Efficacy and Safety of 2 Doses of Tiotropium Respimat® Compared to Placebo in Children 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 (2.5 mcg and 5 mcg) delivered via Respimat® inhaler once daily in the evening over 12 weeks, compared to placebo, as add-on controller therapy on top of usual care in children (6 to 11 years old) with severe persistent asthma.

Official Title
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A Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution (2.5 mcg and 5 mcg) Delivered Via Respimat® Inhaler Once Daily in the Evening Over 12 Weeks as add-on Controller Therapy on Top of Usual Care in Children (6 to 11 Years Old) With Severe Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Placebo
* Drug: Tiotropium low dose mcg
* Drug: Tiotropium high dose


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Inclusion criteria are: All patients' parent(s) (or legal guardian) must sign and date an informed consent prior to participation in the trial. In addition, an informed assent suitable for this age group has to be obtained from patients. A separate informed consent/assent is required for pharmacogenomic sampling. Male or female patients between 6 and 11 years of age. All patients must have at least a 6-month history of asthma. 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 (partly controlled) at Visit 1 and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ-IA) mean score >= 1.5. All patients must have a pre-bronchodilator forced expiratory volume in one 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% 15 to 30 minutes after 200 mcg salbutamol/albuterol. 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: Exclusion criteria are: Patients with a significant disease other than asthma. Patients with a clinically relevant abnormal haematology or blood chemistry at screening. 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 or cardiac arrhythmia requiring intervention 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 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 six weeks prior to Visit 1. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the inhalation solution used with the Respimat inhaler. Pregnant or nursing female patients, including postmenarchal girls with a positive urine pregnancy test at Visit 1. Postmenarchal girls of child-bearing potential not using a highly effective method of birth control. Patients who have been treated with systemic corticosteroids within four weeks prior to Visit 1. Patients who have been treated with systemic beta-adrenergics within four weeks prior to Visit 1. Patients who have been treated with oral beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period. Patients who have been treated with inhaled long-acting anticholinergics or systemic anticholinergic treatment within four weeks prior to Visit 1 and/or during the screening period, or who have been treated with inhaled short-acting anticholinergics within two weeks prior to Visit 1. Patients who have been treated with short-acting theophylline preparations within two weeks prior to Visit 1. Patients who have been treated with non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy within four weeks prior to Visit 1 and/or during the screening period. Patients who have taken an investigational drug within six half lives according to the investigator's information, or four weeks (whichever is greater) prior to Visit 1 and/or during the screening period. Patients who have previously been randomised in this trial or are currently participating in another trial. Patients with any acute asthma exacerbation or respiratory tract infection 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. Patients requiring six or more puffs of rescue medication per day on more than two 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. Patients who are unable to comply with medication restrictions prior to Visit 1 and/or prior to Visit 2. Patients with a 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo QD<br> | Drug: Placebo<br>* 2 actuations once daily in the evening<br>|
| Experimental: Tiotropium low dose QD<br> | Drug: Tiotropium low dose mcg<br>* 2 actuations once daily in the evening<br>|
| Experimental: Tiotropium medium dose QD<br> | Drug: Tiotropium high dose<br>* 2 actuations once daily in the evening<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. 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 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. The measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| Trough FVC Change From Baseline | Change from baseline in Trough (pre-dose) FVC measured at week 12. 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 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 | 
| FEV1 Change From Baseline at Each Individual Timepoint | Forced expiratory volume in one second (FEV1) change from baseline at each individual timepoint. The 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 Change From Baseline at Each Individual Timepoint | FVC change from baseline at each individual timepoint. The 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 ACQ-IA Total Score | Change from baseline in Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) total score measured at week 12. The ACQ-IA 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-IA 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-IA Total Score Responders | Responder categories based on the ACQ-IA 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-IA total score responders. The ACQ-IA 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 Per Day | Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used per 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 | 
| Peak Expiratory Flow (PEF) a.m. Change From Baseline | Change from baseline in the morning (a.m.) peak expiratory flow based on the weekly mean at week 12. Measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| Peak Expiratory Flow (PEF) p.m. Change From Baseline | Change from baseline in the evening (p.m.) peak expiratory flow based on the weekly mean at week 12. Measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| Peak Expiratory Flow (PEF) Variability Change From Baseline | Change from baseline in the peak expiratory flow variability based on the weekly mean at week 12. Measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| FEV1 a.m. Change From Baseline | Change from baseline in morning (a.m.) FEV1 based on the weekly mean at week 12. Measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| FEV1 p.m. Change From Baseline | Change from baseline in evening (p.m.) FEV1 based on the weekly mean at week 12. Measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| Change From Baseline in Nighttime Awakenings | Change from baseline in nighttime awakenings based on the weekly mean at week 12. Nighttime awakenings was assessed by the question Did you wake up during the night due to your asthma? from the e-diary. Scores range from 1 (did not wake up) to 5 (was awake all night). Measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| Change From Baseline in Morning Asthma Symptoms | Change from baseline in morning asthma symptoms based on the weekly mean at week 12. Morning asthma symptoms was assessed by the question how were your asthma symptoms this morning? from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms). Measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| Change From Baseline in Daytime Asthma Symptoms | Change from baseline in daytime asthma symptoms based on the weekly mean at week 12. Daytime asthma symptoms was assessed by the question how were your asthma symptoms during the day? from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms). Measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| Change From Baseline in Daytime Activity Limitations | Change from baseline in daytime activity limitations based on the weekly mean at week 12. Daytime activity limitations was assessed by the question how limited were you in your activities today because of your asthma? from the e-diary. Scores range from 1 (not limited) to 5 (totally limited). Measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| Change From Baseline in Daytime Experiences of Shortness of Breath | Change from baseline in daytime experiences of shortness of breath based on the weekly mean at week 12. Daytime experiences of shortness of breath was assessed by the question how much shortness of breath did you experience during the day from the e-diary. Scores range from 1 (none) to 5 (a very great deal). Measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| Change From Baseline in Daytime Experiences of Wheeze or Cough | Change from baseline in daytime experiences of wheeze or cough based on the weekly mean at week 12. Daytime experiences of wheeze or cough was assessed by the question did you experience wheeze or cough during the day? from the e-diary. Scores range from 1 (not at all) to 5 (all the time). Measured values presented are actually adjusted means. | Baseline and 12 weeks | 
| Change From Baseline in Asthma Symptom-free Days | Change from baseline in asthma symptom-free days based on the weekly mean at week 12. A day was considered as an asthma symptom-free day if there were no symptoms reported via the e-Diary and no use of rescue medication reported via the eDiary during that day. Measured values presented are actually adjusted means. | Baseline and 12 weeks |