Efficacy and Safety of 2 Doses of Tiotropium Respimat Compared to Placebo in Adolescents With Severe Persistent Asthma

Study Overview
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Brief Summary
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The overall purpose of the trial is to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 mcg and 5 mcg once daily) over 12 weeks, compared to placebo, as add-on controller therapy on top of usual care in adolescents (12 to 17 years old) with severe persistent asthma. The primary objective of the trial is to demonstrate superiority of tiotropium (5 mcg and possibly 2.5 mcg once daily in the evening) over placebo with regard to the primary pulmonary function endpoint after 12 weeks of treatment. Secondary objectives are to evaluate efficacy of tiotropium with regard to other endpoints, and to evaluate the safety of tiotropium, compared to placebo, as add-on controller therapy on top of usual care in this patient population.

Official Title
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A Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (2.5 mcg and 5 mcg Once Daily) Over 12 Weeks as add-on Controller Therapy on Top of Usual Care in Adolescents (12 to 17 Years Old) With Severe Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: tiotropium high dose
* Drug: placebo
* Drug: tiotropium low dose


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: All patients and their parent(s) (or legally accepted representative) must sign and date respectively an informed assent and an informed consent consistent with International Conference on Harmonisation - Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) guidelines and local legislation prior to the patient's participation in the trial. A separate informed consent/assent is required for pharmacogenomic sampling. Male or female patients between 12 and 17 years of age (at date of informed consent/assent). All patients must have at least a 3-month history of asthma at the time of enrolment into the trial. All patients must have been on maintenance treatment with an inhaled corticosteroid either at stable high dose in combination with another controller medication, OR at stable medium dose in combination with two other controller medications, for at least 4 weeks before 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 Forced Expiratory Volume in 1 second (FEV1) = 60% and = 90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator, considered as 100%) as compared to Visit 2 (pre-dose) must be within ± 30%. All patients must confirm the diagnosis of asthma by bronchodilator reversibility at Visit 1, resulting in an increase in FEV1 of = 12% and = 200 mL 15 to 30 minutes after 400 µg salbutamol (albuterol). If patients in the lower age range (e.g. 12 to 14 year old patients) exhibit a very small total lung volume, positive reversibility testing might be based solely on the relative (=12%) post-bronchodilator response. All patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment. Patients must 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/ European Respiratory Society (ATS/ERS) standards and use of the electronic diary/peak flow meter (diary compliance of at least 80% is required). Exclusion criteria: Significant disease other than asthma. Abnormal haematology or blood chemistry. History of heart disease, and/or hospitalised for cardiac syncope or failure. Any unstable or life-threatening or requiring intervention or cardiac arrhythmia. Malignancy for which the patient has undergone resection, radiation therapy or chemotherapy. Active tuberculosis. Alcohol or drug abuse. Thoracotomy with pulmonary resection. Pulmonary rehabilitation program. Hypersensitivity to anticholinergic drugs, or any components of the study medication delivery system. Pregnant or nursing adolescent female patients. Female patients of child-bearing potential not using a highly effective method of birth control. Investigational drug within four weeks or six half lives prior to Visit 1. Long-acting anticholinergics within four weeks prior to Visit 1. Systemic corticosteroids at a high dose or at a not stable low dose within four weeks prior to Visit 1. Leukotriene modifiers if not stabilised for at least four weeks prior to Visit 1. Long-acting theophylline preparations if not stabilised for at least two weeks prior to Visit 1. Anti Immunoglobulin E (Anti-IgE) treatment if not stabilised for at least six months prior to Visit 1. Cromones if not stabilised within four weeks prior to Visit 1. Oral beta-blocker medication within four weeks prior to Visit 1. Systemic oral or i.v. or s.c. beta-adrenergics within four weeks prior to Visit 1. Other non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy within four weeks prior to Visit 1. Any acute asthma exacerbation or respiratory tract infection in the four weeks prior to Visit 1and/or in the four weeks prior to Visit 2. In case of an asthma deterioration occurring in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2, the visit must be postponed. Randomised in this trial or currently participating in another trial. Narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated. Moderate to severe renal impairment. Patients requiring 10 or more puffs of rescue medication per day on more than 2 consecutive days in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2. In case of an asthma deterioration occurring in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2, the visit must be postponed.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 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: A<br> | Drug: tiotropium low dose<br>* 2 actuations once daily<br>|
| Experimental: B<br> | Drug: tiotropium high dose<br>* 2 actuations once daily<br>|
| Placebo Comparator: C<br> | Drug: placebo<br>* 2 actuations once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 peak0-3 Change From Baseline | Change from baseline in peak forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak0-3) measured at week 12. Measured values presented are actually adjusted means. | Baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 Change From Baseline | Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 12. Measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| FVC peak0-3 Change From Baseline | Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak0-3h) after 12 weeks of treatment. The measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| FEV1 AUC (0-3h) Change From Baseline | Change from baseline of area under the curve (AUC) from 0 to 3 hours 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). Measured values presented are actually adjusted means. | Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks | 
| FVC AUC (0-3h) Change From Baseline | Change from baseline of area under the curve (AUC) from 0 to 3 hours for FVC (Forced vital capacity) (FVC AUC0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). Measured values presented are actually adjusted means. | Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 12 weeks | 
| Control of Asthma as Assessed by ACQ6 Score. | Change from baseline in Asthma Control Questionnaire (ACQ) 6 score measured at week 12 The ACQ is a scale containing 7 questions, each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ6. The measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| ACQ6 Score Responders | Responder rates based on the ACQ6 score after 12 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline <= -0.5), no change (-0.5 < change from trial baseline <0.5) and worsening (change from trial baseline >= 0.5). The ACQ is a scale containing 7 questions, each question has a 7- point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ6 is calculated as the mean of the responses to the first 6 questions of the ACQ6. No statistical testing was performed on ACQ6 responders. | 12 weeks | 
| Control of Asthma as Assessed by ACQ Total Score | Change from baseline in Asthma Control Questionnaire (ACQ) total score measured at week 12. The ACQ is a scale containing 7 questions. Each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ total score is calculated as the mean of the responses to all 7 questions. The measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| ACQ Total Score Responders | Responder rates based on the ACQ total score after 12 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5 <change from trial baseline <0.5) and worsening (change from trial baseline ≥0.5) No statistical testing was performed for ACQ total score responders. The ACQ is a scale containing 7 questions, each question has a 7-point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. | 12 weeks | 
| Use of PRN Rescue Medication During the Day | Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the day (24 hour period) based on the weekly mean at week 12. The measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| Use of PRN Rescue Medication During the Daytime | Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the daytime based on the weekly mean at week 12. Measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| Use of PRN Rescue Medication During the Night-time | Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the night-time based on the weekly mean at week 12. Measured values presented are actually adjusted means | Baseline and 12 weeks | 
| Time to First Severe Asthma Exacerbation During the 12-week Treatment Period. | Time in days to first severe asthma exacerbation during the 12 week treatment period. The median time to first severe asthma exacerbation was not calculable, so the number of patients who experienced a severe asthma exacerbation are presented for the measured values. A severe asthma exacerbation was defined as a subgroup of all asthma exacerbations that required an initiation of treatment with systemic corticosteroids for at least 3 days or, in case of ongoing and pre-existing systemic corticosteroid therapy, requiring at least doubling of previous daily doses of systemic corticosteroids for at least 3 days. | 12 weeks | 
| Analysis of Time to First Asthma Exacerbation During the 12 Week Treatment Period. | Time in days to first asthma exacerbation during the 12 week treatment period. The median time to first asthma exacerbation was not calculable, so the number of patients who experienced an asthma exacerbation are presented for the measured values. | 12 weeks | 
| Clinically Relevant Abnormalities for Physical Examination, ECG, Vital Signs and Laboratory Tests | Clinically relevant abnormalities for physical examination, ECG, vital signs and laboratory tests. New abnormal findings or worsening of baseline conditions were reported as adverse events. | From first drug administration until 30 days after last drug intake, up to 142 days |