Evaluation of Tiotropium 5 µg/Day Delivered Via the Respimat® Inhaler Over 48 Weeks in Patients With Severe Persistent Asthma on Top of Usual Care (Study 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 (5 mcg/Day) Over 48 Weeks as add-on Controller Therapy on Top of Usual Care in Patients With Severe Persistent Asthma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00776984
• Other study ID #: 205.417
• Secondary ID: 2008-001414-25
• Status: Completed
• Phase: Phase 3
• First received: October 13, 2008
• Last updated: September 9, 2014
• Start date: October 2008

Study information

• Verified date: September 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Australia: Dept of Health and Ageing Therapeutic Goods AdminCanada: Therapeutic Products DirectorateDenmark: The Danish Medicines AgencyGermany: Federal Institute for Drugs and Medical DevicesGreat Britain: MHRAItaly: Ethics CommitteeJapan: Ministry of Health, Labor and WelfareNetherlands: Central Committee on Research Involving Human Subjects (CCMO)New Zealand: Multicentre Ethics Committee/MedsafeRussia: Ministry of Health of the Russian FederationSerbia: Medicines and Medical Devices Agency of Serbia, 11152 BelgradeSouth Africa: Medicines Control CouncilTurkey: Ministry of Health Central Ethics CommitteeUkraine: Ministry of Health Care of Ukraine (MoH of Ukraine)United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The trial is a randomised, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of 5 µg tiotropium over a 48-week treatment period as compared to placebo. Tiotropium inhalation solution delivered by the Respimat® inhaler will be examined as add-on controller therapy on top of usual care in patients with severe persistent asthma. The primary objective of each trial is to evaluate the long term efficacy of tiotropium over placebo on top of usual care in patients with severe persistent asthma as determined by pulmonary function testing, effects on asthma exacerbations, effects on quality of life, on asthma control and health care resource utilisation. The secondary objective of each trial is to compare the long term safety of tiotropium with placebo in this patient population.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 453
• Est. primary completion date: July 2011
• 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 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 5-year history of asthma at the time of enrolment into the trial and the diagnosis of asthma must have been made before the patient´s age of 40.

4. All patients must have a diagnosis of severe persistent asthma and must be symptomatic despite treatment with high, stable doses of inhaled corticosteroids and a long-acting beta adrenergic agent

5. All patients must have a history of one or more asthma exacerbation in the past year.

6. Patients must have evidence of treated, severe, persistent asthma in postbronchodilator pulmonary function tests.

7. Patients should be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment and who have a smoking history of less than 10 pack years

8. Patients must be able to use the Respimat® inhaler correctly

9. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the 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 clinically relevant abnormal screening haematology or blood chemistry.

3. Patients with a recent history (i.e. six months or less) of myocardial infarction, hospitalisation for cardiac failure during the past year, any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year, known active tuberculosis, malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years (treated basal cell carcinoma allowed), lung diseases other than asthma (e.g. COPD), significant alcohol or drug abuse within the past two years, 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.

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

5. Patients using oral corticosteroid medication at stable doses exceeding 5 mg prednisolone or prednisolone equivalent every day or 10 mg prednisolone or prednisolone equivalent every second day.

6. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution.

7. Pregnant or nursing women or women of childbearing potential not using a highly effective method of birth control. Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years.

8. Patients who have taken an investigational drug within four weeks or six half-lives (whichever is greater) prior to Visit 1.

9. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®), beta-blocker medication, oral beta-adrenergics, other non-approved and according to international guidelines not recommended ´experimental´ drugs for routine asthma therapy (e.g. TNF-alpha blockers, methotrexate, cyclosporin) within four weeks prior to the Screening Visit (Visit 1) or during the screening period.

10. Patients with any asthma exacerbation or respiratory tract infection in the four weeks prior to the trial.

11. Patients who have previously been randomised in this trial or in the respective twin trial (205.416 versus 205.417) or are currently participating in another trial.

12. Patients with a known narrow-angle glaucoma.

Note:

As with other anticholinergic drugs, tiotropium should be used with caution in patients with prostatic hyperplasia or bladder neck obstruction.

As with all predominantly renally excreted drugs, patients with moderate to severe renal impairment (known creatinine clearance of <= 50 mL/min) treated with tiotropium should be monitored closely.

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:
• tiotropium 5mcg/day
Intervention = Randomisation: patient to receive double-blind treatment with either 5mcg/day tiotropium inhalation solution or placebo inhalation solution
• placebo
Intervention = Randomisation: patient to receive double-blind treatment with either 5mcg/day tiotropium inhalation solution or placebo inhalation solution

Locations

Country	Name	City	State
Australia	205.417.61051 Boehringer Ingelheim Investigational Site	Concord	New South Wales
Canada	205.417.02051 Boehringer Ingelheim Investigational Site	Mississauga	Ontario
Canada	205.417.02052 Boehringer Ingelheim Investigational Site	Montreal	Quebec
Canada	205.417.02053 Boehringer Ingelheim Investigational Site	Ottawa	Ontario
Denmark	205.417.45052 Boehringer Ingelheim Investigational Site	Aalborg
Denmark	205.417.45051 Boehringer Ingelheim Investigational Site	Aarhus C
Germany	205.417.49052 Boehringer Ingelheim Investigational Site	Berlin
Germany	205.417.49054 Boehringer Ingelheim Investigational Site	Hamburg
Germany	205.417.49053 Boehringer Ingelheim Investigational Site	Lübeck
Germany	205.417.49051 Boehringer Ingelheim Investigational Site	Rüdersdorf
Germany	205.417.49055 Boehringer Ingelheim Investigational Site	Weinheim
Italy	205.417.39052 Boehringer Ingelheim Investigational Site	Bussolengo (vr)
Italy	205.417.39054 Boehringer Ingelheim Investigational Site	Milano
Italy	205.417.39051 Boehringer Ingelheim Investigational Site	Pavia
Italy	205.417.39053 Boehringer Ingelheim Investigational Site	Pietra Ligure (sv)
Japan	205.417.81063 Boehringer Ingelheim Investigational Site	Himeji, Hyogo
Japan	205.417.81056 Boehringer Ingelheim Investigational Site	Hiroshima, Hiroshima
Japan	205.417.81051 Boehringer Ingelheim Investigational Site	Itabashi-ku, Tokyo
Japan	205.417.81059 Boehringer Ingelheim Investigational Site	Kagoshima, Kagoshima
Japan	205.417.81053 Boehringer Ingelheim Investigational Site	Kishiwada, Osaka
Japan	205.417.81057 Boehringer Ingelheim Investigational Site	Kitakyusyu, Fukuoka
Japan	205.417.81058 Boehringer Ingelheim Investigational Site	Koga, Fukuoka
Japan	205.417.81055 Boehringer Ingelheim Investigational Site	Kurashiki, Okayama
Japan	205.417.81064 Boehringer Ingelheim Investigational Site	Kurume, Fukuoka
Japan	205.417.81062 Boehringer Ingelheim Investigational Site	Morioka, Iwate
Japan	205.417.81052 Boehringer Ingelheim Investigational Site	Osaka-sayama, Osaka
Japan	205.417.81066 Boehringer Ingelheim Investigational Site	Sendai, Miyagi
Japan	205.417.81065 Boehringer Ingelheim Investigational Site	Seto, Aichi
Japan	205.417.81060 Boehringer Ingelheim Investigational Site	Urasoe, Okinawa
Japan	205.417.81061 Boehringer Ingelheim Investigational Site	Urasoe, Okinawa
Japan	205.417.81054 Boehringer Ingelheim Investigational Site	Wakayama, Wakayama
Netherlands	205.417.31051 Boehringer Ingelheim Investigational Site	Groningen
Netherlands	205.417.31053 Boehringer Ingelheim Investigational Site	Leeuwarden
Netherlands	205.417.31052 Boehringer Ingelheim Investigational Site	Schiedam
New Zealand	205.417.64054 Boehringer Ingelheim Investigational Site	Auckland NZ
New Zealand	205.417.64053 Boehringer Ingelheim Investigational Site	Christchurch
New Zealand	205.417.64052 Boehringer Ingelheim Investigational Site	Newtown Wellington NZ
New Zealand	205.417.64051 Boehringer Ingelheim Investigational Site	Tauranga
Russian Federation	205.417.07051 Boehringer Ingelheim Investigational Site	St. Petersburg
Russian Federation	205.417.07052 Boehringer Ingelheim Investigational Site	St. Petersburg
Russian Federation	205.417.07053 Boehringer Ingelheim Investigational Site	St. Petersburg
Serbia	205.417.38153 Boehringer Ingelheim Investigational Site	Belgrade
Serbia	205.417.38151 Boehringer Ingelheim Investigational Site	Nis
Serbia	205.417.38152 Boehringer Ingelheim Investigational Site	Sremska Kamenica
South Africa	205.417.27051 Boehringer Ingelheim Investigational Site	Bellville
South Africa	205.417.27052 Boehringer Ingelheim Investigational Site	Cape Town
South Africa	205.417.27053 Boehringer Ingelheim Investigational Site	Cape Town
South Africa	205.417.27054 Boehringer Ingelheim Investigational Site	Cape Town
Turkey	205.417.90052 Boehringer Ingelheim Investigational Site	Ankara
Turkey	205.417.90053 Boehringer Ingelheim Investigational Site	Ankara
Turkey	205.417.90051 Boehringer Ingelheim Investigational Site	Izmit
Ukraine	205.417.38053 Boehringer Ingelheim Investigational Site	Kharkov
Ukraine	205.417.38051 Boehringer Ingelheim Investigational Site	Kiev
Ukraine	205.417.38052 Boehringer Ingelheim Investigational Site	Vinnytsya
United Kingdom	205.417.44051 Boehringer Ingelheim Investigational Site	Chertsey
United Kingdom	205.417.44053 Boehringer Ingelheim Investigational Site	Exeter
United Kingdom	205.417.44052 Boehringer Ingelheim Investigational Site	Windsor
United States	205.417.01062 Boehringer Ingelheim Investigational Site	Albany	New York
United States	205.417.01070 Boehringer Ingelheim Investigational Site	Canton	Ohio
United States	205.417.01059 Boehringer Ingelheim Investigational Site	Chicago	Illinois
United States	205.417.01061 Boehringer Ingelheim Investigational Site	Fountain Valley	California
United States	205.417.01052 Boehringer Ingelheim Investigational Site	Fresno	California
United States	205.417.01058 Boehringer Ingelheim Investigational Site	Great Neck	New York
United States	205.417.01067 Boehringer Ingelheim Investigational Site	High Point	North Carolina
United States	205.417.01063 Boehringer Ingelheim Investigational Site	Louisville	Kentucky
United States	205.417.01064 Boehringer Ingelheim Investigational Site	New Orleans	Louisiana
United States	205.417.01068 Boehringer Ingelheim Investigational Site	Normal	Illinois
United States	205.417.01069 Boehringer Ingelheim Investigational Site	Ocean	New Jersey
United States	205.417.01066 Boehringer Ingelheim Investigational Site	Omaha	Nebraska
United States	205.417.01065 Boehringer Ingelheim Investigational Site	Pensacola	Florida
United States	205.417.01054 Boehringer Ingelheim Investigational Site	Richmond	Virginia
United States	205.417.01055 Boehringer Ingelheim Investigational Site	Rockville Centre	New York
United States	205.417.01051 Boehringer Ingelheim Investigational Site	Stockton	California
United States	205.417.01053 Boehringer Ingelheim Investigational Site	Upland	Pennsylvania
United States	205.417.01056 Boehringer Ingelheim Investigational Site	Waterbury	Connecticut

Sponsors (2)

Lead Sponsor	Collaborator
Boehringer Ingelheim	Pfizer

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Denmark,  Germany,  Italy,  Japan,  Netherlands,  New Zealand,  Russian Federation,  Serbia,  South Africa,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 24 Weeks.	Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 24 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and 24 weeks	No
Primary	Trough FEV1 Response Determined After a Treatment Period of 24 Weeks.	The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 24 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and 24 weeks	No
Primary	Time to First Severe Asthma Exacerbation During the 48-week Treatment of the Pooled Data From the Two Twin Trials 205.416 (NCT00772538) and the Present 205.417 (NCT00776984).	Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.	48 weeks	No
Secondary	Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 24-week Treatment Period.	Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 24 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and 24 weeks	No
Secondary	Trough FVC Response at the End of the 24-week Treatment Period.	The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 24 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and 24 weeks	No
Secondary	FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 24-week Treatment Period.	The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit.	Baseline and 24 weeks	No
Secondary	FVC (AUC0-3h) Response at the End of the 24-week Treatment Period.	The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 24 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit.	Baseline and 24 weeks	No
Secondary	Peak FEV1 0-3h Response at the End of the 48-week Treatment Period.	Peak FEV1 0-3h response was defined as the difference between the maximum FEV1 measured within the first 3 hours post dosing after a treatment period of 48 weeks and the FEV1 baseline measurement (10 minutes before the first dose of trial medication). Mixed Model Repeated Measure (MMRM) results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and 48 weeks	No
Secondary	Trough FEV1 Response at the End of the 48-week Treatment Period.	The trough FEV1 is defined as the pre-dose FEV1 measured 10 minutes before the last administration of randomised treatment. Trough FEV1 response was defined as the difference between the trough FEV1 measured after a treatment period of 48 weeks and the FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and 48 weeks	No
Secondary	AUC0-3h FEV1 Response at the End of the 48-week Treatment Period.	The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FEV1 AUC0-3h after a treatment period of 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit.	Baseline and 48 weeks	No
Secondary	Peak FVC 0-3h Response at the End of the 48-week Treatment Period.	Peak FVC 0-3h response was defined as the difference between the maximum FVC measured within the first 3 hours post dosing after a treatment period of 48 weeks and the FVC baseline measurement (10 minutes before the first dose of trial medication). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and 48 weeks	No
Secondary	Trough FVC Response at the End of the 48-week Treatment Period.	The trough FVC is defined as the pre-dose FVC measured 10 minutes before the last administration of randomised treatment. Trough FVC response was defined as the difference between the trough FVC measured after a treatment period of 48 weeks and the FVC baseline measurement. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and 48 weeks	No
Secondary	FVC AUC0-3h Response at the End of the 48-week Treatment Period.	The AUC0-3h was calculated as area under the curve from zero to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. The trough value was assigned to zero time. Response was defined as change from baseline in FVC AUC0-3h after a treatment period of 48 weeks. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit baseline*visit.	Baseline and 48 weeks	No
Secondary	Mean Pre-dose Morning Peak Expiratory Flow (PEFa.m.) Response (Diary Data) of Last-7-days-before-week-24-visit .	Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and last 7 days before week 24 visit	No
Secondary	Mean Pre-dose Evening Peak Expiratory Flow (PEFp.m.) Response (Diary Data) of Last-7-days-before-week 24-visit.	Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and last 7 days before week 24 visit	No
Secondary	Mean Pre-dose FEV1 a.m. Response (Diary Data) of Last-7-days-before-week 24-visit.	Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and last 7 days before week 24 visit	No
Secondary	Mean Pre-dose FEV1-p.m.Response (Diary Data) of Last-7-days-before-week 24-visit.	Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and last 7 days before week 24 visit	No
Secondary	Mean PEF Variability Response (Absolute Difference Between Morning and Evening PEF Value Divided by Their Mean) of Last-7-days-before-week 24-visit.	Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The PEF variability is the absolute difference between morning and evening PEF value divided by their mean, expressed as a percent. Response was defined as change from baseline. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and last 7 days before week 24 visit	No
Secondary	Time to First Severe Asthma Exacerbation During the 48-week Treatment.	Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.	48 weeks	No
Secondary	Number of Asthma Exacerbations Per Patient During the 48-week Treatment Period.	Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation.	48 weeks	No
Secondary	Number of Severe Asthma Exacerbations Per Patient During the 48-week Treatment Period.	Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.	48 weeks	No
Secondary	Number of Patients With at Least One Asthma Exacerbation During the 48-week Treatment Period.	Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation.	48 weeks	No
Secondary	Number of Patients With at Least One Severe Asthma Exacerbation During the 48-week Treatment Period.	Severe asthma exacerbations were pre-defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days or (in case of ongoing and pre-existing systemic corticosteroid therapy) that required at least a doubling of the previous daily dose of systemic corticosteroids for at least 3 days.	48 weeks	No
Secondary	Time to First Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period.	Asthma exacerbations (including severe, non-severe; symptomatic, asymptomatic) were pre-defined as an episode of progressive increase in 1 or more asthma symptoms (e.g. shortness of breath, cough, wheezing, chest tightness or some combination of these symptoms). Additionally, decrease of patients best PEF a.m. of 30 percent or more from the patients mean PEF a.m. for at least 2 consecutive days was considered to be an objective marker of asthma exacerbation.	48 weeks	No
Secondary	Number of Hospitalisations for Asthma Exacerbations Per Patient During the 48-week Treatment Period.		48 weeks	No
Secondary	Number of Patients With at Least One Hospitalisation for Asthma Exacerbation During the 48-week Treatment Period.		48 weeks	No
Secondary	Quality of Life as Assessed by Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) at the End of the 24-week Treatment Period.	The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	24 weeks	No
Secondary	AQLQ(S) Total Score at the End of the 48-week Treatment Period.	The AQLQ(S) total score was calculated as the mean of the responses to 32 questions for the domains Symptoms, Activity Limitations, Emotional Function and Environmental Stimuli and was analysed as an absolute value. The AQLQ(S) total score ranges from 1 (worst controlled) to 7 (best). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	48 weeks	No
Secondary	Asthma Control as Assessed by Asthma Control Questionnaire (ACQ) at the End of the 24-week Treatment Period.	For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	24 weeks	No
Secondary	ACQ Score at the End of the 48-week Treatment Period.	For the ACQ, the total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment). MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	48 weeks	No
Secondary	Asthma Symptom Free Days Response During the Last-7-days-before-week-24-visit .	Weekly means obtained during the last 7 days before week 24 visit were compared (measured by patients at home using the asthma monitor device). The response is defined as the change of the weekly mean from the baseline weekly mean. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and last 7 days before week 24 visit	No
Secondary	Mean Pro Re Nata (as Needed, PRN) Rescue Medication Use Response During the Last-7-days-before-week-24-visit .	Weekly means obtained during the last 7 days before week 24 visit were compared. The response is defined as the change of the weekly mean from the baseline weekly mean. The use of PRN salbutamol (albuterol rescue medication) is determined by the number of puffs of rescue therapy used per day. MMRM results. Means are adjusted for treatment, centre, visit, baseline, treatment*visit and baseline*visit.	Baseline and last 7 days before week 24 visit	No

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