Efficacy and Safety of 3 Doses of Tiotropium Compared to Placebo in Adolescents (12 to 17 Yrs) With Moderate Asthma

Study Overview
=================
Brief Summary
-----------------
The primary objective of this trial is to evaluate the efficacy and safety of tiotropium 1.25 mcg (2 actuations of 0.625 mcg), tiotropium 2.5 mcg (2 actuations of 1.25 mcg) and tiotropium 5 mcg (2 actuations of 2.5 mcg) once daily in the evening delivered by the Respimat inhaler in adolescents (12 to 17 yrs) with moderate persistent asthma, compared to placebo and on top of maintenance therapy with an inhaled corticosteroid controller medication. It is a randomised, double-blind, placebo-controlled Phase II trial with incomplete cross-over design. Patients need to be still symptomatic, i. e. not fully controlled with their maintenance treatment.

Official Title
-----------------
A Phase II Randomised, Double-blind, Placebo-controlled, Incomplete Crossover Trial With 4-week Treatment Periods to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution (Doses of 1.25 µg, 2.5 µg and 5 µg) Delivered Via Respimat® Inhaler Once Daily in the Evening in Adolescents (12 to 17 Yrs Old) With Moderate Persistent Asthma

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

Intervention / Treatment
-----------------
* Drug: Tiotropium bromide
* Drug: tiotropium bromide
* Drug: tiotropium bromide
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: All patients and legally accepted caregiver(s) must sign and date an Informed Consent form consistent with Good Clinical Practice (GCP) guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and local legislation prior to participation in the trial. Male or female patients between 12 and 17 years of age. All patients must have at least a 3 months history of asthma and fulfill the diagnostic criteria of moderate persistent asthma, according to the current Global Initiative for Asthma (GINA) guidelines at the time of enrolment into the trial. All patients must have been on maintenance treatment with inhaled corticosteroids at a stable medium dose for at least 4 weeks before Visit 1. All patients must be symptomatic (partly controlled) at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ) mean score of equal or above 1.5. All patients must have a pre-bronchodilator FEV1 above 60% and less than or equal 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%. All patients must have an increase in FEV1 of equal or above 12% and 200 mL 15 min. after 400 mcg salbutamol (albuterol) at Visit 1. If patients in the lower age range (e.g., 12 to 14 year olds) exhibit a very small total lung volume, positive reversibility testing might be based solely on the relative (12%) post-bronchodilator response. All patients should be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment. Patients should be able to use the Respimat® inhaler correctly. Patients must be able to perform all trial related procedures including technically acceptable spirometric manoeuvres, according to American Thoracic Society (ATS) standards and the use of the electronic diary/peak flow meter. Exclusion criteria: Patients with a significant disease other than asthma. Patients with a history of congenital or acquired heart disease, and/or have been hospitalised for cardiac syncope or failure during the past year. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention (e. g. pacemaker implantation) or a change in drug therapy within the past year. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with lung diseases other than asthma, e.g. cystic fibrosis (CF). In case of ex-premature infants, a history of significant bronchopulmonary dysplasia (BPD) will be regarded as exclusion criterion Patients with significant alcohol or drug abuse within the past two years. Patients with known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediaminetetraacetic acid (EDTA) or any other components of the tiotropium inhalation solution. Pregnant or nursing adolescent female patients, including female patients with a positive Beta HCG (serum pregnancy) testing at screening (visit 1). Sexually active female patients of child-bearing potential not using a highly effective method of birth control. Patients with a known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated. Patients with renal impairment, as defined by a creatinine clearance less than 50 mL/min/1.73 m2 body surface area (BSA) as calculated by Schwartz Formula.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 17 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: Treatment A<br>patients inhale 2 puffs (dose of 1.25 mcg) once daily in the evening via Respimat inhaler | Drug: Tiotropium bromide<br>* inhalation solution, dose of 1.25 mcg (2 puffs of 0.625 mcg)<br>|
| Experimental: Treatment C<br>patients inhale 2 puffs (dose of 5 mcg) once daily in the evening via Respimat inhaler | Drug: tiotropium bromide<br>* inhalation solution, dose of 5 mcg (2 puffs of 2.5 mcg)<br>|
| Placebo Comparator: Placebo<br>patients inhale 2 puffs of placebo matching tiotropium once daily in the evening via Respimat inhaler | Drug: Placebo<br>* placebo inhalation solution<br>|
| Experimental: Treatment B<br>patients inhale 2 puffs (dose of 2.5 mcg) once daily in the evening via Respimat inhaler | Drug: tiotropium bromide<br>* inhalation solution, dose of 2.5 mcg (2 puffs of 1.25 mcg)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume (FEV1) Peak (0-3h) Response | The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | Baseline and 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 Response | The trough FEV1 is defined as the pre-dose FEV1 measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | Baseline and 4 weeks | 
| FEV1 Area Under the Curve From 0 to 3 h (AUC0-3h) Response | FEV1 (AUC0-3h) will be calculated as the area under the curve from 0 to 3hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | Baseline and 4 weeks | 
| FEV1 Individual Measurements Response at Each Time-point | Individual FEV1 measurements at each time-point (personal best). Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose) | 
| Forced Vital Capacity (FVC) Peak (0-3h) Response | The FVC peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FVC measured within the first 3 hours post dosing and the FVC baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | Baseline and 4 weeks | 
| FVC Trough Response | The trough FVC response is defined as the pre-dose FVC measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | Baseline and 4 weeks | 
| FVC Area Under the Curve From 0 to 3 h (AUC0-3h) Response | FVC (AUC0-3h) will be calculated as the area under the curve from 0 to 3hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | Baseline and 4 weeks | 
| FVC Individual Measurements at Each Time-point | Individual FVC measurements at each time-point (personal best). Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose) | 
| Forced Expiratory Flow (FEF) 25-75% Individual Measurements Response at Each Time Point | FEF 25-75% is the mean forced expiratory flow between 25% and 75% of the FVC determined at the end of the 4-week treatment period. This is often referred to as the maximum midexpiratory flow. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose) | 
| Mean Morning Peak Expiratory Flow (PEF) Response | Mean morning PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | Baseline and 4 weeks | 
| Mean Evening PEF Response | Mean evening PEF assessed by patients at home. Response was defined as the change from baseline. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | Baseline and 4 weeks | 
| Change From Baseline in the Number of Puffs of Rescue Medication Per Day | Mean number of inhalations (puffs) of unscheduled rescue salbutamol therapy during whole day. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | Baseline and 4 weeks | 
| Control of Asthma as Assessed by Asthma Control Questionnaire (ACQ) | ACQ is a questionnaire consisting of a seven point Likert scale ranging from 0 to 6, whereby 0 represents good control and 6 represents poor control of asthma. The scale describes the frequency and severity of asthma symptoms. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | 4 weeks | 
| Change From Baseline in Mean Number of Nighttime Awakenings | Mean number of nighttime awakenings due to asthma symptoms as assessed by patients eDiary incorporated in the AM3® device. Analysis adjusted for treatment, period, patient and baseline using a mixed model. | Baseline and last week of treatment (week 4) |