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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Asthma

Intervention / Treatment
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* Drug: Tiotropium Respimat
* Drug: Placebo Respimat
* Drug: Tiotropium Respimat


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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. Male or female outpatients aged at least 18 years but not more than 75 years at Visit 0. 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. The initial diagnosis of asthma must have been made before the patient's age of 40. 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 . 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. 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. All patients must have a pre-bronchodilator FEV1 at least 60% and less than or equal to 90% of predicted normal at Visit 1. 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. Patients must be able to use the Respimat inhaler correctly, which is judged at the discretion of the investigator.. 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: 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. 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. Patients with a recent history (i.e. 6 months or less) of myocardial infarction prior to Visit 0. Patients who have been hospitalised for cardiac failure during the past year prior to Visit 0. 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. Patients with lung diseases other than asthma (e.g. COPD). Patients with known active tuberculosis. 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. 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. 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. Patients with known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediaminetetraacetic acid (EDTA), or any other components of the study medication delivery systems. Pregnant or nursing women. Women of childbearing potential not using a highly effective method of birth control. Patients who have taken an investigational drug within 4 weeks prior to Visit 1. 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. 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. Patients who have been treated with oral beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period. Patients who have been treated with systemic corticosteroids within four weeks prior to Visit 1 and/or during the screening period. 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. 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. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 and/or during the screening period. Patients who are currently participating in another trial. Patients with narrow-angle glaucoma and/or micturition disorder due to prostatic hyperplasia. Patients with below 80% of the eDiary completion compliance on Visit 2 (diary compliance of at least 80% is required).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tiotropium Respimat (low dose)<br>Tiotropium low dose once daily delivered with Respimat inhaler | Drug: Tiotropium Respimat<br>* Tiotropium low dose once daily delivered with Respimat inhaler<br>|
| Experimental: Tiotropium Respimat (high dose)<br>Tiotropium high dose once daily delivered with Respimat inhaler | Drug: Tiotropium Respimat<br>* Tiotropium high dose once daily delivered with Respimat inhaler<br>|
| Placebo Comparator: Placebo Respimat<br>Tiotropium placebo once daily delivered with Respimat inhaler | Drug: Placebo Respimat<br>* Tiotropium placebo once daily delivered with Respimat inhaler<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Drug-related Adverse Events | The primary endpoint is the number of patients with drug-related adverse events | after the first dose of trial medication and within 30 days after the last dose of trial medication, up to 409 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 Response | Trough FEV1 response was defined as change from baseline at week 52 | baseline and week 52 | 
| Trough FVC Response | Trough FVC response was defined as change from baseline at week 52 | baseline and week 52 | 
| Trough PEF Response | Trough PEF response was defined as change from baseline at week 52 | baseline and week 52 | 
| Weekly Mean PEFam Response | Weekly mean PEFam response was defined as change from baseline at week 52 | baseline and week 52 | 
| Weekly Mean PEFpm Response | Weekly mean PEFpm response was defined as change from baseline at week 52 | baseline and week 52 | 
| Weekly Mean PEF Variability Response | Weekly mean PEF variability response was defined as change from baseline at week 52. 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. | baseline and week 52 | 
| Weekly Mean Number of Puffs of Rescue Medication During the Whole Day (Response) | Response of weekly mean number of puffs of rescue medication during the whole day at week 52. Response was defined as change from baseline. | baseline and week 52 | 
| Weekly Mean Score of Asthma Symptoms in the Morning (Response) | Response of weekly mean score of asthma symptoms in the morning at week 52. Response was defined as change from baseline. 5-point verbal rating scale, with answer 1 representing no impairment at all and answer 5 representing the greatest impairment. | baseline and week 52 | 
| Weekly Mean Score of Asthma Symptoms During the Day (Response) | Response of weekly mean score of asthma symptoms during the day at week 52. Response was defined as change from baseline. 5-point verbal rating scale, with answer 1 representing no impairment at all and answer 5 representing the greatest impairment. | baseline and week 52 |