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

Asthma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01172821
• Other study ID #: 205.419
• Secondary ID: 2009-018005-43
• Status: Completed
• Phase: Phase 3
• First received: July 26, 2010
• Last updated: June 3, 2014
• Start date: August 2010
• Est. completion date: November 2012

Study information

• Verified date: January 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Brazil: National Health Surveillance AgencyChina: Food and Drug AdministrationColombia: Instituto Nacional de Vigilancia de Medicamentos y AlimentosGermany: Federal Institute for Drugs and Medical DevicesIndia: Drugs Controller General of IndiaJapan: Ministry of Health, Labor and WelfareMexico: Federal Commission for Protection Against Health RisksPeru: General Directorate of Pharmaceuticals, Devices, and DrugsPoland: Registration Medicinal Product Medical Device Biocidal ProductRomania: National Medicines AgencyUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1032
• Est. completion date: November 2012
• Est. primary completion date: November 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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.

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

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

10. 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.

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

12. 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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• placebo
Placebo that represents BI drug
• placebo
Placebo that represents comparator
• placebo
Placebo that represents comparator
• tiotropium Respimat® low dose
IMP
• placebo
Placebo that represents BI drug
• tiotropium Respimat® high dose
IMP
• 50 mcg salmeterol HFA MDI
Active comparator
• placebo
Placebo that represents comparator

Locations

Country	Name	City	State
Brazil	205.419.55053 Boehringer Ingelheim Investigational Site	Florianopolis
Brazil	205.419.55054 Boehringer Ingelheim Investigational Site	Porto Alegre
Brazil	205.419.55052 Boehringer Ingelheim Investigational Site	Sao Paulo
Brazil	205.419.55055 Boehringer Ingelheim Investigational Site	Sao Paulo
China	205.419.86061 Boehringer Ingelheim Investigational Site	Chengdu
China	205.419.86053 Boehringer Ingelheim Investigational Site	Chongqing
China	205.419.86056 Boehringer Ingelheim Investigational Site	Guangzhou
China	205.419.86062 Boehringer Ingelheim Investigational Site	Guangzhou
China	205.419.86054 Boehringer Ingelheim Investigational Site	Haikou
China	205.419.86059 Boehringer Ingelheim Investigational Site	Kunming
China	205.419.86058 Boehringer Ingelheim Investigational Site	Nanchang
China	205.419.86064 Boehringer Ingelheim Investigational Site	Nanjing
China	205.419.86051 Boehringer Ingelheim Investigational Site	Shanghai
China	205.419.86052 Boehringer Ingelheim Investigational Site	Shanghai
China	205.419.86055 Boehringer Ingelheim Investigational Site	Shanghai
China	205.419.86066 Boehringer Ingelheim Investigational Site	Shanghai
China	205.419.86057 Boehringer Ingelheim Investigational Site	Xi'An
China	205.419.86065 Boehringer Ingelheim Investigational Site	Xi'An
China	205.419.86063 Boehringer Ingelheim Investigational Site	Xuzhou
China	205.419.86067 Boehringer Ingelheim Investigational Site	Yangzhou
China	205.419.86068 Boehringer Ingelheim Investigational Site	Yinchuan
Colombia	205.419.57051 Boehringer Ingelheim Investigational Site	Bogota
Colombia	205.419.57052 Boehringer Ingelheim Investigational Site	Bogota
Colombia	205.419.57053 Boehringer Ingelheim Investigational Site	Bogota
Colombia	205.419.57054 Boehringer Ingelheim Investigational Site	Medelin
Germany	205.419.49061 Boehringer Ingelheim Investigational Site	Bamberg
Germany	205.419.49051 Boehringer Ingelheim Investigational Site	Berlin
Germany	205.419.49052 Boehringer Ingelheim Investigational Site	Berlin
Germany	205.419.49062 Boehringer Ingelheim Investigational Site	Berlin
Germany	205.419.49063 Boehringer Ingelheim Investigational Site	Berlin
Germany	205.419.49064 Boehringer Ingelheim Investigational Site	Berlin
Germany	205.419.49054 Boehringer Ingelheim Investigational Site	Frankfurt
Germany	205.419.49058 Boehringer Ingelheim Investigational Site	Hamburg
Germany	205.419.49057 Boehringer Ingelheim Investigational Site	Koblenz
Germany	205.419.49056 Boehringer Ingelheim Investigational Site	Lübeck
Germany	205.419.49059 Boehringer Ingelheim Investigational Site	Rüdersdorf
Germany	205.419.49053 Boehringer Ingelheim Investigational Site	Wiesbaden
Germany	205.419.49055 Boehringer Ingelheim Investigational Site	Witten
India	205.419.91057 Boehringer Ingelheim Investigational Site	Ahmedabad
India	205.419.91056 Boehringer Ingelheim Investigational Site	Coimbatore
India	205.419.91055 Boehringer Ingelheim Investigational Site	Hyderabad
India	205.419.91051 Boehringer Ingelheim Investigational Site	Jaipur
India	205.419.91058 Boehringer Ingelheim Investigational Site	Jaipur
India	205.419.91054 Boehringer Ingelheim Investigational Site	Mumbai
India	205.419.91059 Boehringer Ingelheim Investigational Site	Mysore
India	205.419.91053 Boehringer Ingelheim Investigational Site	Nagpur
Japan	205.419.81085 Boehringer Ingelheim Investigational Site	Aira, Kagoshima
Japan	205.419.81062 Boehringer Ingelheim Investigational Site	Chuo-ku, Tokyo
Japan	205.419.81073 Boehringer Ingelheim Investigational Site	Fukuoka, Fukuoka
Japan	205.419.81074 Boehringer Ingelheim Investigational Site	Fukuoka, Fukuoka
Japan	205.419.81072 Boehringer Ingelheim Investigational Site	Fukuyama, Hiroshima
Japan	205.419.81069 Boehringer Ingelheim Investigational Site	Habikino, Osaka
Japan	205.419.81071 Boehringer Ingelheim Investigational Site	Hiroshima, Hiroshima
Japan	205.419.81058 Boehringer Ingelheim Investigational Site	Itabashi-ku, Tokyo
Japan	205.419.81064 Boehringer Ingelheim Investigational Site	Iwata, Shizuoka
Japan	205.419.81063 Boehringer Ingelheim Investigational Site	Kanazawa, Ishikawa
Japan	205.419.81054 Boehringer Ingelheim Investigational Site	Kishiwada, Osaka
Japan	205.419.81075 Boehringer Ingelheim Investigational Site	Kitakyushu, Fukuoka
Japan	205.419.81070 Boehringer Ingelheim Investigational Site	Kobe, Hyogo
Japan	205.419.81061 Boehringer Ingelheim Investigational Site	Koto-ku, Tokyo
Japan	205.419.81067 Boehringer Ingelheim Investigational Site	Kyoto, Kyoto
Japan	205.419.81080 Boehringer Ingelheim Investigational Site	Matsusaka, Mie
Japan	205.419.81081 Boehringer Ingelheim Investigational Site	Meguro-ku, Tokyo
Japan	205.419.81060 Boehringer Ingelheim Investigational Site	Minato-ku, Tokyo
Japan	205.419.81077 Boehringer Ingelheim Investigational Site	Minato-ku, Tokyo
Japan	205.419.81056 Boehringer Ingelheim Investigational Site	Morioka, Iwate
Japan	205.419.81055 Boehringer Ingelheim Investigational Site	Naka-gun, Ibaraki
Japan	205.419.81078 Boehringer Ingelheim Investigational Site	Nakano-ku,Tokyo
Japan	205.419.81084 Boehringer Ingelheim Investigational Site	Oita,Oita
Japan	205.419.81068 Boehringer Ingelheim Investigational Site	Osaka-Sayama, Osaka
Japan	205.419.81053 Boehringer Ingelheim Investigational Site	Sapporo, Hokkaido
Japan	205.419.81057 Boehringer Ingelheim Investigational Site	Sendai, Miyagi
Japan	205.419.81059 Boehringer Ingelheim Investigational Site	Seto, Aichi
Japan	205.419.81082 Boehringer Ingelheim Investigational Site	Shinagawa-ku, Tokyo
Japan	205.419.81065 Boehringer Ingelheim Investigational Site	Shizuoka, Shizuoka
Japan	205.419.81066 Boehringer Ingelheim Investigational Site	Toyota, Aichi
Japan	205.419.81051 Boehringer Ingelheim Investigational Site	Urasoe, Okinawa
Japan	205.419.81052 Boehringer Ingelheim Investigational Site	Urasoe, Okinawa
Japan	205.419.81076 Boehringer Ingelheim Investigational Site	Urasoe, Okinawa
Japan	205.419.81083 Boehringer Ingelheim Investigational Site	Yokohama, Kanagawa
Japan	205.419.81079 Boehringer Ingelheim Investigational Site	Yotsukaido, Chiba
Mexico	205.419.52051 Boehringer Ingelheim Investigational Site	Mexico City
Mexico	205.419.52052 Boehringer Ingelheim Investigational Site	Mexico City
Mexico	205.419.52053 Boehringer Ingelheim Investigational Site	Monterrey
Peru	205.419.51051 Boehringer Ingelheim Investigational Site	Lima
Peru	205.419.51052 Boehringer Ingelheim Investigational Site	Lima
Peru	205.419.51053 Boehringer Ingelheim Investigational Site	Lima
Peru	205.419.51054 Boehringer Ingelheim Investigational Site	Lima
Peru	205.419.51055 Boehringer Ingelheim Investigational Site	Lima
Poland	205.419.48052 Boehringer Ingelheim Investigational Site	Bialystok
Poland	205.419.48054 Boehringer Ingelheim Investigational Site	Bydgoszcz
Poland	205.419.48055 Boehringer Ingelheim Investigational Site	Gorzow Wielkopolski
Poland	205.419.48051 Boehringer Ingelheim Investigational Site	Krakow
Poland	205.419.48057 Boehringer Ingelheim Investigational Site	Poznan
Poland	205.419.48058 Boehringer Ingelheim Investigational Site	Sopot
Poland	205.419.48053 Boehringer Ingelheim Investigational Site	Wloszczowa
Poland	205.419.48056 Boehringer Ingelheim Investigational Site	Wroclaw
Romania	205.419.40055 Boehringer Ingelheim Investigational Site	Brasov
Romania	205.419.40056 Boehringer Ingelheim Investigational Site	Brasov
Romania	205.419.40052 Boehringer Ingelheim Investigational Site	Bucharest
Romania	205.419.40053 Boehringer Ingelheim Investigational Site	Bucharest
Romania	205.419.40054 Boehringer Ingelheim Investigational Site	Bucharest
Romania	205.419.40058 Boehringer Ingelheim Investigational Site	Bucharest
Romania	205.419.40060 Boehringer Ingelheim Investigational Site	Bucharest
Romania	205.419.40051 Boehringer Ingelheim Investigational Site	Bucuresti
Romania	205.419.40059 Boehringer Ingelheim Investigational Site	Constanta
Romania	205.419.40057 Boehringer Ingelheim Investigational Site	Iasi
United States	205.419.01070 Boehringer Ingelheim Investigational Site	Bozeman	Montana
United States	205.419.01061 Boehringer Ingelheim Investigational Site	Centennial	Colorado
United States	205.419.01055 Boehringer Ingelheim Investigational Site	Cincinnati	Ohio
United States	205.419.01066 Boehringer Ingelheim Investigational Site	Denver	Colorado
United States	205.419.01063 Boehringer Ingelheim Investigational Site	El Paso	Texas
United States	205.419.01069 Boehringer Ingelheim Investigational Site	Greenville	South Carolina
United States	205.419.01058 Boehringer Ingelheim Investigational Site	Los Angeles	California
United States	205.419.01068 Boehringer Ingelheim Investigational Site	Novi	Michigan
United States	205.419.01064 Boehringer Ingelheim Investigational Site	Panama City	Florida
United States	205.419.01054 Boehringer Ingelheim Investigational Site	Plymouth	Minnesota
United States	205.419.01065 Boehringer Ingelheim Investigational Site	Portland	Oregon
United States	205.419.01071 Boehringer Ingelheim Investigational Site	Raleigh	North Carolina
United States	205.419.01051 Boehringer Ingelheim Investigational Site	San Antonio	Texas
United States	205.419.01067 Boehringer Ingelheim Investigational Site	Skillman	New Jersey
United States	205.419.01062 Boehringer Ingelheim Investigational Site	St. Louis	Missouri
United States	205.419.01053 Boehringer Ingelheim Investigational Site	Stockton	California
United States	205.419.01056 Boehringer Ingelheim Investigational Site	Union	South Carolina
United States	205.419.01060 Boehringer Ingelheim Investigational Site	Winter Park	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Boehringer Ingelheim	Pfizer

Countries where clinical trial is conducted

United States,  Brazil,  China,  Colombia,  Germany,  India,  Japan,  Mexico,  Peru,  Poland,  Romania, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Peak FEV1 Within 3 Hours Post-dose Response	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.	24 weeks	No
Primary	Trough FEV1 Response	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.	24 weeks	No
Primary	The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)	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.	24 weeks	No
Secondary	Peak FVC Within 3 Hours Post-dose Response	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.	24 weeks	No
Secondary	Trough FVC Response	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.	24 weeks	No
Secondary	FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response	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.	24 weeks	No
Secondary	FVC Area Under Curve 0-3 Hours (AUC0-3h) Response	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.	24 weeks	No
Secondary	Trough PEF Response	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.	24 weeks	No
Secondary	Total Asthma Quality of Life Questionnaire (AQLQs)) Score	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.	24 weeks	No
Secondary	Total Asthma Control Questionnaire (ACQ) Score	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.	24 weeks	No
Secondary	The Responder Rate as Assessed by the ACQ	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).	24 weeks	No
Secondary	Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24	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	Baseline and last 7 days before week 24 visit	No
Secondary	Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24	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.	Baseline and last 7 days before week 24 visit	No
Secondary	PEF Variability	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.	Last 7 days before week 24 visit	No
Secondary	Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24	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.	Baseline and last 7 days before week 24 visit	No
Secondary	Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24	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.	Baseline and last 7 days before week 24 visit	No
Secondary	Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24	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.	Baseline and last 7 days before week 24 visit	No
Secondary	Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24	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.	Baseline and last 7 days before week 24 visit	No
Secondary	Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)	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)	24 weeks	No
Secondary	Time to First Asthma Exacerbation From the Two Twin Trials 205.418 (NCT01172808) and the Present 205.419 (NCT01172821)	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)	24 weeks	No

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