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 I

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

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: Placebo; Drug: tiotropium Respimat® low dose; Drug: Placebo; Drug: tiotropium Respimat® high dose; Drug: 50 mcg salmeterol HFA MDI

• Study Type: Interventional
• Enrollment (Actual): 1071
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Juiz de Fora, Brazil
    • 205.418.55002 Boehringer Ingelheim Investigational Site
  • Porto Alegre, Brazil
    • 205.418.55001 Boehringer Ingelheim Investigational Site
  • Porto Alegre, Brazil
    • 205.418.55004 Boehringer Ingelheim Investigational Site
  • Porto Alegre, Brazil
    • 205.418.55005 Boehringer Ingelheim Investigational Site
  • Rio de Janeiro - RJ, Brazil
    • 205.418.55003 Boehringer Ingelheim Investigational Site
• China
  • Beijing, China
    • 205.418.86001 Boehringer Ingelheim Investigational Site
  • Beijing, China
    • 205.418.86005 Boehringer Ingelheim Investigational Site
  • Beijing, China
    • 205.418.86007 Boehringer Ingelheim Investigational Site
  • Beijing, China
    • 205.418.86012 Boehringer Ingelheim Investigational Site
  • Changsha, China
    • 205.418.86014 Boehringer Ingelheim Investigational Site
  • Chengdu, China
    • 205.418.86011 Boehringer Ingelheim Investigational Site
  • Chengdu, China
    • 205.418.86015 Boehringer Ingelheim Investigational Site
  • Chongqing, China
    • 205.418.86003 Boehringer Ingelheim Investigational Site
  • Guangzhou, China
    • 205.418.86010 Boehringer Ingelheim Investigational Site
  • Kunming, China
    • 205.418.86013 Boehringer Ingelheim Investigational Site
  • Qingdao, China
    • 205.418.86008 Boehringer Ingelheim Investigational Site
  • Shanghai, China
    • 205.418.86002 Boehringer Ingelheim Investigational Site
  • Shenyang, China
    • 205.418.86004 Boehringer Ingelheim Investigational Site
  • Shenyang, China
    • 205.418.86009 Boehringer Ingelheim Investigational Site
  • Xi'An, China
    • 205.418.86006 Boehringer Ingelheim Investigational Site
• Guatemala
  • Guatelama City, Guatemala
    • 205.418.50203 Boehringer Ingelheim Investigational Site
  • Guatelmala City, Guatemala
    • 205.418.50205 Boehringer Ingelheim Investigational Site
  • Guatelmala city, Guatemala
    • 205.418.50204 Boehringer Ingelheim Investigational Site
  • Guatemala City, Guatemala
    • 205.418.50201 Boehringer Ingelheim Investigational Site
  • Guatemala city, Guatemala
    • 205.418.50202 Boehringer Ingelheim Investigational Site
• India
  • Banglore, India
    • 205.418.91008 Boehringer Ingelheim Investigational Site
  • Chennai, India
    • 205.418.91005 Boehringer Ingelheim Investigational Site
  • Coimbatore, India
    • 205.418.91004 Boehringer Ingelheim Investigational Site
  • Coimbatore, India
    • 205.418.91006 Boehringer Ingelheim Investigational Site
  • Hyderabad, India
    • 205.418.91003 Boehringer Ingelheim Investigational Site
  • Jaipur, India
    • 205.418.91009 Boehringer Ingelheim Investigational Site
  • Nagpur, India
    • 205.418.91002 Boehringer Ingelheim Investigational Site
  • Pune, India
    • 205.418.91007 Boehringer Ingelheim Investigational Site
  • Pune, India
    • 205.418.91010 Boehringer Ingelheim Investigational Site
• Japan
  • Adachi-ku, Tokyo, Japan
    • 205.418.81018 Boehringer Ingelheim Investigational Site
  • Ako, Hyogo, Japan
    • 205.418.81030 Boehringer Ingelheim Investigational Site
  • Chiyoda-ku, Tokyo, Japan
    • 205.418.81001 Boehringer Ingelheim Investigational Site
  • Chuo-ku, Tokyo, Japan
    • 205.418.81005 Boehringer Ingelheim Investigational Site
  • Chuo-ku, Tokyo, Japan
    • 205.418.81025 Boehringer Ingelheim Investigational Site
  • Fujioka, Gunma, Japan
    • 205.418.81015 Boehringer Ingelheim Investigational Site
  • Himeji, Hyogo, Japan
    • 205.418.81023 Boehringer Ingelheim Investigational Site
  • Hitachi, Ibaraki, Japan
    • 205.418.81007 Boehringer Ingelheim Investigational Site
  • Iwamizawa, Hokkaido, Japan
    • 205.418.81009 Boehringer Ingelheim Investigational Site
  • Kanazawa, Ishikawa, Japan
    • 205.418.81028 Boehringer Ingelheim Investigational Site
  • Kitakami, Iwate, Japan
    • 205.418.81011 Boehringer Ingelheim Investigational Site
  • Kitakami, Iwate, Japan
    • 205.418.81012 Boehringer Ingelheim Investigational Site
  • Koga, Ibaraki, Japan
    • 205.418.81031 Boehringer Ingelheim Investigational Site
  • Koganei, Tokyo, Japan
    • 205.418.81016 Boehringer Ingelheim Investigational Site
  • Komaki, Aichi, Japan
    • 205.418.81006 Boehringer Ingelheim Investigational Site
  • Kunitachi, Tokyo, Japan
    • 205.418.81002 Boehringer Ingelheim Investigational Site
  • Mito, Ibaraki, Japan
    • 205.418.81004 Boehringer Ingelheim Investigational Site
  • Osaka, Osaka, Japan
    • 205.418.81032 Boehringer Ingelheim Investigational Site
  • Ota-ku, Tokyo, Japan
    • 205.418.81019 Boehringer Ingelheim Investigational Site
  • Sapporo, Hokkaido, Japan
    • 205.418.81008 Boehringer Ingelheim Investigational Site
  • Sendai, Miyagi, Japan
    • 205.418.81013 Boehringer Ingelheim Investigational Site
  • Sendai, Miyagi, Japan
    • 205.418.81014 Boehringer Ingelheim Investigational Site
  • Setagaya-ku, Tokyo, Japan
    • 205.418.81026 Boehringer Ingelheim Investigational Site
  • Takasaki, Gunma, Japan
    • 205.418.81024 Boehringer Ingelheim Investigational Site
  • Tomakomai, Hokkaido, Japan
    • 205.418.81010 Boehringer Ingelheim Investigational Site
  • Toshima-ku, Tokyo, Japan
    • 205.418.81003 Boehringer Ingelheim Investigational Site
  • Toshima-ku, Tokyo, Japan
    • 205.418.81017 Boehringer Ingelheim Investigational Site
  • Yao, Osaka, Japan
    • 205.418.81022 Boehringer Ingelheim Investigational Site
  • Yokohama, Kanagawa, Japan
    • 205.418.81020 Boehringer Ingelheim Investigational Site
  • Yokohama, Kanagawa, Japan
    • 205.418.81021 Boehringer Ingelheim Investigational Site
• Latvia
  • Daugavpils, Latvia
    • 205.418.37004 Boehringer Ingelheim Investigational Site
  • Preili, Latvia
    • 205.418.37008 Boehringer Ingelheim Investigational Site
  • Riga, Latvia
    • 205.418.37001 Boehringer Ingelheim Investigational Site
  • Riga, Latvia
    • 205.418.37002 Boehringer Ingelheim Investigational Site
  • Riga, Latvia
    • 205.418.37005 Boehringer Ingelheim Investigational Site
  • Riga, Latvia
    • 205.418.37006 Boehringer Ingelheim Investigational Site
  • Riga, Latvia
    • 205.418.37007 Boehringer Ingelheim Investigational Site
  • Riga, Latvia
    • 205.418.37009 Boehringer Ingelheim Investigational Site
  • Ventspils, Latvia
    • 205.418.37003 Boehringer Ingelheim Investigational Site
• Mexico
  • Monterrey, Mexico
    • 205.418.52002 Boehringer Ingelheim Investigational Site
  • Zapopan, Mexico
    • 205.418.52003 Boehringer Ingelheim Investigational Site
  • Zona Río, Mexico
    • 205.418.52001 Boehringer Ingelheim Investigational Site
• Peru
  • Callao, Peru
    • 205.418.51003 Boehringer Ingelheim Investigational Site
  • Lima, Peru
    • 205.418.51001 Boehringer Ingelheim Investigational Site
  • Lima, Peru
    • 205.418.51002 Boehringer Ingelheim Investigational Site
• Poland
  • Krakow, Poland
    • 205.418.48006 Boehringer Ingelheim Investigational Site
  • Lodz, Poland
    • 205.418.48001 Boehringer Ingelheim Investigational Site
  • Lodz, Poland
    • 205.418.48005 Boehringer Ingelheim Investigational Site
  • Ostrow Wielkopolska, Poland
    • 205.418.48002 Boehringer Ingelheim Investigational Site
  • Poznan, Poland
    • 205.418.48004 Boehringer Ingelheim Investigational Site
  • Tczew, Poland
    • 205.418.48003 Boehringer Ingelheim Investigational Site
• Russian Federation
  • Gatchina (Leningradskaya oblast), Russian Federation
    • 205.418.07007 Boehringer Ingelheim Investigational Site
  • Moscow, Russian Federation
    • 205.418.07004 Boehringer Ingelheim Investigational Site
  • Moscow, Russian Federation
    • 205.418.07005 Boehringer Ingelheim Investigational Site
  • Moscow, Russian Federation
    • 205.418.07006 Boehringer Ingelheim Investigational Site
  • Moscow, Russian Federation
    • 205.418.07008 Boehringer Ingelheim Investigational Site
  • St. Petersburg, Russian Federation
    • 205.418.07001 Boehringer Ingelheim Investigational Site
  • St. Petersburg, Russian Federation
    • 205.418.07002 Boehringer Ingelheim Investigational Site
  • St. Petersburg, Russian Federation
    • 205.418.07003 Boehringer Ingelheim Investigational Site
• United States
  • California
    • Huntington Beach, California, United States
      • 205.418.01020 Boehringer Ingelheim Investigational Site
    • Mission Viejo, California, United States
      • 205.418.01002 Boehringer Ingelheim Investigational Site
    • San Diego, California, United States
      • 205.418.01014 Boehringer Ingelheim Investigational Site
  • Colorado
    • Wheat Ridge, Colorado, United States
      • 205.418.01011 Boehringer Ingelheim Investigational Site
  • Idaho
    • Coeur d'Alene, Idaho, United States
      • 205.418.01004 Boehringer Ingelheim Investigational Site
  • Illinois
    • Normal, Illinois, United States
      • 205.418.01017 Boehringer Ingelheim Investigational Site
  • Indiana
    • South Bend, Indiana, United States
      • 205.418.01008 Boehringer Ingelheim Investigational Site
  • Maryland
    • Baltimore, Maryland, United States
      • 205.418.01012 Boehringer Ingelheim Investigational Site
  • Massachusetts
    • North Dartmouth, Massachusetts, United States
      • 205.418.01013 Boehringer Ingelheim Investigational Site
    • North Dartmouth, Massachusetts, United States
      • 205.418.01015 Boehringer Ingelheim Investigational Site
  • Minnesota
    • Minneapolis, Minnesota, United States
      • 205.418.01009 Boehringer Ingelheim Investigational Site
  • Nebraska
    • Bellevue, Nebraska, United States
      • 205.418.01006 Boehringer Ingelheim Investigational Site
    • Boys Town, Nebraska, United States
      • 205.418.01016 Boehringer Ingelheim Investigational Site
    • Omaha, Nebraska, United States
      • 205.418.01003 Boehringer Ingelheim Investigational Site
  • North Carolina
    • Winston-Salem, North Carolina, United States
      • 205.418.01021 Boehringer Ingelheim Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • 205.418.01018 Boehringer Ingelheim Investigational Site
  • South Carolina
    • Charleston, South Carolina, United States
      • 205.418.01005 Boehringer Ingelheim Investigational Site
    • Easely, South Carolina, United States
      • 205.418.01010 Boehringer Ingelheim Investigational Site
  • Texas
    • Dallas, Texas, United States
      • 205.418.01007 Boehringer Ingelheim Investigational Site
  • Washington
    • Seattle, Washington, United States
      • 205.418.01019 Boehringer Ingelheim Investigational Site
    • Tacoma, Washington, United States
      • 205.418.01001 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 (205.419) or are currently participating in another trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)	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. The ACQ 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).	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.	24 weeks
Total Asthma Control Questionnaire (ACQ) Score at the End of the 24-week Treatment Period	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. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.	24 weeks
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 ACQ 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).	24 weeks
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
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
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, centre, week, baseline, treatment by week, and baseline by week.	Last 7 days before week 24 visit
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
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
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
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
Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)	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
Time to First Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)	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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Collaborators: Pfizer

Publications and helpful links

General Publications

• Halpin DMG, Hamelmann EH, Frith PA, Moroni-Zentgraf PM, van Hecke B, Unseld A, Kerstjens HAM, Szefler SJ. Comparative Responses in Lung Function Measurements with Tiotropium in Adolescents and Adults, and Across Asthma Severities: A Post Hoc Analysis. Pulm Ther. 2020 Jun;6(1):131-140. doi: 10.1007/s41030-020-00113-w. Epub 2020 Mar 16.
• Casale TB, Aalbers R, Bleecker ER, Meltzer EO, Zaremba-Pechmann L, de la Hoz A, Kerstjens HAM. Tiotropium Respimat(R) add-on therapy to inhaled corticosteroids in patients with symptomatic asthma improves clinical outcomes regardless of baseline characteristics. Respir Med. 2019 Oct-Nov;158:97-109. doi: 10.1016/j.rmed.2019.09.014. Epub 2019 Sep 30.
• Halpin DMG, Meltzer EO, Pisternick-Ruf W, Moroni-Zentgraf P, Engel M, Zaremba-Pechmann L, Casale T, FitzGerald JM. Peak expiratory flow as an endpoint for clinical trials in asthma: a comparison with FEV1. Respir Res. 2019 Jul 18;20(1):159. doi: 10.1186/s12931-019-1119-6.
• Casale TB, Bateman ED, Vandewalker M, Virchow JC, Schmidt H, Engel M, Moroni-Zentgraf P, Kerstjens HAM. Tiotropium Respimat Add-on Is Efficacious in Symptomatic Asthma, Independent of T2 Phenotype. J Allergy Clin Immunol Pract. 2018 May-Jun;6(3):923-935.e9. doi: 10.1016/j.jaip.2017.08.037. Epub 2017 Nov 22.
• Kerstjens HA, Casale TB, Bleecker ER, Meltzer EO, Pizzichini E, Schmidt O, Engel M, Bour L, Verkleij CB, Moroni-Zentgraf P, Bateman ED. Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials. Lancet Respir Med. 2015 May;3(5):367-76. doi: 10.1016/S2213-2600(15)00031-4. Epub 2015 Feb 12.

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: July 26, 2010
• First Submitted That Met QC Criteria: July 29, 2010
• First Posted (Estimate): July 30, 2010

Study Record Updates

• Last Update Posted (Estimate): June 9, 2014
• Last Update Submitted That Met QC Criteria: June 3, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Salmeterol Xinafoate; Tiotropium Bromide
• Other Study ID Numbers: 205.418; 2009-018004-18 (EudraCT Number: EudraCT)