Evaluation of Tiotropium 2.5 and 5 mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo in 1 to 5 Year Old Patients With Persistent Asthma

Study Overview
=================
Brief Summary
-----------------
The primary objective of this trial is to evaluate the safety and efficacy of two doses of tiotropium inhalation solution delivered via the Respimat® inhaler once daily in the afternoon in patients (1 to 5 years old) with persistent asthma on top of inhaled corticosteroid (ICS) treatment.

Official Title
-----------------
A Phase II/III, Randomised, Double-blind, Placebo-controlled, Parallel Group Trial to Evaluate Safety and Efficacy of Tiotropium Inhalation Solution (2.5 µg and 5 µg) Administered Once Daily in the Afternoon Via Respimat® Inhaler for 12 Weeks in Patients 1 to 5 Years Old With Persistent Asthma

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

Intervention / Treatment
-----------------
* Drug: tiotropium-bromide
* Drug: tiotropium-bromide
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: All patients' parents (or legal guardians) must sign and date an informed consent consistent with ICH-GCP guidelines and local legislation prior to participation in the trial. Where appropriate, participants should assent to enroll in the study. Male or female patients between 1 and 5 years of age. By a physician documented (at least 6 month) history of persistent asthma symptoms, including (but not limited to) wheezing, cough, and/or shortness of breath. (persistent = need for inhalation corticosteroid maintenance therapy to control asthma symptoms) For patients aged 5 years and capable of performing technically acceptable Pulmonary Function tests (PFTs): documented impaired lung function (i.e. pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1) is smaller or equal to 90% of predicted normal). All patients must have been on maintenance treatment with an inhaled corticosteroid at stable dose, either as mono treatment or in combination with another controller medication, for at least 4 weeks before Visit 1. All patients must be symptomatic (partly controlled) as defined by the Global Initiative for Asthma (GINA) guideline for children aged 5 years and younger in the week prior to Visit 1 (screening) and in the week prior to randomisation (Visit 2). Further inclusion criteria apply. Exclusion criteria: 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. 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) 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. Patients with clinically significant lung diseases other than asthma. Alternative causes (other causes than asthma) that can lead to respiratory symptoms of wheeze, cough and shortness of breath. Patients with known active tuberculosis. Patients who have undergone thoracotomy with pulmonary resection. 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). Further exclusion criteria apply.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 5 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tiotropium low dose<br>Once daily, delivered with Respimat® inhaler | Drug: tiotropium-bromide<br>* IMP<br>|
| Experimental: tiotropium high dose<br>Once daily, delivered with Respimat® inhaler | Drug: tiotropium-bromide<br>* IMP<br>|
| Placebo Comparator: placebo<br>Once daily, delivered with Respimat® inhaler | Drug: placebo<br>* placebo matching tiotropium<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weekly Mean Combined Daytime Asthma Symptom Score | Change from baseline in the weekly mean combined daytime asthma symptom score as assessed by the Paediatric Asthma Caregivers Diary (PACD) in the last week of the 12 week treatment period. The PACD is a diary designed to evaluate daily asthma symptoms in children aged 2-5 years. The diary consists of three questions to be answered each morning, when the child wakes up, and seven questions to be answered each evening, right after the child goes to bed for the night. A week was defined as 7 days. The combined daytime score is the average of scores from questions 4 - 7 in the diary which are questions regarding severity of cough, wheezing, trouble breathing and interference with activities, scores for each question range from 0 (best) to 5 (worst). The week 12 weekly mean is the mean of the responses for each day averaged over the 7 days in week 12, so combined daytime asthma symptom scores also range from 0 (best) to 5 (worst). The measured values presented are adjusted means. | Baseline and 12 weeks | 
| FEV1 Peak (0-3h) Change From Baseline | Change from baseline in peak Forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak (0-3h)) measured at week 12 | 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weekly Mean Overnight Asthma Symptom Score Response | Change from baseline in the weekly mean overnight asthma symptom score response as assessed by the PACD in the last week of the 12 week treatment period. The overnight score is the score from the following question in the PACD, How much did your child cough last night after your child was put to bed for the night until he/she awoke this morning?. This endpoint was determined only for patients with 2 or more nights with symptoms per week during the baseline period. In this case, the baseline period is the 7 days used to derive the baseline value. A patient has a night with symptoms if the question was answered with scores 1, 2, 3, 4 or 5 or the patient received β-Agonist at least one time since he/she went to bed. A week was defined as 7 days. Scores range from 0 (best) to 4 (worst), a value of 5 indicates severity of symptoms is unknown. The measured values presented are adjusted means | Baseline and 12 weeks | 
| Weekly Percentage of Days Without Asthma Symptoms | Weekly Percentage of days without asthma symptoms at week 12. A day without asthma symptoms was defined as a day during which the patient experienced no asthma symptoms, did not use rescue medication (salbutamol/albuterol) and had no asthma exacerbation/worsening requiring systemic corticosteroids, or unscheduled visits to a doctor's office, emergency department, or hospital. A week was defined as 7 days. The measured values presented are adjusted means | 12 weeks | 
| Weekly Percentage of Days With Use of Salbutamol (Albuterol) Rescue Medication | Weekly percentage of days with use of salbutamol (albuterol) rescue medication at week 12. A week was defined as 7 days. | 12 weeks | 
| Weekly Mean Nighttime Awakenings Due to Asthma Symptoms | Change from baseline in the weekly mean nighttime awakenings due to asthma symptoms as assessed by the PACD, in the last week of the 12 week treatment period. The weekly mean was calculated as the average of the weekly scores for the question Did your child wake up during the night due to his/her asthma? The question was answered on a 5-point verbal rating scale, with scores ranging from 1 (did not wake up) to 5 (was awake all night). A week was defined as 7 days. The measured values presented are adjusted means | Baseline and 12 weeks | 
| Trough FEV1 Change From Baseline | Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 12. | Baseline and 12 weeks | 
| FEV1 AUC (0-3h) Change From Baseline | Change from baseline of area under the curve (AUC) from 0 to 3 h for FEV1 (FEV1 AUC 0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). | 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12 | 
| FVC Peak (0-3h) Change From Baseline | Change from baseline in maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak (0-3h)) after 12 weeks of treatment. | 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12 | 
| Trough FVC Change From Baseline | Change from baseline of trough (pre-dose) forced vital capacity (FVC) measured 10 min before the administration of trial medication after 12 weeks of treatment. | Baseline and 12 weeks | 
| FVC AUC (0-3h) Change From Baseline | Change from baseline of area under the curve (AUC) from 0 to 3 h for FVC (FVC AUC0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). | 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12 | 
| Individual FEV1 Measurements | Change from baseline in individual FEV1 measurements at each timepoint after 12 weeks | Baseline and 12 weeks | 
| Individual FVC Measurements | Change from baseline in individual FVC measurements at each timepoint after 12 weeks | Baseline and 12 weeks |