A Study to Evaluate Efficacy and Safety of Tiotropium in Children 6 to 11 Years Old With Moderate Asthma

Study Overview
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Brief Summary
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The aim of this trial is to select an optimum dose may be selected based on bronchodilator efficacy, safety evaluations and pharmacokinetics of tiotropium bromide.

Official Title
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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 Children 6 to 11 Yrs Old With Moderate Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Tiotropium bromide
* Drug: Tiotropium bromide
* Drug: Tiotropium bromide
* Drug: Tiotropium bromide


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients must meet all of the following inclusion criteria to be eligible for enrollment into this study: All patients' parents (or legally accepted caregivers) must sign and date an informed consent prior to any study procedures including medication washout and restrictions. In addition, an informed assent suitable for this age group has to be obtained from patients. Male or female patients between 6 and 11 years of age (up to 1 day prior to their 12th birthday at Visit 1). All patients must have at least a 6-month history of asthma at the time of enrolment into the trial. All patients must have been on maintenance treatment with inhaled corticosteroids at a stable medium dose - a patient is eligible on =200 µg to =400 µg Budesonide DPI or equivalent. All patients must be symptomatic (partly controlled) at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an ACQ mean score of =1.5. All patients must have a pre-bronchodilator FEV1 =60% and =90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 2 (pre-dose) as compared to values at Visit 2 (pre-bronchodilator) must be within ± 30%. All patients must demonstrate an increase in FEV1 of =12% 15 to 30 min. after 200 µg salbutamol (albuterol) at Visit 1. Patients must be able to inhale from the Respimat® inhaler correctly. Patients must be able to perform all trial related procedures including technically acceptable spirometric manoeuvres according to current ATS/ERS standards and the use of the electronic diary/peak flow meter. Exclusion criteria: Patients with any of the following characteristics will not be eligible for entry into this study: Patients with a significant disease other than asthma. Patients with clinically relevant abnormal screening haematology or blood chemistry will be excluded if the abnormality defines a significant disease as defined in exclusion criterion 1. For participation in PK sampling, a haemoglobin of less than 11.3 g/dL will be regarded as exclusion criterion. Patients with a history of congenital or acquired heart disease, or patients who have been hospitalised for cardiac syncope or failure during the past year. Patients with any unstable or life-threatening cardiac arrhythmia, including cardiac arrhythmia requiring intervention (e.g. pacemaker implantation, catheter ablation etc.) or a change in drug therapy within the past year. Patients with a malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with clinically significant lung diseases other than asthma, such as CF, or bronchopulmonary dysplasia. Patients with known active tuberculosis. 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 who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1). Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution. Patients with known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated. Patients with moderate to severe renal impairment, as defined by a creatinine clearance <50 mL/min./1.73 m2 BSA, as tiotropium is a predominantly renally excreted drug.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 11 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>patients inhale 2 puffs (low dose) once daily in the evening via Respimat inhaler | Drug: Tiotropium bromide<br>* inhalation solution administered via Respimat in 3 different doses<br>|
| Experimental: Treatment B<br>patients inhale 2 puffs (medium dose) once daily in the evening via Respimat inhaler | Drug: Tiotropium bromide<br>* inhalation solution administered via Respimat in 3 different doses<br>|
| Experimental: Treatment C<br>patients inhale 2 puffs (high dose) once daily in the evening via Respimat inhaler | Drug: Tiotropium bromide<br>* inhalation solution administered via Respimat in 3 different doses<br>|
| Placebo Comparator: Treatment D<br>patients inhale 2 puffs of placebo inhalation solution matching tiotropium once daily in the evening via Respimat inhaler | Drug: Tiotropium bromide<br>* inhalation solution administered via Respimat in 3 different doses<br>|

What is the study measuring?
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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 | 
| 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 | 
| 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 3 hours 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 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 3 hours 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 | 
| 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 Period (24 h, Daytime and Night-time Use) | Mean number of inhalations (puffs) of unscheduled rescue salbutamol therapy during whole day (24 h, daytime and night-time use). 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 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. The scores for this question used the following scale where: 1='Did not wake up', 2='Woke up once', 3='Woke up 2-5 times', 4='Woke up more than 5 times' and 5='Was awake all night'. | Baseline and last week of treatment (week 4) |