepatic failure	1/3006 (0%)		0/2986 (0%)
Bile duct obstruction	0/3006 (0%)		1/2986 (0%)
Bile duct stone	2/3006 (0.1%)		6/2986 (0.2%)
Biliary colic	0/3006 (0%)		3/2986 (0.1%)
Biliary dyskinesia	0/3006 (0%)		1/2986 (0%)
Cholangitis	2/3006 (0.1%)		1/2986 (0%)
Cholangitis acute	0/3006 (0%)		1/2986 (0%)
Cholecystitis	5/3006 (0.2%)		7/2986 (0.2%)
Cholecystitis acute	4/3006 (0.1%)		6/2986 (0.2%)
Cholecystitis chronic	1/3006 (0%)		1/2986 (0%)
Cholelithiasis	18/3006 (0.6%)		11/2986 (0.4%)
Cholelithiasis obstructive	1/3006 (0%)		0/2986 (0%)
Cholestasis	2/3006 (0.1%)		0/2986 (0%)
Chronic hepatitis	1/3006 (0%)		0/2986 (0%)
Gallbladder disorder	1/3006 (0%)		0/2986 (0%)
Hepatic cirrhosis	0/3006 (0%)		3/2986 (0.1%)
Hepatic failure	1/3006 (0%)		2/2986 (0.1%)
Hepatic function abnormal	1/3006 (0%)		0/2986 (0%)
Hepatitis	1/3006 (0%)		0/2986 (0%)
Hepatitis acute	1/3006 (0%)		0/2986 (0%)
Hepatitis alcoholic	2/3006 (0.1%)		1/2986 (0%)
Hepatomegaly	1/3006 (0%)		0/2986 (0%)
Jaundice	1/3006 (0%)		0/2986 (0%)
Jaundice cholestatic	0/3006 (0%)		1/2986 (0%)
Immune system disorders
Anaphylactic reaction	0/3006 (0%)		1/2986 (0%)
Anaphylactic shock	1/3006 (0%)		0/2986 (0%)
Food allergy	1/3006 (0%)		1/2986 (0%)
Hypersensitivity	0/3006 (0%)		2/2986 (0.1%)
Infections and infestations
Abdominal infection	1/3006 (0%)		0/2986 (0%)
Abdominal sepsis	0/3006 (0%)		1/2986 (0%)
Abdominal wall abscess	1/3006 (0%)		0/2986 (0%)
Abscess	0/3006 (0%)		1/2986 (0%)
Abscess intestinal	1/3006 (0%)		0/2986 (0%)
Abscess limb	1/3006 (0%)		1/2986 (0%)
Appendiceal abscess	0/3006 (0%)		1/2986 (0%)
Appendicitis	2/3006 (0.1%)		9/2986 (0.3%)
Arthritis infective	1/3006 (0%)		1/2986 (0%)
Bacteraemia	1/3006 (0%)		2/2986 (0.1%)
Bacterial infection	0/3006 (0%)		1/2986 (0%)
Biliary tract infection	1/3006 (0%)		0/2986 (0%)
Cellulitis	12/3006 (0.4%)		9/2986 (0.3%)
Cholecystitis infective	0/3006 (0%)		1/2986 (0%)
Clostridial infection	0/3006 (0%)		1/2986 (0%)
Clostridium difficile colitis	3/3006 (0.1%)		1/2986 (0%)
Corynebacterium infection	0/3006 (0%)		1/2986 (0%)
Cystitis escherichia	0/3006 (0%)		1/2986 (0%)
Dengue fever	0/3006 (0%)		1/2986 (0%)
Dermo-hypodermitis	1/3006 (0%)		0/2986 (0%)
Device related infection	0/3006 (0%)		1/2986 (0%)
Diverticulitis	8/3006 (0.3%)		7/2986 (0.2%)
Empyema	0/3006 (0%)		2/2986 (0.1%)
Endocarditis	0/3006 (0%)		1/2986 (0%)
Enterococcal sepsis	1/3006 (0%)		0/2986 (0%)
Erysipelas	0/3006 (0%)		5/2986 (0.2%)
Escherichia sepsis	0/3006 (0%)		1/2986 (0%)
Fungaemia	1/3006 (0%)		1/2986 (0%)
Fungal infection	0/3006 (0%)		1/2986 (0%)
Gangrene	3/3006 (0.1%)		0/2986 (0%)
Gastritis viral	1/3006 (0%)		0/2986 (0%)
Gastroenteritis	3/3006 (0.1%)		5/2986 (0.2%)
Gastroenteritis Escherichia coli	1/3006 (0%)		0/2986 (0%)
Gastroenteritis salmonella	0/3006 (0%)		2/2986 (0.1%)
Gastroenteritis viral	1/3006 (0%)		0/2986 (0%)
Groin abscess	1/3006 (0%)		1/2986 (0%)
Haemorrhoid infection	1/3006 (0%)		0/2986 (0%)
Helicobacter infection	0/3006 (0%)		1/2986 (0%)
Herpes zoster	1/3006 (0%)		0/2986 (0%)
Herpes zoster infection neurological	1/3006 (0%)		0/2986 (0%)
Hydrocele male infected	0/3006 (0%)		1/2986 (0%)
Incision site infection	1/3006 (0%)		0/2986 (0%)
Infection	0/3006 (0%)		1/2986 (0%)
Intertrigo candida	1/3006 (0%)		0/2986 (0%)
Intervertebral discitis	1/3006 (0%)		0/2986 (0%)
Joint abscess	0/3006 (0%)		1/2986 (0%)
Klebsiella sepsis	0/3006 (0%)		1/2986 (0%)
Localised infection	0/3006 (0%)		1/2986 (0%)
Meningitis	0/3006 (0%)		2/2986 (0.1%)
Meningitis listeria	1/3006 (0%)		0/2986 (0%)
Meningococcal bacteraemia	0/3006 (0%)		1/2986 (0%)
Mycobacterial infection	0/3006 (0%)		1/2986 (0%)
Necrotising fasciitis	1/3006 (0%)		1/2986 (0%)
Neutropenic sepsis	0/3006 (0%)		1/2986 (0%)
Nosocomial infection	1/3006 (0%)		0/2986 (0%)
Oesophageal candidiasis	0/3006 (0%)		1/2986 (0%)
Orchitis	1/3006 (0%)		1/2986 (0%)
Oropharyngeal candidiasis	2/3006 (0.1%)		0/2986 (0%)
Osteomyelitis	1/3006 (0%)		3/2986 (0.1%)
Otitis media	0/3006 (0%)		1/2986 (0%)
Parotitis	0/3006 (0%)		1/2986 (0%)
Perianal abscess	0/3006 (0%)		1/2986 (0%)
Periodontal infection	0/3006 (0%)		1/2986 (0%)
Periorbital cellulitis	1/3006 (0%)		0/2986 (0%)
Perirectal abscess	1/3006 (0%)		0/2986 (0%)
Peritoneal abscess	0/3006 (0%)		1/2986 (0%)
Peritoneal infection	1/3006 (0%)		0/2986 (0%)
Pneumococcal sepsis	1/3006 (0%)		0/2986 (0%)
Post procedural infection	0/3006 (0%)		1/2986 (0%)
Post procedural pneumonia	1/3006 (0%)		0/2986 (0%)
Postoperative wound infection	2/3006 (0.1%)		3/2986 (0.1%)
Pseudomonas infection	1/3006 (0%)		0/2986 (0%)
Sepsis	26/3006 (0.9%)		16/2986 (0.5%)
Sepsis syndrome	1/3006 (0%)		2/2986 (0.1%)
Septic shock	11/3006 (0.4%)		9/2986 (0.3%)
Skin infection	2/3006 (0.1%)		0/2986 (0%)
Staphylococcal infection	1/3006 (0%)		2/2986 (0.1%)
Staphylococcal sepsis	1/3006 (0%)		1/2986 (0%)
Subcutaneous abscess	0/3006 (0%)		1/2986 (0%)
Toxic shock syndrome	0/3006 (0%)		1/2986 (0%)
Tuberculosis	4/3006 (0.1%)		4/2986 (0.1%)
Urinary tract infection	17/3006 (0.6%)		24/2986 (0.8%)
Urosepsis	3/3006 (0.1%)		1/2986 (0%)
Wound infection	1/3006 (0%)		2/2986 (0.1%)
Wound infection staphylococcal	0/3006 (0%)		1/2986 (0%)
Wound sepsis	1/3006 (0%)		0/2986 (0%)
Injury, poisoning and procedural complications
Abdominal injury	0/3006 (0%)		1/2986 (0%)
Accident	0/3006 (0%)		3/2986 (0.1%)
Acetabulum fracture	0/3006 (0%)		1/2986 (0%)
Alcohol poisoning	4/3006 (0.1%)		3/2986 (0.1%)
Anaemia postoperative	1/3006 (0%)		0/2986 (0%)
Anastomotic stenosis	0/3006 (0%)		1/2986 (0%)
Ankle fracture	5/3006 (0.2%)		6/2986 (0.2%)
Arteriovenous fistula site complication	1/3006 (0%)		0/2986 (0%)
Arteriovenous fistula site haemorrhage	1/3006 (0%)		0/2986 (0%)
Back injury	1/3006 (0%)		0/2986 (0%)
Bladder injury	1/3006 (0%)		0/2986 (0%)
Brain contusion	1/3006 (0%)		1/2986 (0%)
Brain herniation	0/3006 (0%)		1/2986 (0%)
Burn of internal organs	0/3006 (0%)		1/2986 (0%)
Bursa injury	1/3006 (0%)		0/2986 (0%)
Cardiac pacemaker malfunction	1/3006 (0%)		0/2986 (0%)
Caustic injury	0/3006 (0%)		1/2986 (0%)
Cervical vertebral fracture	0/3006 (0%)		4/2986 (0.1%)
Chest injury	0/3006 (0%)		1/2986 (0%)
Concussion	2/3006 (0.1%)		7/2986 (0.2%)
Contusion	3/3006 (0.1%)		5/2986 (0.2%)
Decerebration	0/3006 (0%)		1/2986 (0%)
Delayed recovery from anaesthesia	1/3006 (0%)		0/2986 (0%)
Device failure	0/3006 (0%)		1/2986 (0%)
Device malfunction	0/3006 (0%)		1/2986 (0%)
Dislocation of joint prosthesis	1/3006 (0%)		1/2986 (0%)
Drug toxicity	4/3006 (0.1%)		1/2986 (0%)
Face injury	1/3006 (0%)		1/2986 (0%)
Facial bones fracture	3/3006 (0.1%)		2/2986 (0.1%)
Fall	12/3006 (0.4%)		19/2986 (0.6%)
Femoral neck fracture	5/3006 (0.2%)		9/2986 (0.3%)
Femur fracture	6/3006 (0.2%)		7/2986 (0.2%)
Fibula fracture	2/3006 (0.1%)		0/2986 (0%)
Foot fracture	1/3006 (0%)		0/2986 (0%)
Foreign body trauma	0/3006 (0%)		2/2986 (0.1%)
Fracture	1/3006 (0%)		0/2986 (0%)
Gastrointestinal disorder postoperative	0/3006 (0%)		1/2986 (0%)
Gastrointestinal injury	1/3006 (0%)		0/2986 (0%)
Hand fracture	1/3006 (0%)		0/2986 (0%)
Head injury	3/3006 (0.1%)		1/2986 (0%)
Hip fracture	8/3006 (0.3%)		9/2986 (0.3%)
Humerus fracture	3/3006 (0.1%)		3/2986 (0.1%)
Ilium fracture	0/3006 (0%)		1/2986 (0%)
Incision site haemorrhage	1/3006 (0%)		0/2986 (0%)
Incisional hernia	2/3006 (0.1%)		1/2986 (0%)
Injury	0/3006 (0%)		2/2986 (0.1%)
Internal injury	0/3006 (0%)		1/2986 (0%)
Joint dislocation	1/3006 (0%)		1/2986 (0%)
Joint injury	1/3006 (0%)		1/2986 (0%)
Joint sprain	1/3006 (0%)		0/2986 (0%)
Limb injury	0/3006 (0%)		2/2986 (0.1%)
Lower limb fracture	0/3006 (0%)		4/2986 (0.1%)
Lumbar vertebral fracture	2/3006 (0.1%)		0/2986 (0%)
Meniscus lesion	2/3006 (0.1%)		2/2986 (0.1%)
Multiple injuries	1/3006 (0%)		0/2986 (0%)
Neck injury	1/3006 (0%)		1/2986 (0%)
Operative haemorrhage	0/3006 (0%)		1/2986 (0%)
Overdose	1/3006 (0%)		1/2986 (0%)
Pacemaker complication	0/3006 (0%)		2/2986 (0.1%)
Pancreatic injury	1/3006 (0%)		0/2986 (0%)
Patella fracture	0/3006 (0%)		1/2986 (0%)
Pelvic fracture	1/3006 (0%)		0/2986 (0%)
Post gastric surgery syndrome	1/3006 (0%)		0/2986 (0%)
Post procedural bile leak	0/3006 (0%)		1/2986 (0%)
Post procedural fistula	0/3006 (0%)		1/2986 (0%)
Post procedural haemorrhage	2/3006 (0.1%)		0/2986 (0%)
Post-traumatic pain	0/3006 (0%)		1/2986 (0%)
Postoperative ileus	3/3006 (0.1%)		2/2986 (0.1%)
Postoperative wound complication	1/3006 (0%)		0/2986 (0%)
Procedural hypotension	1/3006 (0%)		1/2986 (0%)
Pubic rami fracture	0/3006 (0%)		1/2986 (0%)
Radius fracture	0/3006 (0%)		2/2986 (0.1%)
Rib fracture	6/3006 (0.2%)		9/2986 (0.3%)
Road traffic accident	1/3006 (0%)		8/2986 (0.3%)
Scapula fracture	1/3006 (0%)		1/2986 (0%)
Shunt thrombosis	0/3006 (0%)		1/2986 (0%)
Skin injury	0/3006 (0%)		1/2986 (0%)
Skin laceration	3/3006 (0.1%)		4/2986 (0.1%)
Skull fracture	1/3006 (0%)		0/2986 (0%)
Spinal compression fracture	6/3006 (0.2%)		8/2986 (0.3%)
Spinal fracture	1/3006 (0%)		1/2986 (0%)
Stent occlusion	0/3006 (0%)		1/2986 (0%)
Stent-graft endoleak	1/3006 (0%)		0/2986 (0%)
Subdural haematoma	1/3006 (0%)		1/2986 (0%)
Subdural haemorrhage	0/3006 (0%)		2/2986 (0.1%)
Synovial rupture	1/3006 (0%)		0/2986 (0%)
Tendon injury	1/3006 (0%)		1/2986 (0%)
Tendon rupture	0/3006 (0%)		3/2986 (0.1%)
Therapeutic agent toxicity	0/3006 (0%)		1/2986 (0%)
Thermal burn	1/3006 (0%)		0/2986 (0%)
Thoracic vertebral fracture	2/3006 (0.1%)		2/2986 (0.1%)
Thrombosis in device	0/3006 (0%)		1/2986 (0%)
Tibia fracture	2/3006 (0.1%)		1/2986 (0%)
Traumatic brain injury	0/3006 (0%)		3/2986 (0.1%)
Traumatic fracture	1/3006 (0%)		0/2986 (0%)
Ulna fracture	0/3006 (0%)		1/2986 (0%)
Ulnar nerve injury	0/3006 (0%)		1/2986 (0%)
Upper limb fracture	1/3006 (0%)		5/2986 (0.2%)
Urinary tract injury	0/3006 (0%)		1/2986 (0%)
Vaccination complication	1/3006 (0%)		0/2986 (0%)
Vascular bypass dysfunction	1/3006 (0%)		0/2986 (0%)
Vascular graft occlusion	0/3006 (0%)		1/2986 (0%)
Vena cava injury	1/3006 (0%)		0/2986 (0%)
Wound	0/3006 (0%)		1/2986 (0%)
Wound dehiscence	0/3006 (0%)		4/2986 (0.1%)
Wound secretion	0/3006 (0%)		1/2986 (0%)
Wrist fracture	5/3006 (0.2%)		2/2986 (0.1%)
Investigations
Blood calcium decreased	1/3006 (0%)		0/2986 (0%)
Blood creatine phosphokinase increased	0/3006 (0%)		1/2986 (0%)
Blood glucose increased	1/3006 (0%)		1/2986 (0%)
Blood pressure increased	1/3006 (0%)		1/2986 (0%)
Blood sodium decreased	0/3006 (0%)		1/2986 (0%)
Body temperature increased	0/3006 (0%)		1/2986 (0%)
C-reactive protein increased	0/3006 (0%)		1/2986 (0%)
Cardiac murmur	0/3006 (0%)		1/2986 (0%)
Electrocardiogram QT prolonged	0/3006 (0%)		1/2986 (0%)
Heart rate irregular	1/3006 (0%)		1/2986 (0%)
Hepatic enzyme increased	0/3006 (0%)		1/2986 (0%)
International normalised ratio increased	0/3006 (0%)		1/2986 (0%)
Investigation	0/3006 (0%)		5/2986 (0.2%)
Oxygen saturation decreased	1/3006 (0%)		2/2986 (0.1%)
Physical examination	0/3006 (0%)		1/2986 (0%)
Platelet count decreased	0/3006 (0%)		1/2986 (0%)
Prostatic specific antigen increased	0/3006 (0%)		1/2986 (0%)
Urine calcium increased	1/3006 (0%)		0/2986 (0%)
Urine output decreased	0/3006 (0%)		1/2986 (0%)
Weight decreased	3/3006 (0.1%)		3/2986 (0.1%)
White blood cell count decreased	0/3006 (0%)		1/2986 (0%)
White blood cell count increased	0/3006 (0%)		1/2986 (0%)
Metabolism and nutrition disorders
Acidosis	1/3006 (0%)		0/2986 (0%)
Anorexia	0/3006 (0%)		1/2986 (0%)
Cachexia	4/3006 (0.1%)		1/2986 (0%)
Dehydration	10/3006 (0.3%)		14/2986 (0.5%)
Diabetes mellitus	7/3006 (0.2%)		8/2986 (0.3%)
Diabetes mellitus inadequate control	1/3006 (0%)		3/2986 (0.1%)
Diabetic ketoacidosis	3/3006 (0.1%)		0/2986 (0%)
Electrolyte imbalance	1/3006 (0%)		1/2986 (0%)
Failure to thrive	1/3006 (0%)		0/2986 (0%)
Food intolerance	0/3006 (0%)		1/2986 (0%)
Gout	1/3006 (0%)		2/2986 (0.1%)
Hyperglycaemia	3/3006 (0.1%)		1/2986 (0%)
Hyperkalaemia	3/3006 (0.1%)		3/2986 (0.1%)
Hypertriglyceridaemia	0/3006 (0%)		1/2986 (0%)
Hypoglycaemia	4/3006 (0.1%)		3/2986 (0.1%)
Hypokalaemia	5/3006 (0.2%)		2/2986 (0.1%)
Hypomagnesaemia	1/3006 (0%)		0/2986 (0%)
Hyponatraemia	6/3006 (0.2%)		5/2986 (0.2%)
Hypophosphataemia	0/3006 (0%)		1/2986 (0%)
Hypovolaemia	0/3006 (0%)		1/2986 (0%)
Malnutrition	0/3006 (0%)		1/2986 (0%)
Metabolic acidosis	1/3006 (0%)		0/2986 (0%)
Obesity	0/3006 (0%)		2/2986 (0.1%)
Polydipsia	0/3006 (0%)		1/2986 (0%)
Type 2 diabetes mellitus	0/3006 (0%)		3/2986 (0.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/3006 (0.1%)		0/2986 (0%)
Arthritis	1/3006 (0%)		3/2986 (0.1%)
Back pain	10/3006 (0.3%)		8/2986 (0.3%)
Bone cyst	0/3006 (0%)		1/2986 (0%)
Bone pain	2/3006 (0.1%)		1/2986 (0%)
Bursitis	1/3006 (0%)		1/2986 (0%)
Costochondritis	0/3006 (0%)		1/2986 (0%)
Dupuytren's contracture	1/3006 (0%)		2/2986 (0.1%)
Facet joint syndrome	0/3006 (0%)		1/2986 (0%)
Foot deformity	1/3006 (0%)		0/2986 (0%)
Fracture nonunion	0/3006 (0%)		1/2986 (0%)
Intervertebral disc degeneration	1/3006 (0%)		2/2986 (0.1%)
Intervertebral disc displacement	0/3006 (0%)		2/2986 (0.1%)
Intervertebral disc protrusion	3/3006 (0.1%)		6/2986 (0.2%)
Joint swelling	0/3006 (0%)		1/2986 (0%)
Loose body in joint	1/3006 (0%)		0/2986 (0%)
Lumbar spinal stenosis	1/3006 (0%)		3/2986 (0.1%)
Metatarsalgia	0/3006 (0%)		1/2986 (0%)
Muscle spasms	2/3006 (0.1%)		0/2986 (0%)
Muscular weakness	1/3006 (0%)		0/2986 (0%)
Musculoskeletal chest pain	4/3006 (0.1%)		7/2986 (0.2%)
Myalgia	2/3006 (0.1%)		0/2986 (0%)
Myalgia intercostal	0/3006 (0%)		2/2986 (0.1%)
Myopathy steroid	0/3006 (0%)		1/2986 (0%)
Neck pain	1/3006 (0%)		0/2986 (0%)
Osteoarthritis	20/3006 (0.7%)		28/2986 (0.9%)
Osteonecrosis	1/3006 (0%)		3/2986 (0.1%)
Osteopenia	0/3006 (0%)		1/2986 (0%)
Osteoporosis	1/3006 (0%)		4/2986 (0.1%)
Osteoporotic fracture	0/3006 (0%)		2/2986 (0.1%)
Pain in extremity	3/3006 (0.1%)		1/2986 (0%)
Pathological fracture	3/3006 (0.1%)		0/2986 (0%)
Periarthritis	0/3006 (0%)		1/2986 (0%)
Polymyositis	0/3006 (0%)		1/2986 (0%)
Rhabdomyolysis	0/3006 (0%)		1/2986 (0%)
Rheumatoid arthritis	1/3006 (0%)		1/2986 (0%)
Rotator cuff syndrome	3/3006 (0.1%)		3/2986 (0.1%)
Spinal column stenosis	2/3006 (0.1%)		1/2986 (0%)
Spinal osteoarthritis	8/3006 (0.3%)		3/2986 (0.1%)
Spondylitis	2/3006 (0.1%)		0/2986 (0%)
Spondylolisthesis	1/3006 (0%)		1/2986 (0%)
Synovial cyst	2/3006 (0.1%)		0/2986 (0%)
Tendonitis	1/3006 (0%)		0/2986 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acoustic neuroma	1/3006 (0%)		0/2986 (0%)
Acute leukaemia	0/3006 (0%)		1/2986 (0%)
Adenocarcinoma	3/3006 (0.1%)		3/2986 (0.1%)
Adenocarcinoma pancreas	1/3006 (0%)		0/2986 (0%)
Adrenal neoplasm	1/3006 (0%)		0/2986 (0%)
B-cell lymphoma	1/3006 (0%)		1/2986 (0%)
Basal cell carcinoma	22/3006 (0.7%)		23/2986 (0.8%)
Basosquamous carcinoma	1/3006 (0%)		0/2986 (0%)
Basosquamous carcinoma of skin	0/3006 (0%)		1/2986 (0%)
Benign colonic neoplasm	1/3006 (0%)		0/2986 (0%)
Benign salivary gland neoplasm	1/3006 (0%)		1/2986 (0%)
Bile duct cancer	2/3006 (0.1%)		0/2986 (0%)
Bladder adenocarcinoma stage unspecified	0/3006 (0%)		1/2986 (0%)
Bladder cancer	7/3006 (0.2%)		11/2986 (0.4%)
Bladder cancer recurrent	1/3006 (0%)		3/2986 (0.1%)
Bladder cancer stage II	1/3006 (0%)		0/2986 (0%)
Bladder cancer stage IV	1/3006 (0%)		0/2986 (0%)
Bladder neoplasm	6/3006 (0.2%)		5/2986 (0.2%)
Bladder transitional cell carcinoma	3/3006 (0.1%)		5/2986 (0.2%)
Bone cancer metastatic	1/3006 (0%)		0/2986 (0%)
Bone neoplasm malignant	1/3006 (0%)		0/2986 (0%)
Bowen's disease	0/3006 (0%)		2/2986 (0.1%)
Brain neoplasm	1/3006 (0%)		1/2986 (0%)
Breast cancer	6/3006 (0.2%)		8/2986 (0.3%)
Breast cancer female	0/3006 (0%)		1/2986 (0%)
Breast cancer metastatic	0/3006 (0%)		2/2986 (0.1%)
Breast cancer recurrent	0/3006 (0%)		1/2986 (0%)
Breast neoplasm	2/3006 (0.1%)		0/2986 (0%)
Carcinoid tumour of the small bowel	1/3006 (0%)		0/2986 (0%)
Carcinoma in situ of bladder	1/3006 (0%)		0/2986 (0%)
Cerebellar tumour	0/3006 (0%)		1/2986 (0%)
Cervix carcinoma	1/3006 (0%)		1/2986 (0%)
Chronic lymphocytic leukaemia	1/3006 (0%)		1/2986 (0%)
Chronic myeloid leukaemia	0/3006 (0%)		1/2986 (0%)
Colon cancer	10/3006 (0.3%)		11/2986 (0.4%)
Colon cancer metastatic	1/3006 (0%)		1/2986 (0%)
Colon cancer stage II	0/3006 (0%)		1/2986 (0%)
Colon neoplasm	1/3006 (0%)		1/2986 (0%)
Colorectal cancer	2/3006 (0.1%)		0/2986 (0%)
Gallbladder cancer	2/3006 (0.1%)		0/2986 (0%)
Gastric adenoma	0/3006 (0%)		1/2986 (0%)
Gastric cancer	7/3006 (0.2%)		2/2986 (0.1%)
Gastric cancer recurrent	1/3006 (0%)		0/2986 (0%)
Gastric cancer stage 0	2/3006 (0.1%)		0/2986 (0%)
Gastric cancer stage I	0/3006 (0%)		1/2986 (0%)
Gastric cancer stage III	1/3006 (0%)		1/2986 (0%)
Gastric neoplasm	3/3006 (0.1%)		0/2986 (0%)
Gastrointestinal carcinoma	1/3006 (0%)		0/2986 (0%)
Gastrointestinal neoplasm	0/3006 (0%)		1/2986 (0%)
Gastrointestinal tract adenoma	1/3006 (0%)		0/2986 (0%)
Glioblastoma	2/3006 (0.1%)		0/2986 (0%)
Head and neck cancer	0/3006 (0%)		2/2986 (0.1%)
Hepatic cancer metastatic	0/3006 (0%)		2/2986 (0.1%)
Hepatic neoplasm	3/3006 (0.1%)		2/2986 (0.1%)
Hepatic neoplasm malignant	3/3006 (0.1%)		4/2986 (0.1%)
Hodgkin's disease	1/3006 (0%)		0/2986 (0%)
Large intestine carcinoma	0/3006 (0%)		1/2986 (0%)
Lentigo maligna stage unspecified	0/3006 (0%)		2/2986 (0.1%)
Leukaemia	0/3006 (0%)		1/2986 (0%)
Lip neoplasm	0/3006 (0%)		1/2986 (0%)
Lipoma	1/3006 (0%)		0/2986 (0%)
Liposarcoma	1/3006 (0%)		0/2986 (0%)
Lymph node cancer metastatic	0/3006 (0%)		1/2986 (0%)
Lymphoma	1/3006 (0%)		0/2986 (0%)
Malignant ascites	1/3006 (0%)		0/2986 (0%)
Malignant melanoma	0/3006 (0%)		2/2986 (0.1%)
Malignant melanoma stage II	0/3006 (0%)		1/2986 (0%)
Malignant neoplasm of renal pelvis	0/3006 (0%)		1/2986 (0%)
Malignant neoplasm progression	1/3006 (0%)		0/2986 (0%)
Malignant palate neoplasm	1/3006 (0%)		1/2986 (0%)
Malignant pericardial neoplasm	0/3006 (0%)		1/2986 (0%)
Malignant respiratory tract neoplasm	0/3006 (0%)		1/2986 (0%)
Malignant urinary tract neoplasm	0/3006 (0%)		1/2986 (0%)
Meningioma	1/3006 (0%)		2/2986 (0.1%)
Mesothelioma	0/3006 (0%)		2/2986 (0.1%)
Metastases to adrenals	0/3006 (0%)		1/2986 (0%)
Metastases to bone	4/3006 (0.1%)		7/2986 (0.2%)
Metastases to breast	0/3006 (0%)		1/2986 (0%)
Metastases to central nervous system	4/3006 (0.1%)		3/2986 (0.1%)
Metastases to liver	9/3006 (0.3%)		10/2986 (0.3%)
Metastases to lymph nodes	3/3006 (0.1%)		4/2986 (0.1%)
Metastases to skin	0/3006 (0%)		1/2986 (0%)
Metastases to soft tissue	1/3006 (0%)		0/2986 (0%)
Metastases to spine	2/3006 (0.1%)		0/2986 (0%)
Metastasis	1/3006 (0%)		2/2986 (0.1%)
Metastatic carcinoma of the bladder	0/3006 (0%)		1/2986 (0%)
Metastatic malignant melanoma	1/3006 (0%)		1/2986 (0%)
Metastatic neoplasm	2/3006 (0.1%)		0/2986 (0%)
Metastatic pain	0/3006 (0%)		1/2986 (0%)
Metastatic squamous cell carcinoma	1/3006 (0%)		2/2986 (0.1%)
Multiple myeloma	2/3006 (0.1%)		1/2986 (0%)
Mycosis fungoides	0/3006 (0%)		1/2986 (0%)
Myelofibrosis	1/3006 (0%)		0/2986 (0%)
Neoplasm	3/3006 (0.1%)		1/2986 (0%)
Neoplasm malignant	3/3006 (0.1%)		2/2986 (0.1%)
Neoplasm recurrence	0/3006 (0%)		2/2986 (0.1%)
Neuroendocrine tumour	0/3006 (0%)		1/2986 (0%)
Non-Hodgkin's lymphoma	1/3006 (0%)		4/2986 (0.1%)
Oesophageal cancer metastatic	0/3006 (0%)		2/2986 (0.1%)
Oesophageal carcinoma	1/3006 (0%)		4/2986 (0.1%)
Oral neoplasm	0/3006 (0%)		1/2986 (0%)
Ovarian neoplasm	0/3006 (0%)		1/2986 (0%)
Pancreatic carcinoma	3/3006 (0.1%)		4/2986 (0.1%)
Pancreatic neoplasm	1/3006 (0%)		0/2986 (0%)
Papillary thyroid cancer	0/3006 (0%)		1/2986 (0%)
Papilloma	1/3006 (0%)		0/2986 (0%)
Penis carcinoma	1/3006 (0%)		0/2986 (0%)
Penis carcinoma metastatic	0/3006 (0%)		1/2986 (0%)
Prostate cancer	22/3006 (0.7%)		31/2986 (1%)
Prostate cancer metastatic	3/3006 (0.1%)		0/2986 (0%)
Prostate cancer stage I	1/3006 (0%)		0/2986 (0%)
Prostate cancer stage III	0/3006 (0%)		2/2986 (0.1%)
Prostatic adenoma	1/3006 (0%)		1/2986 (0%)
Rectal adenoma	1/3006 (0%)		0/2986 (0%)
Rectal cancer	2/3006 (0.1%)		3/2986 (0.1%)
Rectal neoplasm	0/3006 (0%)		1/2986 (0%)
Rectosigmoid cancer	1/3006 (0%)		0/2986 (0%)
Renal cancer	0/3006 (0%)		2/2986 (0.1%)
Renal cancer metastatic	1/3006 (0%)		0/2986 (0%)
Renal cancer stage IV	0/3006 (0%)		1/2986 (0%)
Renal cell carcinoma	0/3006 (0%)		2/2986 (0.1%)
Renal neoplasm	1/3006 (0%)		0/2986 (0%)
Retroperitoneal neoplasm	0/3006 (0%)		1/2986 (0%)
Sarcoma	0/3006 (0%)		1/2986 (0%)
Seborrhoeic keratosis	1/3006 (0%)		0/2986 (0%)
Skin cancer	1/3006 (0%)		0/2986 (0%)
Small cell carcinoma	0/3006 (0%)		2/2986 (0.1%)
Small intestine carcinoma	1/3006 (0%)		0/2986 (0%)
Small intestine carcinoma metastatic	0/3006 (0%)		1/2986 (0%)
Squamous cell carcinoma	7/3006 (0.2%)		5/2986 (0.2%)
Squamous cell carcinoma of skin	2/3006 (0.1%)		5/2986 (0.2%)
Thyroid adenoma	0/3006 (0%)		1/2986 (0%)
Thyroid cancer	2/3006 (0.1%)		0/2986 (0%)
Thyroid neoplasm	0/3006 (0%)		1/2986 (0%)
Tongue neoplasm malignant stage unspecified	3/3006 (0.1%)		1/2986 (0%)
Transitional cell carcinoma	3/3006 (0.1%)		3/2986 (0.1%)
Tumour invasion	1/3006 (0%)		0/2986 (0%)
Ureteric cancer	0/3006 (0%)		1/2986 (0%)
Nervous system disorders
Altered state of consciousness	2/3006 (0.1%)		2/2986 (0.1%)
Amnesia	1/3006 (0%)		1/2986 (0%)
Amyotrophic lateral sclerosis	0/3006 (0%)		1/2986 (0%)
Anoxic encephalopathy	1/3006 (0%)		0/2986 (0%)
Aphasia	1/3006 (0%)		0/2986 (0%)
Brain injury	1/3006 (0%)		0/2986 (0%)
Brain oedema	1/3006 (0%)		1/2986 (0%)
Brain stem infarction	0/3006 (0%)		1/2986 (0%)
Burning sensation	0/3006 (0%)		1/2986 (0%)
Carotid artery disease	2/3006 (0.1%)		1/2986 (0%)
Carotid artery occlusion	3/3006 (0.1%)		2/2986 (0.1%)
Carotid artery stenosis	12/3006 (0.4%)		9/2986 (0.3%)
Carpal tunnel syndrome	0/3006 (0%)		1/2986 (0%)
Cerebellar syndrome	0/3006 (0%)		1/2986 (0%)
Cerebral atrophy	0/3006 (0%)		1/2986 (0%)
Cerebral haematoma	1/3006 (0%)		0/2986 (0%)
Cerebral haemorrhage	5/3006 (0.2%)		3/2986 (0.1%)
Cerebral infarction	7/3006 (0.2%)		7/2986 (0.2%)
Cerebral ischaemia	2/3006 (0.1%)		3/2986 (0.1%)
Cerebrovascular accident	28/3006 (0.9%)		28/2986 (0.9%)
Cerebrovascular disorder	1/3006 (0%)		1/2986 (0%)
Cervical cord compression	0/3006 (0%)		1/2986 (0%)
Cervical myelopathy	0/3006 (0%)		1/2986 (0%)
Cervicobrachial syndrome	0/3006 (0%)		1/2986 (0%)
Chronic inflammatory demyelinating polyradiculoneuropathy	1/3006 (0%)		0/2986 (0%)
Coma	4/3006 (0.1%)		3/2986 (0.1%)
Coma hepatic	0/3006 (0%)		1/2986 (0%)
Complex regional pain syndrome	2/3006 (0.1%)		0/2986 (0%)
Convulsion	5/3006 (0.2%)		5/2986 (0.2%)
Coordination abnormal	0/3006 (0%)		1/2986 (0%)
Dementia	1/3006 (0%)		0/2986 (0%)
Dementia Alzheimer's type	0/3006 (0%)		1/2986 (0%)
Depressed level of consciousness	1/3006 (0%)		0/2986 (0%)
Diabetic coma	1/3006 (0%)		0/2986 (0%)
Dizziness	9/3006 (0.3%)		7/2986 (0.2%)
Dysarthria	3/3006 (0.1%)		0/2986 (0%)
Dyskinesia	0/3006 (0%)		1/2986 (0%)
Embolic stroke	0/3006 (0%)		1/2986 (0%)
Encephalitis	1/3006 (0%)		0/2986 (0%)
Encephalopathy	4/3006 (0.1%)		0/2986 (0%)
Epilepsy	2/3006 (0.1%)		2/2986 (0.1%)
Extrapyramidal disorder	0/3006 (0%)		1/2986 (0%)
Global amnesia	1/3006 (0%)		0/2986 (0%)
Grand mal convulsion	2/3006 (0.1%)		0/2986 (0%)
Guillain-Barre syndrome	1/3006 (0%)		0/2986 (0%)
Haemorrhage intracranial	0/3006 (0%)		1/2986 (0%)
Haemorrhagic stroke	0/3006 (0%)		1/2986 (0%)
Headache	2/3006 (0.1%)		3/2986 (0.1%)
Hemiparesis	4/3006 (0.1%)		2/2986 (0.1%)
Hemiplegia	1/3006 (0%)		1/2986 (0%)
Hyperaesthesia	1/3006 (0%)		0/2986 (0%)
Hypercapnic encephalopathy	1/3006 (0%)		0/2986 (0%)
Hypoaesthesia	1/3006 (0%)		1/2986 (0%)
Hypoxic encephalopathy	1/3006 (0%)		0/2986 (0%)
Intercostal neuralgia	0/3006 (0%)		1/2986 (0%)
Intracranial aneurysm	0/3006 (0%)		2/2986 (0.1%)
Intracranial haematoma	1/3006 (0%)		1/2986 (0%)
Intracranial hypotension	1/3006 (0%)		0/2986 (0%)
Ischaemic cerebral infarction	2/3006 (0.1%)		0/2986 (0%)
Ischaemic stroke	3/3006 (0.1%)		8/2986 (0.3%)
Lethargy	1/3006 (0%)		0/2986 (0%)
Locked-in syndrome	0/3006 (0%)		1/2986 (0%)
Loss of consciousness	2/3006 (0.1%)		0/2986 (0%)
Mental impairment	0/3006 (0%)		2/2986 (0.1%)
Migraine	1/3006 (0%)		1/2986 (0%)
Nervous system disorder	0/3006 (0%)		1/2986 (0%)
Neuralgia	2/3006 (0.1%)		0/2986 (0%)
Neuropathy peripheral	3/3006 (0.1%)		1/2986 (0%)
Paralysis	0/3006 (0%)		1/2986 (0%)
Paraparesis	1/3006 (0%)		1/2986 (0%)
Paraplegia	0/3006 (0%)		1/2986 (0%)
Paresis	2/3006 (0.1%)		0/2986 (0%)
Parkinson's disease	0/3006 (0%)		1/2986 (0%)
Polyneuropathy	0/3006 (0%)		1/2986 (0%)
Presyncope	2/3006 (0.1%)		5/2986 (0.2%)
Quadriparesis	0/3006 (0%)		1/2986 (0%)
Radicular pain	0/3006 (0%)		1/2986 (0%)
Radiculitis cervical	0/3006 (0%)		1/2986 (0%)
Radiculopathy	2/3006 (0.1%)		0/2986 (0%)
Ruptured cerebral aneurysm	1/3006 (0%)		0/2986 (0%)
Sciatica	0/3006 (0%)		1/2986 (0%)
Sensory disturbance	0/3006 (0%)		1/2986 (0%)
Somnolence	2/3006 (0.1%)		0/2986 (0%)
Spinal cord compression	2/3006 (0.1%)		0/2986 (0%)
Spinal cord infarction	0/3006 (0%)		1/2986 (0%)
Spinal cord ischaemia	0/3006 (0%)		1/2986 (0%)
Status epilepticus	2/3006 (0.1%)		0/2986 (0%)
Subarachnoid haemorrhage	0/3006 (0%)		1/2986 (0%)
Syncope	10/3006 (0.3%)		13/2986 (0.4%)
Syncope vasovagal	0/3006 (0%)		1/2986 (0%)
Transient ischaemic attack	12/3006 (0.4%)		14/2986 (0.5%)
Tremor	1/3006 (0%)		0/2986 (0%)
Vertebrobasilar insufficiency	3/3006 (0.1%)		2/2986 (0.1%)
Psychiatric disorders
Acute psychosis	0/3006 (0%)		1/2986 (0%)
Agitation	1/3006 (0%)		0/2986 (0%)
Alcohol abuse	1/3006 (0%)		3/2986 (0.1%)
Alcohol withdrawal syndrome	6/3006 (0.2%)		0/2986 (0%)
Alcoholism	2/3006 (0.1%)		0/2986 (0%)
Anxiety	3/3006 (0.1%)		1/2986 (0%)
Completed suicide	2/3006 (0.1%)		1/2986 (0%)
Confusional state	1/3006 (0%)		2/2986 (0.1%)
Delirium	2/3006 (0.1%)		1/2986 (0%)
Depressed mood	1/3006 (0%)		0/2986 (0%)
Depression	9/3006 (0.3%)		8/2986 (0.3%)
Disorientation	1/3006 (0%)		0/2986 (0%)
Drug abuse	0/3006 (0%)		1/2986 (0%)
Drug dependence	2/3006 (0.1%)		0/2986 (0%)
Dysthymic disorder	1/3006 (0%)		0/2986 (0%)
Hallucination, auditory	1/3006 (0%)		0/2986 (0%)
Insomnia	1/3006 (0%)		0/2986 (0%)
Major depression	2/3006 (0.1%)		1/2986 (0%)
Mental disorder due to a general medical condition	1/3006 (0%)		0/2986 (0%)
Mental status changes	0/3006 (0%)		2/2986 (0.1%)
Neurosis	0/3006 (0%)		1/2986 (0%)
Nicotine dependence	1/3006 (0%)		1/2986 (0%)
Panic attack	2/3006 (0.1%)		1/2986 (0%)
Psychotic disorder	0/3006 (0%)		1/2986 (0%)
Suicidal ideation	1/3006 (0%)		1/2986 (0%)
Suicide attempt	1/3006 (0%)		0/2986 (0%)
Tobacco withdrawal symptoms	1/3006 (0%)		0/2986 (0%)
Renal and urinary disorders
Anuria	0/3006 (0%)		1/2986 (0%)
Bladder disorder	0/3006 (0%)		1/2986 (0%)
Bladder diverticulum	1/3006 (0%)		0/2986 (0%)
Bladder neck obstruction	1/3006 (0%)		1/2986 (0%)
Calculus bladder	1/3006 (0%)		0/2986 (0%)
Calculus ureteric	0/3006 (0%)		1/2986 (0%)
Calculus urinary	2/3006 (0.1%)		0/2986 (0%)
Cystitis noninfective	1/3006 (0%)		0/2986 (0%)
Dysuria	0/3006 (0%)		1/2986 (0%)
Glomerulonephritis	1/3006 (0%)		0/2986 (0%)
Haematuria	7/3006 (0.2%)		4/2986 (0.1%)
Hydronephrosis	1/3006 (0%)		5/2986 (0.2%)
Nephrolithiasis	6/3006 (0.2%)		8/2986 (0.3%)
Nephrotic syndrome	1/3006 (0%)		0/2986 (0%)
Oliguria	0/3006 (0%)		1/2986 (0%)
Renal aneurysm	1/3006 (0%)		0/2986 (0%)
Renal artery stenosis	3/3006 (0.1%)		1/2986 (0%)
Renal colic	0/3006 (0%)		3/2986 (0.1%)
Renal cyst	0/3006 (0%)		1/2986 (0%)
Renal failure	7/3006 (0.2%)		13/2986 (0.4%)
Renal failure acute	16/3006 (0.5%)		16/2986 (0.5%)
Renal failure chronic	0/3006 (0%)		3/2986 (0.1%)
Renal pain	1/3006 (0%)		1/2986 (0%)
Renal tubular necrosis	1/3006 (0%)		0/2986 (0%)
Stress urinary incontinence	1/3006 (0%)		0/2986 (0%)
Urethral disorder	0/3006 (0%)		1/2986 (0%)
Urethral obstruction	0/3006 (0%)		1/2986 (0%)
Urethral stenosis	1/3006 (0%)		6/2986 (0.2%)
Urinary bladder polyp	2/3006 (0.1%)		0/2986 (0%)
Urinary incontinence	1/3006 (0%)		1/2986 (0%)
Urinary retention	8/3006 (0.3%)		15/2986 (0.5%)
Urinary tract disorder	0/3006 (0%)		1/2986 (0%)
Urinary tract obstruction	1/3006 (0%)		0/2986 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	14/3006 (0.5%)		20/2986 (0.7%)
Calculus prostatic	1/3006 (0%)		0/2986 (0%)
Cervical dysplasia	0/3006 (0%)		1/2986 (0%)
Epididymal cyst	0/3006 (0%)		1/2986 (0%)
Epididymitis	0/3006 (0%)		2/2986 (0.1%)
Erectile dysfunction	1/3006 (0%)		1/2986 (0%)
Menorrhagia	1/3006 (0%)		0/2986 (0%)
Metrorrhagia	1/3006 (0%)		1/2986 (0%)
Organic erectile dysfunction	0/3006 (0%)		1/2986 (0%)
Ovarian cyst	1/3006 (0%)		1/2986 (0%)
Postmenopausal haemorrhage	0/3006 (0%)		1/2986 (0%)
Prostatic obstruction	1/3006 (0%)		0/2986 (0%)
Prostatism	2/3006 (0.1%)		1/2986 (0%)
Prostatitis	6/3006 (0.2%)		1/2986 (0%)
Prostatomegaly	1/3006 (0%)		0/2986 (0%)
Scrotal oedema	0/3006 (0%)		1/2986 (0%)
Uterine cyst	1/3006 (0%)		0/2986 (0%)
Uterine enlargement	0/3006 (0%)		1/2986 (0%)
Respiratory, thoracic and mediastinal disorders
Actinomycotic pulmonary infection	0/3006 (0%)		1/2986 (0%)
Acute pulmonary oedema	6/3006 (0.2%)		1/2986 (0%)
Acute respiratory failure	31/3006 (1%)		29/2986 (1%)
Alveolitis allergic	0/3006 (0%)		1/2986 (0%)
Aspergilloma	0/3006 (0%)		3/2986 (0.1%)
Aspiration	1/3006 (0%)		1/2986 (0%)
Asthma	2/3006 (0.1%)		0/2986 (0%)
Atelectasis	2/3006 (0.1%)		1/2986 (0%)
Bronchial obstruction	0/3006 (0%)		1/2986 (0%)
Bronchiectasis	3/3006 (0.1%)		3/2986 (0.1%)
Bronchitis	27/3006 (0.9%)		35/2986 (1.2%)
Bronchopulmonary aspergillosis	0/3006 (0%)		1/2986 (0%)
Bronchospasm	3/3006 (0.1%)		1/2986 (0%)
COPD exacerbation	742/3006 (24.7%)		688/2986 (23%)
Chronic respiratory failure	5/3006 (0.2%)		7/2986 (0.2%)
Cough	1/3006 (0%)		2/2986 (0.1%)
Cryptogenic organising pneumonia	0/3006 (0%)		1/2986 (0%)
Dyspnoea	54/3006 (1.8%)		36/2986 (1.2%)
Emphysema	5/3006 (0.2%)		9/2986 (0.3%)
Foreign body aspiration	1/3006 (0%)		0/2986 (0%)
Haemoptysis	10/3006 (0.3%)		14/2986 (0.5%)
Haemothorax	0/3006 (0%)		2/2986 (0.1%)
Hiccups	0/3006 (0%)		1/2986 (0%)
Idiopathic pulmonary fibrosis	1/3006 (0%)		0/2986 (0%)
Interstitial lung disease	0/3006 (0%)		1/2986 (0%)
Lower respiratory tract infection	12/3006 (0.4%)		12/2986 (0.4%)
Lung abscess	2/3006 (0.1%)		4/2986 (0.1%)
Lung disorder	7/3006 (0.2%)		1/2986 (0%)
Lung infection	3/3006 (0.1%)		6/2986 (0.2%)
Lung infection pseudomonal	2/3006 (0.1%)		5/2986 (0.2%)
Lung infiltration	2/3006 (0.1%)		6/2986 (0.2%)
Lung injury	0/3006 (0%)		1/2986 (0%)
Middle lobe syndrome	1/3006 (0%)		1/2986 (0%)
Pleural effusion	6/3006 (0.2%)		4/2986 (0.1%)
Pleurisy	3/3006 (0.1%)		2/2986 (0.1%)
Pleuritic pain	3/3006 (0.1%)		1/2986 (0%)
Pneumocystis jiroveci pneumonia	0/3006 (0%)		1/2986 (0%)
Pneumonia aspiration	4/3006 (0.1%)		4/2986 (0.1%)
Pneumonia klebsiella	0/3006 (0%)		1/2986 (0%)
Pneumonia necrotising	0/3006 (0%)		1/2986 (0%)
Pneumonia staphylococcal	3/3006 (0.1%)		2/2986 (0.1%)
Pneumonia	290/3006 (9.6%)		296/2986 (9.9%)
Pneumonitis	2/3006 (0.1%)		0/2986 (0%)
Pneumothorax	24/3006 (0.8%)		26/2986 (0.9%)
Pneumothorax traumatic	1/3006 (0%)		1/2986 (0%)
Productive cough	1/3006 (0%)		1/2986 (0%)
Pseudomonas bronchitis	0/3006 (0%)		1/2986 (0%)
Pulmonary bulla	1/3006 (0%)		0/2986 (0%)
Pulmonary congestion	0/3006 (0%)		1/2986 (0%)
Pulmonary fibrosis	0/3006 (0%)		1/2986 (0%)
Pulmonary haemorrhage	0/3006 (0%)		1/2986 (0%)
Pulmonary mass	2/3006 (0.1%)		1/2986 (0%)
Pulmonary oedema	5/3006 (0.2%)		7/2986 (0.2%)
Pulmonary tuberculoma	1/3006 (0%)		0/2986 (0%)
Pulmonary tuberculosis	2/3006 (0.1%)		4/2986 (0.1%)
Pyothorax	1/3006 (0%)		1/2986 (0%)
Radiation pneumonitis	1/3006 (0%)		0/2986 (0%)
Respiratory arrest	5/3006 (0.2%)		3/2986 (0.1%)
Respiratory failure	113/3006 (3.8%)		85/2986 (2.8%)
Respiratory fume inhalation disorder	1/3006 (0%)		1/2986 (0%)
Respiratory tract haemorrhage	1/3006 (0%)		0/2986 (0%)
Status asthmaticus	0/3006 (0%)		1/2986 (0%)
Tracheobronchitis	2/3006 (0.1%)		3/2986 (0.1%)
Wheezing	2/3006 (0.1%)		0/2986 (0%)
Apnoea	0/3006 (0%)		1/2986 (0%)
Benign lung neoplasm	0/3006 (0%)		2/2986 (0.1%)
Bronchial carcinoma	9/3006 (0.3%)		15/2986 (0.5%)
Bronchial neoplasm	2/3006 (0.1%)		0/2986 (0%)
Bronchogenic cyst	0/3006 (0%)		1/2986 (0%)
Cyanosis	0/3006 (0%)		1/2986 (0%)
Hypercapnia	3/3006 (0.1%)		3/2986 (0.1%)
Hypopharyngeal cancer	1/3006 (0%)		0/2986 (0%)
Hypoxia	8/3006 (0.3%)		12/2986 (0.4%)
Large cell carcinoma of the respir. tract stage unspecified	2/3006 (0.1%)		3/2986 (0.1%)
Laryngeal cancer	3/3006 (0.1%)		1/2986 (0%)
Lung adenocarcinoma	11/3006 (0.4%)		6/2986 (0.2%)
Lung adenocarcinoma metastatic	3/3006 (0.1%)		0/2986 (0%)
Lung adenocarcinoma recurrent	0/3006 (0%)		1/2986 (0%)
Lung cancer metastatic	4/3006 (0.1%)		5/2986 (0.2%)
Lung carcinoma cell type unspecified recurrent	0/3006 (0%)		1/2986 (0%)
Lung carcinoma cell type unspecified stage 0	1/3006 (0%)		0/2986 (0%)
Lung carcinoma cell type unspecified stage III	1/3006 (0%)		0/2986 (0%)
Lung neoplasm	7/3006 (0.2%)		12/2986 (0.4%)
Lung neoplasm malignant	34/3006 (1.1%)		40/2986 (1.3%)
Lung squamous cell carcinoma stage III	1/3006 (0%)		0/2986 (0%)
Lung squamous cell carcinoma stage IV	1/3006 (0%)		1/2986 (0%)
Lung squamous cell carcinoma stage unspecified	6/3006 (0.2%)		6/2986 (0.2%)
Lymphadenopathy mediastinal	2/3006 (0.1%)		1/2986 (0%)
Malignant mediastinal neoplasm	1/3006 (0%)		1/2986 (0%)
Malignant pleural effusion	1/3006 (0%)		1/2986 (0%)
Mediastinum neoplasm	0/3006 (0%)		1/2986 (0%)
Metastases to lung	2/3006 (0.1%)		5/2986 (0.2%)
Metastatic bronchial carcinoma	2/3006 (0.1%)		0/2986 (0%)
Non-small cell lung cancer	12/3006 (0.4%)		10/2986 (0.3%)
Non-small cell lung cancer metastatic	4/3006 (0.1%)		6/2986 (0.2%)
Pharyngeal cancer stage unspecified	0/3006 (0%)		1/2986 (0%)
Pulmonary arterial hypertension	0/3006 (0%)		1/2986 (0%)
Pulmonary embolism	29/3006 (1%)		25/2986 (0.8%)
Pulmonary hilum mass	1/3006 (0%)		0/2986 (0%)
Pulmonary hypertension	2/3006 (0.1%)		3/2986 (0.1%)
Respiratory acidosis	3/3006 (0.1%)		1/2986 (0%)
Respiratory depression	0/3006 (0%)		1/2986 (0%)
Respiratory distress	1/3006 (0%)		0/2986 (0%)
Scoliosis	1/3006 (0%)		0/2986 (0%)
Sleep apnoea syndrome	0/3006 (0%)		1/2986 (0%)
Small cell lung cancer extensive stage	1/3006 (0%)		1/2986 (0%)
Small cell lung cancer limited stage	0/3006 (0%)		1/2986 (0%)
Small cell lung cancer metastatic	1/3006 (0%)		4/2986 (0.1%)
Small cell lung cancer stage unspecified	8/3006 (0.3%)		8/2986 (0.3%)
Throat cancer	1/3006 (0%)		0/2986 (0%)
Tracheal neoplasm	1/3006 (0%)		0/2986 (0%)
Chronic tonsillitis	1/3006 (0%)		0/2986 (0%)
Dysphonia	1/3006 (0%)		0/2986 (0%)
Epistaxis	6/3006 (0.2%)		4/2986 (0.1%)
Influenza	4/3006 (0.1%)		5/2986 (0.2%)
Laryngeal inflammation	0/3006 (0%)		1/2986 (0%)
Laryngitis	1/3006 (0%)		1/2986 (0%)
Laryngospasm	0/3006 (0%)		1/2986 (0%)
Nasal congestion	1/3006 (0%)		1/2986 (0%)
Nasal polyps	0/3006 (0%)		2/2986 (0.1%)
Nasal septum deviation	1/3006 (0%)		0/2986 (0%)
Nasopharyngitis	1/3006 (0%)		0/2986 (0%)
Oropharyngeal swelling	0/3006 (0%)		1/2986 (0%)
Pharyngeal abscess	1/3006 (0%)		0/2986 (0%)
Pharyngeal disorder	1/3006 (0%)		0/2986 (0%)
Pharyngeal fistula	0/3006 (0%)		1/2986 (0%)
Pharyngitis	1/3006 (0%)		1/2986 (0%)
Pharyngoesophageal diverticulum	1/3006 (0%)		0/2986 (0%)
Pharyngolaryngeal abscess	1/3006 (0%)		0/2986 (0%)
Rhinitis allergic	0/3006 (0%)		1/2986 (0%)
Sinus polyp	0/3006 (0%)		1/2986 (0%)
Sinusitis	3/3006 (0.1%)		7/2986 (0.2%)
Tracheal disorder	0/3006 (0%)		1/2986 (0%)
Tracheostomy malfunction	2/3006 (0.1%)		0/2986 (0%)
Upper respiratory tract infection	13/3006 (0.4%)		19/2986 (0.6%)
Vocal cord paralysis	0/3006 (0%)		1/2986 (0%)
Skin and subcutaneous tissue disorders
Angioedema	0/3006 (0%)		2/2986 (0.1%)
Decubitus ulcer	4/3006 (0.1%)		3/2986 (0.1%)
Dermal cyst	1/3006 (0%)		0/2986 (0%)
Dermatitis allergic	2/3006 (0.1%)		0/2986 (0%)
Dermatitis atopic	1/3006 (0%)		0/2986 (0%)
Eczema	1/3006 (0%)		2/2986 (0.1%)
Parapsoriasis	1/3006 (0%)		0/2986 (0%)
Pemphigoid	1/3006 (0%)		0/2986 (0%)
Seborrhoeic dermatitis	1/3006 (0%)		0/2986 (0%)
Skin haemorrhage	1/3006 (0%)		0/2986 (0%)
Skin ulcer	2/3006 (0.1%)		1/2986 (0%)
Stasis dermatitis	0/3006 (0%)		1/2986 (0%)
Subcutaneous emphysema	2/3006 (0.1%)		0/2986 (0%)
Urticaria	0/3006 (0%)		1/2986 (0%)
Social circumstances
Alcohol use	1/3006 (0%)		0/2986 (0%)
Social problem	0/3006 (0%)		1/2986 (0%)
Social stay hospitalisation	2/3006 (0.1%)		2/2986 (0.1%)
Victim of homicide	0/3006 (0%)		1/2986 (0%)
Surgical and medical procedures
Adhesiolysis	0/3006 (0%)		1/2986 (0%)
Alcohol detoxification	0/3006 (0%)		1/2986 (0%)
Appendicectomy	0/3006 (0%)		1/2986 (0%)
Arteriovenous fistula operation	1/3006 (0%)		0/2986 (0%)
Bladder operation	1/3006 (0%)		0/2986 (0%)
Cardiac pacemaker battery replacement	1/3006 (0%)		0/2986 (0%)
Cardiac pacemaker insertion	0/3006 (0%)		1/2986 (0%)
Cardiac pacemaker replacement	1/3006 (0%)		1/2986 (0%)
Cataract operation	0/3006 (0%)		3/2986 (0.1%)
Catheter placement	1/3006 (0%)		0/2986 (0%)
Cholecystectomy	0/3006 (0%)		1/2986 (0%)
Colectomy	0/3006 (0%)		1/2986 (0%)
Coronary angioplasty	0/3006 (0%)		1/2986 (0%)
Coronary arterial stent insertion	0/3006 (0%)		1/2986 (0%)
Finger amputation	1/3006 (0%)		1/2986 (0%)
Gastrointestinal tube insertion	1/3006 (0%)		0/2986 (0%)
Hernia repair	0/3006 (0%)		1/2986 (0%)
Hip arthroplasty	1/3006 (0%)		1/2986 (0%)
Hip surgery	0/3006 (0%)		1/2986 (0%)
Hospitalisation	0/3006 (0%)		1/2986 (0%)
Ileostomy	0/3006 (0%)		1/2986 (0%)
Intervertebral disc operation	1/3006 (0%)		0/2986 (0%)
Joint arthroplasty	0/3006 (0%)		2/2986 (0.1%)
Medical device removal	0/3006 (0%)		1/2986 (0%)
Nasal polypectomy	1/3006 (0%)		0/2986 (0%)
Oxygen supplementation	1/3006 (0%)		0/2986 (0%)
Rehabilitation therapy	1/3006 (0%)		3/2986 (0.1%)
Removal of internal fixation	1/3006 (0%)		0/2986 (0%)
Respiratory therapy	0/3006 (0%)		1/2986 (0%)
Shoulder operation	0/3006 (0%)		1/2986 (0%)
Surgery	1/3006 (0%)		1/2986 (0%)
Transurethral prostatectomy	1/3006 (0%)		0/2986 (0%)
Umbilical hernia repair	1/3006 (0%)		0/2986 (0%)
Vascular disorders
Aortic aneurysm	11/3006 (0.4%)		15/2986 (0.5%)
Aortic aneurysm rupture	5/3006 (0.2%)		3/2986 (0.1%)
Aortic disorder	0/3006 (0%)		1/2986 (0%)
Aortic dissection	1/3006 (0%)		0/2986 (0%)
Aortic occlusion	0/3006 (0%)		1/2986 (0%)
Aortic rupture	1/3006 (0%)		0/2986 (0%)
Aortic stenosis	4/3006 (0.1%)		4/2986 (0.1%)
Aortic thrombosis	0/3006 (0%)		2/2986 (0.1%)
Arterial disorder	1/3006 (0%)		0/2986 (0%)
Arterial insufficiency	0/3006 (0%)		1/2986 (0%)
Arterial occlusive disease	1/3006 (0%)		4/2986 (0.1%)
Arterial thrombosis	1/3006 (0%)		0/2986 (0%)
Arterial thrombosis limb	2/3006 (0.1%)		1/2986 (0%)
Arteriosclerosis	2/3006 (0.1%)		4/2986 (0.1%)
Arteriosclerosis obliterans	0/3006 (0%)		1/2986 (0%)
Arteritis	1/3006 (0%)		1/2986 (0%)
Bleeding varicose vein	1/3006 (0%)		0/2986 (0%)
Cardiovascular insufficiency	0/3006 (0%)		2/2986 (0.1%)
Circulatory collapse	6/3006 (0.2%)		1/2986 (0%)
Deep vein thrombosis	8/3006 (0.3%)		14/2986 (0.5%)
Embolism	1/3006 (0%)		0/2986 (0%)
Femoral artery occlusion	0/3006 (0%)		4/2986 (0.1%)
Haematoma	5/3006 (0.2%)		2/2986 (0.1%)
Haemorrhage	0/3006 (0%)		1/2986 (0%)
Hypertension	13/3006 (0.4%)		11/2986 (0.4%)
Hypertensive crisis	2/3006 (0.1%)		1/2986 (0%)
Hypotension	9/3006 (0.3%)		11/2986 (0.4%)
Hypovolaemic shock	1/3006 (0%)		0/2986 (0%)
Iliac artery occlusion	0/3006 (0%)		1/2986 (0%)
Iliac artery stenosis	1/3006 (0%)		2/2986 (0.1%)
Intermittent claudication	0/3006 (0%)		6/2986 (0.2%)
Ischaemia	1/3006 (0%)		1/2986 (0%)
Jugular vein thrombosis	1/3006 (0%)		0/2986 (0%)
Orthostatic hypotension	3/3006 (0.1%)		5/2986 (0.2%)
Peripheral arterial occlusive disease	2/3006 (0.1%)		2/2986 (0.1%)
Peripheral artery aneurysm	2/3006 (0.1%)		1/2986 (0%)
Peripheral embolism	1/3006 (0%)		0/2986 (0%)
Peripheral ischaemia	0/3006 (0%)		7/2986 (0.2%)
Peripheral vascular disorder	4/3006 (0.1%)		3/2986 (0.1%)
Shock	4/3006 (0.1%)		4/2986 (0.1%)
Shock haemorrhagic	2/3006 (0.1%)		1/2986 (0%)
Subclavian artery stenosis	0/3006 (0%)		1/2986 (0%)
Superior vena caval occlusion	1/3006 (0%)		1/2986 (0%)
Thrombophlebitis	0/3006 (0%)		2/2986 (0.1%)
Thrombophlebitis superficial	0/3006 (0%)		1/2986 (0%)
Thrombosis	1/3006 (0%)		6/2986 (0.2%)
Varicose ulceration	1/3006 (0%)		0/2986 (0%)
Varicose vein	2/3006 (0.1%)		0/2986 (0%)
Vascular shunt	0/3006 (0%)		1/2986 (0%)
Venous stasis	1/3006 (0%)		0/2986 (0%)
Venous thrombosis	3/3006 (0.1%)		1/2986 (0%)
Venous thrombosis limb	1/3006 (0%)		2/2986 (0.1%)
Wound haemorrhage	1/3006 (0%)		0/2986 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Tiotropium Bromide Inhalation Capsules 18 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2622/ (NaN)		2643/ (NaN)
Gastrointestinal disorders
Mouth dry	80/3006 (2.7%)		152/2986 (5.1%)
Infections and infestations
Urinary tract infection	157/3006 (5.2%)		173/2986 (5.8%)
Musculoskeletal and connective tissue disorders
Back pain	179/3006 (6%)		190/2986 (6.4%)
Nervous system disorders
Headache	135/3006 (4.5%)		169/2986 (5.7%)
Respiratory, thoracic and mediastinal disorders
Bronchitis	214/3006 (7.1%)		207/2986 (6.9%)
COPD exacerbation	1743/3006 (58%)		1706/2986 (57.1%)
Cough	212/3006 (7.1%)		236/2986 (7.9%)
Dyspnoea	404/3006 (13.4%)		338/2986 (11.3%)
Pneumonia	156/3006 (5.2%)		157/2986 (5.3%)
Influenza	155/3006 (5.2%)		153/2986 (5.1%)
Nasopharyngitis	323/3006 (10.7%)		373/2986 (12.5%)
Sinusitis	157/3006 (5.2%)		190/2986 (6.4%)
Upper respiratory tract infection	282/3006 (9.4%)		285/2986 (9.5%)
Vascular disorders
Hypertension	273/3006 (9.1%)		265/2986 (8.9%)

Limitations/Caveats

Tio patients had significantly longer drug exposure,thus had increased chance of AE.Simple frequencies are biased for AE comparisons;exposure-adjusted incidence rates (IR) should be used. IR for serious AE(>1% patients) are in Outcome Measures.

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:

NCT00144339

Other Study ID Numbers:

205.235

First Posted:

Sep 5, 2005

Last Update Posted:

May 20, 2014

Last Verified:

Apr 1, 2014