Efficacy and Safety of 2 Doses of Tiotropium Via Respimat in Adult Patients With Mild Persistent Asthma

Study Overview
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Brief Summary
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The aim of this trial is to evaluate the efficacy and safety of 2.5 and 5 mcg tiotropium compared to placebo over 12 week treatment period. Tiotropium inhalation solution will be delivered via Respimat inhaler and will be examined on top of maintenance inhaled corticosteroid treatment in patients with mild persistent asthma. Efficacy and safety will be assessed by measuring the effects on lung functions, effects on lung exacerbations, effects on asthma control and numbers of adverse events.

Official Title
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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 ug and 5 ug Once Daily) Compared to Placebo Over 12 Weeks in Mild Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: placebo
* Drug: tiotropium 2.5 mcg
* Drug: tiotropium 5 mcg


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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). Male or female patients aged 18 years or more at Visit 0 and 75 years or less at Visit 0. All patients must have at least a 3 months history of asthma at the time of enrolment into the trial. The initial diagnosis of asthma must have been made before the patient's age of 40; a pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1)= 60% predicted and = 90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%. Patient's diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (within 10 minutes pre and 15-30 minutes after 400 µg salbutamol/albuterol) resulting in a FEV1 increase of = 12% and = 200mL. If this is not achieved the reversibility test may be repeated once within two weeks. All patients must be symptomatic despite their current maintenance treatment with low doses of inhaled corticosteroids. All patients must be symptomatic at Visit 1 (screening) and Visit 2 as defined by an Asthma Control Questionnaire (ACQ) mean score of = 1.5. All patients must have been on maintenance treatment with a low, stable dose of inhaled corticosteroids for at least 4 weeks prior to Visit 1. Patients must 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 ((see Appendix 10.3 for calculation). Patients must be able to use the Respimat® inhaler correctly. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the e-Diary/peak flow meter (e-Diary-compliance of at least 80% is required; refer to Section 6.2.1 for instructions). Patients taking a chronic pulmonary medication allowed by the study protocol must be willing to continue this therapy for the entire duration of the study (exception: times of acute disease deterioration). 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) 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 number 1. Patients requiring more than 10 puffs of rescue medication (salbutamol/albuterol MDI) per 24 hours on 2 consecutive days during the screening period. Patients with a recent history (i.e. six months or less) of Acute Coronary Syndrome (STEMI, Non-STEMI and Unstable Angina Pectoris). Patients who have been hospitalised for cardiac failure during the past year. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year. Patients with lung diseases other than asthma (e.g. COPD). Patients with known active tuberculosis. 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. 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 on Investigator's assessment within the past two years. 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). Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution. Pregnant or nursing woman, including female patients with positive beta-HCG test at Visit 1. Female patients of child-bearing potential not using highly effective method of birth control As defined in ICH (M3). 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 oral or patch beta-adrenergics, systemic, i.e. oral or intravenous corticosteroids, long-acting anticholinergic tiotropium (Spiriva®) within four weeks prior to Visit 1 and/or during the screening period. Patients who have been treated with depot corticosteroids within six months prior to Visit 1 and/or during the screening period. Patients who have ever been treated with anti-IgE antibodies. Patients who have been treated with leukotriene modifiers, systemic anticholinergics, cromolyn sodium or nedocromil sodium and methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period. Patients who have been treated with inhaled long acting beta adrenergics and long acting beta adrenergics combination products within four weeks prior to Visit 0 and/or during the screening period. Patients who have taken an investigational drug within four weeks or six half lives whichever is greater prior to Visit 1. Patients who have been treated with other non-approved and according to international guidelines not recommended, experimental drugs for routine asthma therapy (e.g. TNFalpha blockers, methotrexate, cyclosporin) within four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). Current participation in another trial.

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 5 mcg<br>once daily delivered via Respimat inhaler | Drug: tiotropium 5 mcg<br>* To evaluate efficacy and safety of 2.5 and 5 mcg tiotropium versus placebo delivered via Respimat inhaler<br>|
| Experimental: tiotropium 2.5 mcg<br>once daily delivered via Respimat inhaler | Drug: tiotropium 2.5 mcg<br>* To evaluate efficacy and safety of 2.5 and 5 mcg tiotropium versus placebo delivered via Respimat inhaler<br>|
| Placebo Comparator: placebo<br>once daily delivered via Respimat inhaler | Drug: placebo<br>* To evaluate efficacy and safety of 2.5 and 5 mcg tiotropium versus placebo delivered via Respimat inhaler<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Forced Expiratory Volume in 1 Second (FEV1) Response Within 3 Hours Post Dosing (0-3h) After a Treatment Period of 12 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 12 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, pooled centre, visit, baseline, treatment*visit and baseline*visit. | Baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 Response Determined After a Treatment Period of 12 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 12 weeks and the trough FEV1 baseline measurement. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit and baseline*visit. | Baseline and 12 weeks | 
| Peak (Within 3 Hours Post-dosing) Forced Vital Capacity (FVC) Response at the End of the 12-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 12 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, pooled centre, visit, baseline, treatment*visit and baseline*visit. | Baseline and 12 weeks | 
| FEV1 Area Under the Curve (AUC0-3h) Response at the End of the 12-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 12 weeks. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit baseline*visit. | Baseline and 12 weeks | 
| FVC (AUC0-3h) Response at the End of the 12-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 12 weeks. MMRM results. Means are adjusted for treatment, pooled centre, visit, baseline, treatment*visit baseline*visit. | Baseline and 12 weeks | 
| Asthma Control Questionnaire (ACQ) Responder After 12 Weeks of Treatment | For the ACQ, the total score was calculated as the mean of the responses to 6 self administered questions and one question which was completed by clinical staff based upon pre-bronchodilator FEV1. The score ranges from 0 (no impairment) to 6 (maximum impairment). Response was categorised as: responder (change from baseline <= -0.5), no change (-0.5 <change from baseline < 0.5) and worsening (change from baseline >= 0.5). | 12 weeks | 
| Time to First Severe Asthma Exacerbation During the 12-week Treatment. | Severe asthma exacerbations are defined as all asthma exacerbations that required treatment with systemic (including oral) corticosteroids for at least 3 days. | 12 weeks | 
| Time to First Asthma Exacerbation During the 12-week Treatment. | An asthma exacerbation was defined as an episode of progressive increase in 1 or more asthma symptom that were outside the patient's usual range of day-to-day asthma symptoms and lasted for at least 2 consecutive days or as a decrease in a patient's best morning PEF of 30% or more from a patient's mean morning PEF for at least 2 consecutive days that may or may not have been accompanied by symptoms. | 12 weeks | 
| Use of Rescue Medication During 24h Period | Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during 24 h period), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5. The mean was adjusted for treatment, centre, week, baseline, treatment*week and baseline*week. | Baseline and 12 weeks | 
| Use of Rescue Medication During Daytime | Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during daytime), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5. The mean was adjusted for treatment, centre, week, baseline, treatment*week and baseline*week. | Baseline and 12 weeks | 
| Use of Rescue Medication During Nighttime | Use of PRN (pro re nata, or as necessary) salbutamol/albuterol rescue medication (puffs during nighttime), determined as a weekly mean response from baseline for each week during the treatment period as well as for the last 7 days before treatment stop/Visit 5. The mean was adjusted for treatment, centre, week, baseline, treatment*week and baseline*week. | Baseline and 12 weeks |