Evaluation of Tiotropium 2.5 and 5 mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo and Salmeterol HydroFluoroAlkane (HFA) Metered Dose Inhaler (MDI) (50 mcg Twice Daily) in Patient With Moderate Persistent Asthma II

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01172821
• Collaborator: Pfizer (Industry)
• Enrollment: 1,032
• Locations: 125
• Arms: 4
• Duration (Months): 27
• Patients Per Site: 8.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The aim of this trial is to evaluate the efficacy and safety of 2.5 and 5 mcg tiotropium over a 24-week treatment period as compared to placebo and salmeterol (50 mcg twice daily). Tiotropium inhalation solution delivered by the Respimat® inhaler will be examined on top of maintenance treatment with inhaled corticosteroid controller medication in patients with moderate persistent asthma. Efficacy and safety will be assessed by measuring effects on lung function, effects on asthma exacerbations, effects on quality of life, effects on asthma control, effects on health care resource utilisation, and number of adverse events.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: placebo; Drug: placebo; Drug: placebo; Drug: tiotropium Respimat® low dose; Drug: placebo; Drug: tiotropium Respimat® high dose; Drug: 50 mcg salmeterol HFA MDI; Drug: placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1032 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Phase III Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (2.5 and 5 µg Once Daily) Compared With Placebo and Salmeterol HFA MDI (50 µg Twice Daily) Over 24 Weeks in Moderate Persistent Asthma
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: tiotropium low dose Once daily, delivered with Respimat® inhaler (+ inhalation of placebo HFA MDI twice daily)	Drug: placebo; Placebo that represents comparator; Drug: tiotropium Respimat® low dose; IMP
Experimental: tiotropium high dose Once daily, delivered with Respimat® inhaler (+ inhalation of placebo HFA MDI twice daily)	Drug: tiotropium Respimat® high dose; IMP; Drug: placebo; Placebo that represents comparator
Active Comparator: 50 mcg salmeterol Twice daily, delivered with HFA MDI (+ inhalation of placebo Respimat® inhaler once daily)	Drug: placebo; Placebo that represents BI drug; Drug: 50 mcg salmeterol HFA MDI; Active comparator
Placebo Comparator: placebo Once daily, delivered with Respimat® inhaler + twice daily delivered with HFA MDI	Drug: placebo; Placebo that represents BI drug; Drug: placebo; Placebo that represents comparator

Outcome Measures

Primary Outcome Measures

1. Peak FEV1 Within 3 Hours Post-dose Response [24 weeks]

   Peak forced expiratory volume in one second (FEV1) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

2. Trough FEV1 Response [24 weeks]

   Trough FEV1 response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

3. The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) [24 weeks]

   The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period (on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points.

Secondary Outcome Measures

1. Peak FVC Within 3 Hours Post-dose Response [24 weeks]

   Peak forced vital capacity (FVC) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

2. Trough FVC Response [24 weeks]

   Trough FVC response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

3. FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response [24 weeks]

   Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24- week treatment. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

4. FVC Area Under Curve 0-3 Hours (AUC0-3h) Response [24 weeks]

   Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24- week treatment. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

5. Trough PEF Response [24 weeks]

   Trough peak expiratory flow (PEF) response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

6. Total Asthma Quality of Life Questionnaire (AQLQs)) Score [24 weeks]

   Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ(s)) determined at the end of 24-week treatment. The AQLQ(s) contains 32 questions, each question has a 7 point scale from 1 (highest intensity) till 7 (no symptoms). Total score was defined as the sum of all items divided by the number of items and ranges from from 1 (highest intensity) till 7 (no symptoms). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

7. Total Asthma Control Questionnaire (ACQ) Score [24 weeks]

   Control of asthma as assessed by the ACQ determined at the end of 24-week treatment. The ACQ contains 7 questions, each question has a 7 point scale from 0 (no symptoms) till 6 (highest intensity). Total score was defined as the sum of all items divided by the number of items and ranges from from 0 (no symptoms) till 6 (highest intensity). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

8. The Responder Rate as Assessed by the ACQ [24 weeks]

   The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period. A patient was considered to be a responder if he or she was reported with an improvement (decrease) in ACQ total score of at least 0.5 points.The score ranges from 0 (no impairment) to 6 (maximum impairment).

9. Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24 [Baseline and last 7 days before week 24 visit]

   Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week

10. Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24 [Baseline and last 7 days before week 24 visit]

    Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

11. PEF Variability [Last 7 days before week 24 visit]

    PEF daily variability was assesed by patients at home using the AM3 device. PEF variability is the absolute difference between morning and evening PEF value divided by their mean, based on the weekly mean response at week 24. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

12. Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24 [Baseline and last 7 days before week 24 visit]

    Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

13. Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24 [Baseline and last 7 days before week 24 visit]

    Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

14. Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24 [Baseline and last 7 days before week 24 visit]

    Daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

15. Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24 [Baseline and last 7 days before week 24 visit]

    Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. An asthma symptom-free day was defined as a day with no reported symptoms and no use of rescue medication.

16. Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) [24 weeks]

    Time to first severe asthma exacerbation during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)

17. Time to First Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821) [24 weeks]

    Time to first asthma exacerbation (including severe, non-severe; symptomatic, asymptomatic; i.e. any exacerbation) during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. All patients must sign and date an Informed Consent Form consistent with International Conference on Harmonisation - Good Clinical Practice (ICH-GCP) guidelines and local legislation prior to participation in the trial (i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test at Visit 1).

2. Male or female patients aged at least 18 years but not more than 75 years.

3. All patients must have at least a 3 month history of asthma at the time of enrolment into the trial. The diagnosis should be confirmed at Visit 1 by fulfilling inclusion criterion 5.

4. The initial diagnosis of asthma must have been made before the patient's age of 40.

5. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (15 minutes after 400 mcg salbutamol (albuterol)) resulting in a Forced Expiratory Volume in one second (FEV1) increase of at least 12% and at least 200mL.

6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids for at least for 4 weeks prior to Visit 1. 7. All patients must be symptomatic at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ) mean score of at least 1.5.

7. All patients must have a pre-bronchodilator FEV1 at least 60% and less than or equal to 90% of predicted normal at Visit 1.

8. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%.

9. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack years.

10. Patients must be able to use the Respimat® inhaler and metered dose inhaler correctly.

11. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of electronic diary/peak flow meter.

Exclusion criteria:

1. Patients with a significant disease other than asthma. A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial.

2. Patients with a clinically relevant abnormal screening (Visit 1) haematology or blood chemistry if the abnormality defines a significant disease as defined in exclusion criterion 1.

3. Patients with a recent history (i.e. six months or less) of myocardial infarction.

4. Patients who have been hospitalised for cardiac failure during the past year.

5. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.

6. Patients with lung diseases other than asthma (e.g. Chronic Obstructive Pulmonary Disease (COPD)).

7. Patients with known active tuberculosis.

8. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed.

9. Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion no. 1.

10. Patients with significant alcohol or drug abuse within the past two years.

11. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening).

12. Patients with known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediamineteraacetic acid (EDTA), salmeterol xinafoate or any other components of the study medication delivery systems.

13. Pregnant or nursing woman.

14. Women of childbearing potential not using a highly effective method of birth control.

15. Patients who have taken an investigational drug within four weeks prior to Visit 1.

16. Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period. Topical cardio-selective beta-blocker eye medications for non-narrow angle glaucoma are allowed.

17. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®) within four weeks prior to Visit 1 and/or during the screening period.

18. Patients who have been treated with oral or patch beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period.

19. Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 and/or during the screening period.

20. Patients who have been treated with anti-IgE antibodies, e.g. omalizumab (Xolair®), within 6 months prior to Visit 1 and/or during the screening period.

21. Patients who have been treated with cromone within two weeks prior to Visit 1 and/or during the screening period.

22. Patients who have been treated with methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period.

23. Patients who have been treated with other non-approved and according to international guidelines not recommended "experimental" drugs for routine asthma therapy within four weeks prior to Visit 1 and/or during the screening period.

24. Patients with any asthma exacerbation or any respiratory tract infection iin the four weeks prior to Visit 1 and/or during the screening period.

25. Patients who have previously been randomised in this trial or in the respective twin trial (205.418) or are currently participating in another trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	205.419.01058 Boehringer Ingelheim Investigational Site	Los Angeles	California	United States
2	205.419.01053 Boehringer Ingelheim Investigational Site	Stockton	California	United States
3	205.419.01061 Boehringer Ingelheim Investigational Site	Centennial	Colorado	United States
4	205.419.01066 Boehringer Ingelheim Investigational Site	Denver	Colorado	United States
5	205.419.01064 Boehringer Ingelheim Investigational Site	Panama City	Florida	United States
6	205.419.01060 Boehringer Ingelheim Investigational Site	Winter Park	Florida	United States
7	205.419.01068 Boehringer Ingelheim Investigational Site	Novi	Michigan	United States
8	205.419.01054 Boehringer Ingelheim Investigational Site	Plymouth	Minnesota	United States
9	205.419.01062 Boehringer Ingelheim Investigational Site	St. Louis	Missouri	United States
10	205.419.01070 Boehringer Ingelheim Investigational Site	Bozeman	Montana	United States
11	205.419.01067 Boehringer Ingelheim Investigational Site	Skillman	New Jersey	United States
12	205.419.01071 Boehringer Ingelheim Investigational Site	Raleigh	North Carolina	United States
13	205.419.01055 Boehringer Ingelheim Investigational Site	Cincinnati	Ohio	United States
14	205.419.01065 Boehringer Ingelheim Investigational Site	Portland	Oregon	United States
15	205.419.01069 Boehringer Ingelheim Investigational Site	Greenville	South Carolina	United States
16	205.419.01056 Boehringer Ingelheim Investigational Site	Union	South Carolina	United States
17	205.419.01063 Boehringer Ingelheim Investigational Site	El Paso	Texas	United States
18	205.419.01051 Boehringer Ingelheim Investigational Site	San Antonio	Texas	United States
19	205.419.55053 Boehringer Ingelheim Investigational Site	Florianopolis		Brazil
20	205.419.55054 Boehringer Ingelheim Investigational Site	Porto Alegre		Brazil
21	205.419.55052 Boehringer Ingelheim Investigational Site	Sao Paulo		Brazil
22	205.419.55055 Boehringer Ingelheim Investigational Site	Sao Paulo		Brazil
23	205.419.86061 Boehringer Ingelheim Investigational Site	Chengdu		China
24	205.419.86053 Boehringer Ingelheim Investigational Site	Chongqing		China
25	205.419.86056 Boehringer Ingelheim Investigational Site	Guangzhou		China
26	205.419.86062 Boehringer Ingelheim Investigational Site	Guangzhou		China
27	205.419.86054 Boehringer Ingelheim Investigational Site	Haikou		China
28	205.419.86059 Boehringer Ingelheim Investigational Site	Kunming		China
29	205.419.86058 Boehringer Ingelheim Investigational Site	Nanchang		China
30	205.419.86064 Boehringer Ingelheim Investigational Site	Nanjing		China
31	205.419.86051 Boehringer Ingelheim Investigational Site	Shanghai		China
32	205.419.86052 Boehringer Ingelheim Investigational Site	Shanghai		China
33	205.419.86055 Boehringer Ingelheim Investigational Site	Shanghai		China
34	205.419.86066 Boehringer Ingelheim Investigational Site	Shanghai		China
35	205.419.86057 Boehringer Ingelheim Investigational Site	Xi'An		China
36	205.419.86065 Boehringer Ingelheim Investigational Site	Xi'An		China
37	205.419.86063 Boehringer Ingelheim Investigational Site	Xuzhou		China
38	205.419.86067 Boehringer Ingelheim Investigational Site	Yangzhou		China
39	205.419.86068 Boehringer Ingelheim Investigational Site	Yinchuan		China
40	205.419.57051 Boehringer Ingelheim Investigational Site	Bogota		Colombia
41	205.419.57052 Boehringer Ingelheim Investigational Site	Bogota		Colombia
42	205.419.57053 Boehringer Ingelheim Investigational Site	Bogota		Colombia
43	205.419.57054 Boehringer Ingelheim Investigational Site	Medelin		Colombia
44	205.419.49061 Boehringer Ingelheim Investigational Site	Bamberg		Germany
45	205.419.49051 Boehringer Ingelheim Investigational Site	Berlin		Germany
46	205.419.49052 Boehringer Ingelheim Investigational Site	Berlin		Germany
47	205.419.49062 Boehringer Ingelheim Investigational Site	Berlin		Germany
48	205.419.49063 Boehringer Ingelheim Investigational Site	Berlin		Germany
49	205.419.49064 Boehringer Ingelheim Investigational Site	Berlin		Germany
50	205.419.49054 Boehringer Ingelheim Investigational Site	Frankfurt		Germany
51	205.419.49058 Boehringer Ingelheim Investigational Site	Hamburg		Germany
52	205.419.49057 Boehringer Ingelheim Investigational Site	Koblenz		Germany
53	205.419.49056 Boehringer Ingelheim Investigational Site	Lübeck		Germany
54	205.419.49059 Boehringer Ingelheim Investigational Site	Rüdersdorf		Germany
55	205.419.49053 Boehringer Ingelheim Investigational Site	Wiesbaden		Germany
56	205.419.49055 Boehringer Ingelheim Investigational Site	Witten		Germany
57	205.419.91057 Boehringer Ingelheim Investigational Site	Ahmedabad		India
58	205.419.91056 Boehringer Ingelheim Investigational Site	Coimbatore		India
59	205.419.91055 Boehringer Ingelheim Investigational Site	Hyderabad		India
60	205.419.91051 Boehringer Ingelheim Investigational Site	Jaipur		India
61	205.419.91058 Boehringer Ingelheim Investigational Site	Jaipur		India
62	205.419.91054 Boehringer Ingelheim Investigational Site	Mumbai		India
63	205.419.91059 Boehringer Ingelheim Investigational Site	Mysore		India
64	205.419.91053 Boehringer Ingelheim Investigational Site	Nagpur		India
65	205.419.81085 Boehringer Ingelheim Investigational Site	Aira, Kagoshima		Japan
66	205.419.81062 Boehringer Ingelheim Investigational Site	Chuo-ku, Tokyo		Japan
67	205.419.81073 Boehringer Ingelheim Investigational Site	Fukuoka, Fukuoka		Japan
68	205.419.81074 Boehringer Ingelheim Investigational Site	Fukuoka, Fukuoka		Japan
69	205.419.81072 Boehringer Ingelheim Investigational Site	Fukuyama, Hiroshima		Japan
70	205.419.81069 Boehringer Ingelheim Investigational Site	Habikino, Osaka		Japan
71	205.419.81071 Boehringer Ingelheim Investigational Site	Hiroshima, Hiroshima		Japan
72	205.419.81058 Boehringer Ingelheim Investigational Site	Itabashi-ku, Tokyo		Japan
73	205.419.81064 Boehringer Ingelheim Investigational Site	Iwata, Shizuoka		Japan
74	205.419.81063 Boehringer Ingelheim Investigational Site	Kanazawa, Ishikawa		Japan
75	205.419.81054 Boehringer Ingelheim Investigational Site	Kishiwada, Osaka		Japan
76	205.419.81075 Boehringer Ingelheim Investigational Site	Kitakyushu, Fukuoka		Japan
77	205.419.81070 Boehringer Ingelheim Investigational Site	Kobe, Hyogo		Japan
78	205.419.81061 Boehringer Ingelheim Investigational Site	Koto-ku, Tokyo		Japan
79	205.419.81067 Boehringer Ingelheim Investigational Site	Kyoto, Kyoto		Japan
80	205.419.81080 Boehringer Ingelheim Investigational Site	Matsusaka, Mie		Japan
81	205.419.81081 Boehringer Ingelheim Investigational Site	Meguro-ku, Tokyo		Japan
82	205.419.81060 Boehringer Ingelheim Investigational Site	Minato-ku, Tokyo		Japan
83	205.419.81077 Boehringer Ingelheim Investigational Site	Minato-ku, Tokyo		Japan
84	205.419.81056 Boehringer Ingelheim Investigational Site	Morioka, Iwate		Japan
85	205.419.81055 Boehringer Ingelheim Investigational Site	Naka-gun, Ibaraki		Japan
86	205.419.81078 Boehringer Ingelheim Investigational Site	Nakano-ku,Tokyo		Japan
87	205.419.81084 Boehringer Ingelheim Investigational Site	Oita,Oita		Japan
88	205.419.81068 Boehringer Ingelheim Investigational Site	Osaka-Sayama, Osaka		Japan
89	205.419.81053 Boehringer Ingelheim Investigational Site	Sapporo, Hokkaido		Japan
90	205.419.81057 Boehringer Ingelheim Investigational Site	Sendai, Miyagi		Japan
91	205.419.81059 Boehringer Ingelheim Investigational Site	Seto, Aichi		Japan
92	205.419.81082 Boehringer Ingelheim Investigational Site	Shinagawa-ku, Tokyo		Japan
93	205.419.81065 Boehringer Ingelheim Investigational Site	Shizuoka, Shizuoka		Japan
94	205.419.81066 Boehringer Ingelheim Investigational Site	Toyota, Aichi		Japan
95	205.419.81051 Boehringer Ingelheim Investigational Site	Urasoe, Okinawa		Japan
96	205.419.81052 Boehringer Ingelheim Investigational Site	Urasoe, Okinawa		Japan
97	205.419.81076 Boehringer Ingelheim Investigational Site	Urasoe, Okinawa		Japan
98	205.419.81083 Boehringer Ingelheim Investigational Site	Yokohama, Kanagawa		Japan
99	205.419.81079 Boehringer Ingelheim Investigational Site	Yotsukaido, Chiba		Japan
100	205.419.52051 Boehringer Ingelheim Investigational Site	Mexico City		Mexico
101	205.419.52052 Boehringer Ingelheim Investigational Site	Mexico City		Mexico
102	205.419.52053 Boehringer Ingelheim Investigational Site	Monterrey		Mexico
103	205.419.51051 Boehringer Ingelheim Investigational Site	Lima		Peru
104	205.419.51052 Boehringer Ingelheim Investigational Site	Lima		Peru
105	205.419.51053 Boehringer Ingelheim Investigational Site	Lima		Peru
106	205.419.51054 Boehringer Ingelheim Investigational Site	Lima		Peru
107	205.419.51055 Boehringer Ingelheim Investigational Site	Lima		Peru
108	205.419.48052 Boehringer Ingelheim Investigational Site	Bialystok		Poland
109	205.419.48054 Boehringer Ingelheim Investigational Site	Bydgoszcz		Poland
110	205.419.48055 Boehringer Ingelheim Investigational Site	Gorzow Wielkopolski		Poland
111	205.419.48051 Boehringer Ingelheim Investigational Site	Krakow		Poland
112	205.419.48057 Boehringer Ingelheim Investigational Site	Poznan		Poland
113	205.419.48058 Boehringer Ingelheim Investigational Site	Sopot		Poland
114	205.419.48053 Boehringer Ingelheim Investigational Site	Wloszczowa		Poland
115	205.419.48056 Boehringer Ingelheim Investigational Site	Wroclaw		Poland
116	205.419.40055 Boehringer Ingelheim Investigational Site	Brasov		Romania
117	205.419.40056 Boehringer Ingelheim Investigational Site	Brasov		Romania
118	205.419.40052 Boehringer Ingelheim Investigational Site	Bucharest		Romania
119	205.419.40053 Boehringer Ingelheim Investigational Site	Bucharest		Romania
120	205.419.40054 Boehringer Ingelheim Investigational Site	Bucharest		Romania
121	205.419.40058 Boehringer Ingelheim Investigational Site	Bucharest		Romania
122	205.419.40060 Boehringer Ingelheim Investigational Site	Bucharest		Romania
123	205.419.40051 Boehringer Ingelheim Investigational Site	Bucuresti		Romania
124	205.419.40059 Boehringer Ingelheim Investigational Site	Constanta		Romania
125	205.419.40057 Boehringer Ingelheim Investigational Site	Iasi		Romania

Sponsors and Collaborators

• Boehringer Ingelheim
• Pfizer

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01172821
• Other Study ID Numbers: 205.419; 2009-018005-43
• First Posted: Jul 30, 2010
• Last Update Posted: Jun 9, 2014
• Last Verified: Jan 1, 2014

• Additional relevant MeSH terms: Asthma; Tiotropium Bromide; Salmeterol Xinafoate

Study Results

Participant Flow

Pre-assignment Detail	There was 1 patient in the TIO R2.5 and 1 patient in the TIO R5 group randomized but not treated.

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Period Title: Overall Study
STARTED	254	257	253	266
COMPLETED	240	245	240	249
NOT COMPLETED	14	12	13	17

Baseline Characteristics

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol	Total
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Total of all reporting groups
Overall Participants	254	257	253	266	1030
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.0 (13.0)	43.0 (12.6)	44.3 (12.7)	41.5 (13.1)	42.9 (12.9)
Sex: Female, Male (Count of Participants)
Female	145 57.1%	160 62.3%	146 57.7%	153 57.5%	604 58.6%
Male	109 42.9%	97 37.7%	107 42.3%	113 42.5%	426 41.4%

Outcome Measures

1. Primary Outcome

Title	Peak FEV1 Within 3 Hours Post-dose Response
Description	Peak forced expiratory volume in one second (FEV1) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) - all treated patients who had baseline data and at least 1 on-treatment efficacy measurement.

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	242	245	240	251
Mean (Standard Error) [Litre]	0.075 (0.020)	0.287 (0.020)	0.244 (0.020)	0.252 (0.019)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.211
	Confidence Interval	(2-Sided) 95%; 0.159 to 0.264
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.169
	Confidence Interval	(2-Sided) 95%; 0.116 to 0.222
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments	Tio R5 - Placebo

2. Primary Outcome

Title	Trough FEV1 Response
Description	Trough FEV1 response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	242	245	240	251
Mean (Standard Error) [Litre]	-0.012 (0.021)	0.164 (0.021)	0.121 (0.021)	0.094 (0.021)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.176
	Confidence Interval	(2-Sided) 95%; 0.120 to 0.233
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.029
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.133
	Confidence Interval	(2-Sided) 95%; 0.076 to 0.190
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.029
	Estimation Comments	Tio R5 - Placebo

3. Secondary Outcome

Title	Peak FVC Within 3 Hours Post-dose Response
Description	Peak forced vital capacity (FVC) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	242	245	240	251
Mean (Standard Error) [Litre]	0.071 (0.022)	0.181 (0.022)	0.160 (0.022)	0.188 (0.021)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.110
	Confidence Interval	(2-Sided) 95%; 0.052 to 0.168
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.030
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0031
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.089
	Confidence Interval	(2-Sided) 95%; 0.030 to 0.147
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.030
	Estimation Comments	Tio R5 - Placebo

4. Secondary Outcome

Title	Trough FVC Response
Description	Trough FVC response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	242	245	240	251
Mean (Standard Error) [Litre]	-0.048 (0.027)	0.039 (0.027)	0.035 (0.027)	0.020 (0.027)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0061
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.087
	Confidence Interval	(2-Sided) 95%; 0.025 to 0.149
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.032
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0093
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.083
	Confidence Interval	(2-Sided) 95%; 0.021 to 0.146
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.032
	Estimation Comments	Tio R5 - Placebo

5. Secondary Outcome

Title	FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response
Description	Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24- week treatment. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	242	245	240	251
Mean (Standard Error) [Litre]	-0.005 (0.019)	0.196 (0.019)	0.158 (0.019)	0.173 (0.019)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.201
	Confidence Interval	(2-Sided) 95%; 0.150 to 0.252
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.163
	Confidence Interval	(2-Sided) 95%; 0.112 to 0.215
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Tio R5 - Placebo

6. Secondary Outcome

Title	FVC Area Under Curve 0-3 Hours (AUC0-3h) Response
Description	Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24- week treatment. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	242	245	240	251
Mean (Standard Error) [Litre]	-0.065 (0.024)	0.043 (0.024)	0.024 (0.025)	0.066 (0.024)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.108
	Confidence Interval	(2-Sided) 95%; 0.052 to 0.164
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.029
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.089
	Confidence Interval	(2-Sided) 95%; 0.033 to 0.145
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.029
	Estimation Comments	Tio R5 - Placebo

7. Secondary Outcome

Title	Trough PEF Response
Description	Trough peak expiratory flow (PEF) response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	242	245	240	251
Mean (Standard Error) [Litre/min]	7.938 (3.659)	36.698 (3.614)	36.117 (3.646)	29.352 (3.572)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	28.759
	Confidence Interval	(2-Sided) 95%; 19.025 to 38.494
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.963
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	28.178
	Confidence Interval	(2-Sided) 95%; 18.401 to 37.956
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.985
	Estimation Comments	Tio R5 - Placebo

8. Secondary Outcome

Title	Total Asthma Quality of Life Questionnaire (AQLQs)) Score
Description	Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ(s)) determined at the end of 24-week treatment. The AQLQ(s) contains 32 questions, each question has a 7 point scale from 1 (highest intensity) till 7 (no symptoms). Total score was defined as the sum of all items divided by the number of items and ranges from from 1 (highest intensity) till 7 (no symptoms). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	240	245	240	250
Mean (Standard Error) [units on a scale]	5.551 (0.050)	5.562 (0.049)	5.548 (0.050)	5.634 (0.048)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8700
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.011
	Confidence Interval	(2-Sided) 95%; -0.122 to 0.144
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.068
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9612
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.003
	Confidence Interval	(2-Sided) 95%; -0.137 to 0.130
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.068
	Estimation Comments	Tio R5 - Placebo

9. Secondary Outcome

Title	Total Asthma Control Questionnaire (ACQ) Score
Description	Control of asthma as assessed by the ACQ determined at the end of 24-week treatment. The ACQ contains 7 questions, each question has a 7 point scale from 0 (no symptoms) till 6 (highest intensity). Total score was defined as the sum of all items divided by the number of items and ranges from from 0 (no symptoms) till 6 (highest intensity). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	240	245	240	250
Mean (Standard Error) [units on a scale]	1.442 (0.043)	1.315 (0.042)	1.359 (0.043)	1.318 (0.042)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0305
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.127
	Confidence Interval	(2-Sided) 95%; -0.241 to -0.012
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.059
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1602
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.083
	Confidence Interval	(2-Sided) 95%; -0.198 to 0.033
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.059
	Estimation Comments	Tio R5 - Placebo

10. Secondary Outcome

Title	The Responder Rate as Assessed by the ACQ
Description	The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period. A patient was considered to be a responder if he or she was reported with an improvement (decrease) in ACQ total score of at least 0.5 points.The score ranges from 0 (no impairment) to 6 (maximum impairment).
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	253	256	252	264
Number [Percentage of participants]	62.5 24.6%	66.4 25.8%	61.9 24.5%	64.4 24.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4012
	Comments	Calculated as 2*one-sided-p-value in the direction corresponding to testing the null hypothesis
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.74
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tio R2.5 / Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.1727
	Comments	Calculated as 2*one-sided-p-value in the direction corresponding to testing the null hypothesis
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tio R5 / Placebo

11. Secondary Outcome

Title	Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24
Description	Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week
Time Frame	Baseline and last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	235	238	236	247
Mean (Standard Error) [Litre/min]	2.764 (3.292)	23.377 (3.267)	27.521 (3.294)	19.779 (3.219)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	20.613
	Confidence Interval	(2-Sided) 95%; 11.795 to 29.431
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.496
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	24.757
	Confidence Interval	(2-Sided) 95%; 15.907 to 33.607
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.513
	Estimation Comments	Tio R5 - Placebo

12. Secondary Outcome

Title	Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24
Description	Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time Frame	Baseline and last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	236	238	236	247
Mean (Standard Error) [Litre/min]	-0.072 (3.328)	15.919 (3.303)	21.175 (3.330)	11.617 (3.256)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	15.991
	Confidence Interval	(2-Sided) 95%; 7.074 to 24.908
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.547
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	21.247
	Confidence Interval	(2-Sided) 95%; 12.302 to 30.193
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.561
	Estimation Comments	Tio R5 - Placebo

13. Secondary Outcome

Title	PEF Variability
Description	PEF daily variability was assesed by patients at home using the AM3 device. PEF variability is the absolute difference between morning and evening PEF value divided by their mean, based on the weekly mean response at week 24. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time Frame	Last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	232	237	234	244
Mean (Standard Error) [Percentage of Mean PEF]	-0.448 (0.484)	-1.401 (0.480)	-0.627 (0.487)	-1.518 (0.472)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1114
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.953
	Confidence Interval	(2-Sided) 95%; -2.125 to 0.220
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.598
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7665
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.178
	Confidence Interval	(2-Sided) 95%; -1.355 to 0.999
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.600
	Estimation Comments	Tio R5 - Placebo

14. Secondary Outcome

Title	Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24
Description	Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time Frame	Baseline and last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	235	238	236	247
Mean (Standard Error) [Litre]	0.020 (0.023)	0.099 (0.023)	0.084 (0.023)	0.103 (0.022)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0111
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.079
	Confidence Interval	(2-Sided) 95%; 0.018 to 0.140
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.031
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0395
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.064
	Confidence Interval	(2-Sided) 95%; 0.003 to 0.126
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.031
	Estimation Comments	Tio R5 - Placebo

15. Secondary Outcome

Title	Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24
Description	Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time Frame	Baseline and last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	236	238	236	247
Mean (Standard Error) [Litre]	-0.002 (0.024)	0.066 (0.023)	0.064 (0.024)	0.048 (0.023)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0357
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.068
	Confidence Interval	(2-Sided) 95%; 0.005 to 0.131
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.032
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0422
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.066
	Confidence Interval	(2-Sided) 95%; 0.002 to 0.129
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.032
	Estimation Comments	Tio R5 - Placebo

16. Secondary Outcome

Title	Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24
Description	Daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
Time Frame	Baseline and last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	237	238	236	247
Mean (Standard Error) [Number of Puffs]	-0.952 (0.093)	-1.123 (0.092)	-0.843 (0.093)	-1.078 (0.091)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1927
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.171
	Confidence Interval	(2-Sided) 95%; -0.427 to 0.086
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.131
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4053
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.109
	Confidence Interval	(2-Sided) 95%; -0.148 to 0.367
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.131
	Estimation Comments	Tio R5 - Placebo

17. Secondary Outcome

Title	Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24
Description	Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. An asthma symptom-free day was defined as a day with no reported symptoms and no use of rescue medication.
Time Frame	Baseline and last 7 days before week 24 visit

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	237	238	236	247
Mean (Standard Error) [Days]	0.189 (0.023)	0.164 (0.023)	0.196 (0.023)	0.195 (0.022)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3501
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.026
	Confidence Interval	(2-Sided) 95%; -0.079 to 0.028
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments	Tio R2.5 - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments	Analyses included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8045
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.007
	Confidence Interval	(2-Sided) 95%; -0.047 to 0.061
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.028
	Estimation Comments	Tio R5 - Placebo

18. Primary Outcome

Title	The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)
Description	The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period (on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS of combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821).

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	518	515	513	535
Number [Percentage of participants]	57.7 22.7%	64.5 25.1%	64.3 25.4%	66.5 25%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R2.5
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0308
	Comments	Calculated as 2*one-sided-p-value in the direction corresponding to testing the null hypothesis
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.33
	Confidence Interval	(2-Sided) 95%; 1.03 to 1.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tio R2.5 / Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tio R5
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0348
	Comments	Calculated as 2*one-sided-p-value in the direction corresponding to testing the null hypothesis
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; 1.02 to 1.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tio R5 / Placebo

19. Secondary Outcome

Title	Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)
Description	Time to first severe asthma exacerbation during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS of combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	518	515	513	535
Median (95% Confidence Interval) [weeks]	NA	NA	NA	NA

20. Secondary Outcome

Title	Time to First Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)
Description	Time to first asthma exacerbation (including severe, non-severe; symptomatic, asymptomatic; i.e. any exacerbation) during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS of combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)

Arm/Group Title	Placebo	Tio R2.5	Tio R5	Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
Measure Participants	518	515	513	535
Median (95% Confidence Interval) [weeks]	NA	NA	NA	NA

Adverse Events

Time Frame	24 weeks
Arm/Group Title	Placebo		Tio R2.5		Tio R5		Salmeterol
Arm/Group Description	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).		Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.		Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.		Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
All Cause Mortality
	Placebo		Tio R2.5		Tio R5		Salmeterol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Tio R2.5		Tio R5		Salmeterol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/254 (1.6%)		7/257 (2.7%)		7/253 (2.8%)		4/266 (1.5%)
Gastrointestinal disorders
Anal fistula	0/254 (0%)		1/257 (0.4%)		0/253 (0%)		0/266 (0%)
Colitis	0/254 (0%)		0/257 (0%)		1/253 (0.4%)		0/266 (0%)
Ileus paralytic	0/254 (0%)		0/257 (0%)		0/253 (0%)		1/266 (0.4%)
General disorders
Suprapubic pain	0/254 (0%)		1/257 (0.4%)		0/253 (0%)		0/266 (0%)
Immune system disorders
Anaphylactic reaction	0/254 (0%)		0/257 (0%)		1/253 (0.4%)		0/266 (0%)
Infections and infestations
Pneumonia	0/254 (0%)		1/257 (0.4%)		0/253 (0%)		0/266 (0%)
Pyelonephritis	1/254 (0.4%)		0/257 (0%)		0/253 (0%)		0/266 (0%)
Injury, poisoning and procedural complications
Chemical poisoning	0/254 (0%)		0/257 (0%)		1/253 (0.4%)		0/266 (0%)
Intestinal anastomosis complication	0/254 (0%)		0/257 (0%)		0/253 (0%)		1/266 (0.4%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/254 (0%)		0/257 (0%)		0/253 (0%)		1/266 (0.4%)
Rhabdomyolysis	0/254 (0%)		1/257 (0.4%)		0/253 (0%)		0/266 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ovarian adenoma	0/254 (0%)		0/257 (0%)		1/253 (0.4%)		0/266 (0%)
Nervous system disorders
Cerebral haemorrhage	1/254 (0.4%)		0/257 (0%)		0/253 (0%)		0/266 (0%)
Cervicobrachial syndrome	0/254 (0%)		1/257 (0.4%)		0/253 (0%)		0/266 (0%)
Pregnancy, puerperium and perinatal conditions
Ectopic pregnancy	0/254 (0%)		1/257 (0.4%)		0/253 (0%)		0/266 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/254 (0%)		0/257 (0%)		0/253 (0%)		1/266 (0.4%)
Parovarian cyst	0/254 (0%)		0/257 (0%)		1/253 (0.4%)		0/266 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	2/254 (0.8%)		2/257 (0.8%)		1/253 (0.4%)		1/266 (0.4%)
Eosinophilic pneumonia	0/254 (0%)		0/257 (0%)		0/253 (0%)		1/266 (0.4%)
Nasal polyps	0/254 (0%)		0/257 (0%)		1/253 (0.4%)		0/266 (0%)
Sleep apnoea syndrome	0/254 (0%)		1/257 (0.4%)		0/253 (0%)		0/266 (0%)
Vascular disorders
Hypertension	0/254 (0%)		1/257 (0.4%)		0/253 (0%)		0/266 (0%)
Hypertensive crisis	0/254 (0%)		0/257 (0%)		1/253 (0.4%)		0/266 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Tio R2.5		Tio R5		Salmeterol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	102/254 (40.2%)		89/257 (34.6%)		87/253 (34.4%)		90/266 (33.8%)
Infections and infestations
Nasopharyngitis	26/254 (10.2%)		31/257 (12.1%)		19/253 (7.5%)		25/266 (9.4%)
Upper respiratory tract infection	22/254 (8.7%)		11/257 (4.3%)		12/253 (4.7%)		16/266 (6%)
Investigations
Peak expiratory flow rate decreased	28/254 (11%)		21/257 (8.2%)		25/253 (9.9%)		18/266 (6.8%)
Respiratory, thoracic and mediastinal disorders
Asthma	54/254 (21.3%)		44/257 (17.1%)		50/253 (19.8%)		52/266 (19.5%)

Limitations/Caveats

[Not Specified]

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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.