Randomised, Double- Blind, Cross-over Efficacy and Safety Comparison of Three Different Doses of Tiotropium Administered Once Daily Versus Placebo in Patients With Moderate Persistent Asthma.

Study Overview
=================
Brief Summary
-----------------
Rationale for the current trial is to evaluate the efficacy and safety of three doses (1.25 µg, 2.5 µg and 5.0 µg ex mouthpiece) of tiotropium inhalation solution in patients with moderate persistent asthma who are still symptomatic despite regular maintenance therapy with inhaled corticosteroids (ICS). The data collected in the present trial will provide useful information to health care providers and patients regarding the efficacy and safety of a once daily inhalation of three different doses of tiotropium solution delivered by the Respimat® inhaler in addition to inhaled corticosteroids in the treatment of not fully controlled moderate asthma in comparison to placebo. The Pharmacokinetics (PK) of tiotropium is well established in COPD patients. However, there is currently no PK data available for the 3 doses of tiotropium being tested in this trial in patients with moderate persistent asthma. Tiotropium is a once daily drug. Hence, the rationale for blood and urine sampling for PK analysis over 24 hours in a subset of patients is to confirm the PK of the 3 doses in moderate asthma patients. Rationale for the 24-hour pulmonary function test sub-investigation is to demonstrate that a once daily dosing of tiotropium inhalation solution is effective and safe in the treatment of moderate persistent asthma.

Official Title
-----------------
A Phase II Randomised, Double-blind, Placebo Controlled, Cross-over Efficacy and Safety Comparison of Three Doses of Tiotropium Inhalation Solution Delivered Via Respimat Inhaler (1.25, 2.5 and 5.0 Mcg Once Daily) Versus Placebo in Patients With Moderate Persistent Asthma.

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: tiotropium bromide 2.5µg once daily
* Drug: Tiotropium matching Placebo once daily
* Drug: tiotropium bromide high dose once daily
* Drug: tiotropium bromide 1.25µg once daily


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: All patients must sign and date an Informed Consent Form consistent with the Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) 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 between 18 and 75 years (at date of informed consent). 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 no. 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 to 30 minutes after 4 puffs of 100 µg salbutamol) resulting in a Forced Expiratory Volume in one second (FEV1) increase of = 12% and = 200mL. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids (alone or in a fixed combination with a long acting or short acting beta agonist [LABA or SABA]) 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 = 1.5. All patients must have a pre-bronchodilator FEV1 = 60% and = 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to the European Community for Steel and Coal (ECSC). Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%. 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. 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 electronic diary/peak flow meter (diary compliance of at least 80% is required). Exclusion criteria: Patients with a significant disease other than asthma. 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. Patients with a recent history (i.e. six months or less) of myocardial infarction. 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. 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 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 known moderate to severe renal impairment. Patients with known narrow angle glaucoma or any other disease where anticholinergic treatment is contraindicated. Patients with significant symptomatic prostatic hyperplasia or bladder-neck obstruction. Patients whose symptoms are controlled on treatment may be included. Patients with significant alcohol or drug abuse within the past two years (to the discretion of the investigator). Patients who are currently in a pulmonary rehabilitation program or have completed pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening) or who will start a rehabilitation program during the study. Patients with known hypersensitivity to anticholinergic drugs, Benzalkonium chloride (BAC), Ethylenediaminetetraacetate (EDTA) or any other components of the study medication delivery system (Respimat®/ tiotropium inhalation solution). Pregnant or nursing woman. Women of childbearing potential not using a highly effective method of birth control. Patients who have taken an investigational drug within four 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 (period between Visit 1 and Visit 2). Topical cardio-selective beta-blocker eye medications for non-arrow 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 (period between Visit 1 and Visit 2). Patients who have been treated with oral or patch beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period (period between Visit 1 and Visit 2) Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 and/or during the screening period. Patients who have been treated with anti-Immunoglobuline E (anti-IgE) antibodies, e.g. omalizumab, within 6 months prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). Patients who have been treated with cromone within two weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). Patients who have been treated with methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). Patients who have been treated with other non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy (e.g. Tumor Necrosis Factor (TNF)-alpha blockers, methotrexate, cyclosporin) within four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). Patient with any asthma exacerbation or respiratory tract infection in the 4 weeks prior to visit 1 and/or during the screening period.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tiotropium low dose once daily<br>once daily, delivered by the Respimat® inhaler | Drug: tiotropium bromide 1.25µg once daily<br>* IMP<br>|
| Experimental: tiotropium medium dose once daily<br>once daily, delivered by the Respimat® inhaler | Drug: tiotropium bromide 2.5µg once daily<br>* Efficacy and safety comparison of 3 doses of inhaled tiotropium (1.25µg, 2.5µg and 5µg) versus placebo<br>|
| Experimental: tiotropium high dose once daily<br>once daily, delivered by the Respimat® inhaler | Drug: tiotropium bromide high dose once daily<br>* Efficacy and safety comparison of 3 doses of inhaled tiotropium (1.25µg, 2.5µg and 5µg) versus placebo<br>|
| Placebo Comparator: Placebo once daily<br>once daily, delivered by the Respimat® inhaler | Drug: Tiotropium matching Placebo once daily<br>* Efficacy and safety comparison of 3 doses of inhaled tiotropium (1.25µg, 2.5µg and 5µg) versus placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in One Second (FEV1) Peak Within 0-3 Hours Post-dose Response | Mixed model repeated measurement (MMRM) results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. | 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 Response | MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Trough FEV1 was measured just prior to the last administration of randomised treatment. | Baseline and 4 weeks | 
| FEV1 Area Under the Curve 0-3 Hours (AUC0-3h) Response | MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC0-3h was calculated using the trapezoidal rule divided by the observation time (3 hours) to report in litres. | 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration | 
| Forced Vital Capacity (FVC) Peak Within 0-3 Hours Post-dose Response | MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. | 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration | 
| Trough FVC Response | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Trough FVC was measured just prior to the last administration of randomised treatment. | Baseline and 4 weeks | 
| FVC AUC0-3h Response | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FVC AUC0-3h was calculated using the trapezoidal rule divided by the observation time (3 hours) to report in litres. | 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h after drug administration | 
| Individual FEV1 Over Time (at Each Timepoint at Visits) Response | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. | Baseline and 4 weeks | 
| Individual FVC Over Time (at Each Timepoint at Visits) Response | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. | Baseline and 4 weeks | 
| Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. | Baseline and 4 weeks | 
| Mean Pre-dose Morning PEF (PEF a.m.) Response During the Last Week on Treatment | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). | Baseline and 4 weeks | 
| Mean Pre-dose Evening PEF (PEF p.m.) Response During the Last Week on Treatment | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). | Baseline and 4 weeks | 
| PEF Variability Response (Last Week on Treatment) | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. PEF variability is the absolute difference between morning and evening PEF value divided by the mean of these two values, expressed as a percent . Weekly means obtained during the last week of each period of randomised treatment will be compared. | Baseline and 4 weeks | 
| Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values) | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). | Baseline and 4 weeks | 
| Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values) | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). | Baseline and 4 weeks | 
| Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values) | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). | Baseline and 4 weeks | 
| Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values) | MMRM results. Response was defined as change from baseline at the end of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared (measured by patients at home using the AM2+ device). | Baseline and 4 weeks | 
| FEV1 Area Under the Curve Within 24 Hours (h) Response (FEV1 AUC0-12h, FEV1 AUC12-24h, FEV1 AUC0-24h) | MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FEV1 AUC0-12, FEV1 AUC12-24 and FEV1 AUC0-24 were calculated using the trapezoidal rule divided by the observation time (12h resp. 24h) to report in litres. | 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h, 4h, 11h 50min, 12h 30min, 13h, 14h, 15h, 16h, 18h, 20h, 22h, 23h, 23h 50min after drug administration | 
| FVC Area Under the Curve Within 24 Hours (h) Response (FVC AUC0-12h, FVC AUC12-24h, FVC AUC0-24h) | MMRM results. Response was defined as change from baseline at the end of of each 4-week treatment period. Means are adjusted for treatment, period, patient and study baseline. FVC AUC0-12, FVC AUC12-24 and FVC AUC0-24 were calculated using the trapezoidal rule divided by the observation time (12h resp. 24h) to report in litres. | 10 minutes (min) before drug administration and 30 min, 1h, 2h, 3h, 4h, 11h 50min, 12h 30min, 13h, 14h, 15h, 16h, 18h, 20h, 22h, 23h, 23h 50min after drug administration |