Clinical trial NCT01340209: Evaluation of Tiotropium 2.5 and 5 µg Once Daily Delivered Via the Respimat Inhaler Compared to Placebo in Patient With Moderate to Severe Persistent Asthma
Official title: A Phase III Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Safety and Efficacy of Tiotropium Inhalation Solution Delivered Via Respimat Inhaler (2.5 and 5 µg Once Daily) Compared With Placebo Over 52 Weeks in Patients With Moderate to Severe Persistent Asthma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
First posted: 2011-04-22
Enrollment: 285
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of this trial is to evaluate the safety and efficacy of 2.5 and 5 µg tiotropium over a 52-week treatment period as compared to placebo. 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 to severe persistent asthma. Efficacy and safety will be assessed by measuring effects on lung function, effects on asthma exacerbations, effects on asthma control, and number of adverse events.


Eligibility criteria: Inclusion criteria:

1. All patients including the patients under age (under 20 years old) must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and Good Clinical Practice (GCP) prior to participation in the trial \[i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test (PFT) at Visit 1\]. Regarding patients under age, a guardian or a legally authorised representative must also sign and date an Informed Consent Form.
2. Male or female outpatients aged at least 18 years but not more than 75 years at Visit 0.
3. All patients must have at least a 12-week history of asthma at the time of enrolment (Visit 0) 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 (15-30 minutes after 400 µg salbutamol) resulting in a Forced Expiratory Volume in one second (FEV1) increase of at least 12% and at least 200 mL .
6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids (ICS) \[alone or in a fixed combination with a Long-acting beta-adrenergic (LABA)\] for at least 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. Patients must be never-smokers or ex-smokers who stopped smoking at least one year (52 weeks) 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 correctly, which is judged at the discretion of the investigator..
11. Patients must be able to perform all trial related procedures including technically acceptable PFTs and use of electronic diary (eDiary)/peak flow meter, which is judged at the discretion of the investigator.

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 no 1.
3. Patients with a recent history (i.e. 6 months or less) of myocardial infarction prior to Visit 0.
4. Patients who have been hospitalised for cardiac failure during the past year prior to Visit 0.
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 prior to Visit 0.
6. Patients with lung diseases other than asthma (e.g. COPD).
7. Patients with known active tuberculosis.
8. Patients with malignancy and/or patients who have undergone resection, radiation therapy or chemotherapy for malignancy within the last 5 years prior to Visit 0. 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, which is judged at the discretion of the investigator, within the past 2 years prior to Visit 0.
11. Patients with known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediaminetetraacetic acid (EDTA), or any other components of the study medication delivery systems.
12. Pregnant or nursing women.
13. Women of childbearing potential not using a highly effective method of birth control.
14. Patients who have taken an investigational drug within 4 weeks prior to Visit 1.
15. 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.
16. 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.
17. Patients who have been treated with oral beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period.
18. Patients who have been treated with systemic corticosteroids within four weeks prior to Visit 1 and/or during the screening period.
19. 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.
20. 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.
21. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 and/or during the screening period.
22. Patients who are currently participating in another trial.
23. Patients with narrow-angle glaucoma and/or micturition disorder due to prostatic hyperplasia.
24. Patients with below 80% of the eDiary completion compliance on Visit 2 (diary compliance of at least 80% is required).

Primary outcomes:
measure: Number of Patients With Drug-related Adverse Events
timeFrame: after the first dose of trial medication and within 30 days after the last dose of trial medication, up to 409
Secondary outcomes:
measure: Trough FEV1 Response
timeFrame: baseline and week 52
measure: Trough FVC Response
timeFrame: baseline and week 52
measure: Trough PEF Response
timeFrame: baseline and week 52
measure: Weekly Mean PEFam Response
timeFrame: baseline and week 52
measure: Weekly Mean PEFpm Response
timeFrame: baseline and week 52
measure: Weekly Mean PEF Variability Response
timeFrame: baseline and week 52
measure: Weekly Mean Number of Puffs of Rescue Medication During the Whole Day (Response)
timeFrame: baseline and week 52
measure: Weekly Mean Score of Asthma Symptoms in the Morning (Response)
timeFrame: baseline and week 52
measure: Weekly Mean Score of Asthma Symptoms During the Day (Response)
timeFrame: baseline and week 52
Other outcomes:
Locations:
city: Asahikawa, Hokkaido
country: Japan
facility: 205.464.81020 Boehringer Ingelheim Investigational Site
city: Atsugi, Kanagawa
country: Japan
facility: 205.464.81031 Boehringer Ingelheim Investigational Site
city: Chigasaki, Kanagawa
country: Japan
facility: 205.464.81029 Boehringer Ingelheim Investigational Site
city: Chino, Nagano
country: Japan
facility: 205.464.81011 Boehringer Ingelheim Investigational Site
city: Chuo-ku, Tokyo
country: Japan
facility: 205.464.81050 Boehringer Ingelheim Investigational Site
city: Chuo-ku, Tokyo
country: Japan
facility: 205.464.81051 Boehringer Ingelheim Investigational Site
city: Edogawa-ku, Tokyo
country: Japan
facility: 205.464.81006 Boehringer Ingelheim Investigational Site
city: Fujisawa, Kanagawa
country: Japan
facility: 205.464.81010 Boehringer Ingelheim Investigational Site
city: Fukuoka, Fukuoka
country: Japan
facility: 205.464.81016 Boehringer Ingelheim Investigational Site
city: Hanno, Saitama
country: Japan
facility: 205.464.81004 Boehringer Ingelheim Investigational Site
city: Himeji, Hyogo
country: Japan
facility: 205.464.81040 Boehringer Ingelheim Investigational Site
city: Himeji, Hyogo
country: Japan
facility: 205.464.81041 Boehringer Ingelheim Investigational Site
city: Himeji, Hyogo
country: Japan
facility: 205.464.81053 Boehringer Ingelheim Investigational Site
city: Hino, Tokyo
country: Japan
facility: 205.464.81007 Boehringer Ingelheim Investigational Site
city: Hiroshima, Hiroshima
country: Japan
facility: 205.464.81015 Boehringer Ingelheim Investigational Site
city: Hitachinaka, Ibaraki
country: Japan
facility: 205.464.81002 Boehringer Ingelheim Investigational Site
city: Iizuka, Fukuoka
country: Japan
facility: 205.464.81048 Boehringer Ingelheim Investigational Site
city: Itabashi-ku, Tokyo
country: Japan
facility: 205.464.81005 Boehringer Ingelheim Investigational Site
city: Kaga, Ishikawa
country: Japan
facility: 205.464.81033 Boehringer Ingelheim Investigational Site
city: Kagoshima, Kagoshima
country: Japan
facility: 205.464.81017 Boehringer Ingelheim Investigational Site
city: Kamogawa, Chiba
country: Japan
facility: 205.464.81023 Boehringer Ingelheim Investigational Site
city: Kisarazu, Chiba
country: Japan
facility: 205.464.81024 Boehringer Ingelheim Investigational Site
city: Kitakyusyu,Fukuoka
country: Japan
facility: 205.464.81047 Boehringer Ingelheim Investigational Site
city: Kiyose, Tokyo
country: Japan
facility: 205.464.81008 Boehringer Ingelheim Investigational Site
city: Kochi, Kochi
country: Japan
facility: 205.464.81046 Boehringer Ingelheim Investigational Site
city: Kodaira, Tokyo
country: Japan
facility: 205.464.81025 Boehringer Ingelheim Investigational Site
city: Koshigaya, Saitama
country: Japan
facility: 205.464.81022 Boehringer Ingelheim Investigational Site
city: Kurashiki, Okayama
country: Japan
facility: 205.464.81043 Boehringer Ingelheim Investigational Site
city: Kure, Hiroshima
country: Japan
facility: 205.464.81044 Boehringer Ingelheim Investigational Site
city: Kyoto, Kyoto
country: Japan
facility: 205.464.81014 Boehringer Ingelheim Investigational Site
city: Kyoto, Kyoto
country: Japan
facility: 205.464.81038 Boehringer Ingelheim Investigational Site
city: Maebashi, Gumma
country: Japan
facility: 205.464.81003 Boehringer Ingelheim Investigational Site
city: Matsue, Shimane
country: Japan
facility: 205.464.81042 Boehringer Ingelheim Investigational Site
city: Minato-ku, Tokyo
country: Japan
facility: 205.464.81026 Boehringer Ingelheim Investigational Site
city: Nagoya, Aichi
country: Japan
facility: 205.464.81012 Boehringer Ingelheim Investigational Site
city: Nagoya, Aichi
country: Japan
facility: 205.464.81013 Boehringer Ingelheim Investigational Site
city: Nagoya, Aichi
country: Japan
facility: 205.464.81034 Boehringer Ingelheim Investigational Site
city: Nagoya, Aichi
country: Japan
facility: 205.464.81035 Boehringer Ingelheim Investigational Site
city: Nagoya, Aichi
country: Japan
facility: 205.464.81036 Boehringer Ingelheim Investigational Site
city: Nagoya, Aichi
country: Japan
facility: 205.464.81037 Boehringer Ingelheim Investigational Site
city: Obihiro, Hokkaido
country: Japan
facility: 205.464.81001 Boehringer Ingelheim Investigational Site
city: Obihiro, Hokkaido
country: Japan
facility: 205.464.81018 Boehringer Ingelheim Investigational Site
city: Oita, Oita
country: Japan
facility: 205.464.81054 Boehringer Ingelheim Investigational Site
city: Oita, Oita
country: Japan
facility: 205.464.81055 Boehringer Ingelheim Investigational Site
city: Osaka, Osaka
country: Japan
facility: 205.464.81039 Boehringer Ingelheim Investigational Site
city: Saga, Saga
country: Japan
facility: 205.464.81049 Boehringer Ingelheim Investigational Site
city: Sapporo, Hokkaido
country: Japan
facility: 205.464.81019 Boehringer Ingelheim Investigational Site
city: Sendai, Miyagi
country: Japan
facility: 205.464.81021 Boehringer Ingelheim Investigational Site
city: Setagaya-Ku, Tokyo
country: Japan
facility: 205.464.81027 Boehringer Ingelheim Investigational Site
city: Setagaya-ku, Tokyo
country: Japan
facility: 205.464.81028 Boehringer Ingelheim Investigational Site
city: Toon, Ehime
country: Japan
facility: 205.464.81045 Boehringer Ingelheim Investigational Site
city: Yokohama, Kanagawa
country: Japan
facility: 205.464.81009 Boehringer Ingelheim Investigational Site
city: Yokohama, Kanagawa
country: Japan
facility: 205.464.81052 Boehringer Ingelheim Investigational Site
city: Yokosuka, Kanagawa
country: Japan
facility: 205.464.81030 Boehringer Ingelheim Investigational Site
city: Zama, Kanagawa
country: Japan
facility: 205.464.81032 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: 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.
citation: Ohta K, Ichinose M, Tohda Y, Engel M, Moroni-Zentgraf P, Kunimitsu S, Sakamoto W, Adachi M. Long-Term Once-Daily Tiotropium Respimat(R) Is Well Tolerated and Maintains Efficacy over 52 Weeks in Patients with Symptomatic Asthma in Japan: A Randomised, Placebo-Controlled Study. PLoS One. 2015 Apr 20;10(4):e0124109. doi: 10.1371/journal.pone.0124109. eCollection 2015.