Research in Severe Asthma (RISA) Trial

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of the Alair System for the treatment of severe refractory asthma. This will be a multicenter, randomized controlled study comparing the effects of treatment with the Alair System to standard drug therapy in patients with severe asthma refractory to standard medication therapy. A total of 30 subjects will be randomized 1:1 to the Alair Group (Medical management + Alair Treatment) OR the Control Group (Medical management only).

Detailed Description
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Multicenter, randomized, clinical trial conducted at 8 Investigational Sites in 3 countries. Subjects in the Alair group to be administered the Alair treatment in 3 separate bronchoscopy sessions, while subjects in the Control group will complete 3 Control Visits to the Physicians office, timed to coincide with the 3 treatment bronchoscopy sessions. Following completion of all three procedures or Control Visits subjects will be evaluated at 6 weeks and 12 weeks. All subjects to remain on their maintenance asthma medications until they are evaluated again at 22 weeks after the last procedure or Control Visit. This phase from the last procedure or Control Visit out to 22 Weeks after the last procedure or Control Visit is termed the Steroid Stable Phase. Subjects will undergo a 14 week period from 22 Weeks to 36 Weeks (termed the Steroid Wean Phase) during which an attempt will be made to wean them off either their maintenance inhaled corticosteroids (ICS) or, if taking maintenance oral corticosteroids (OCS), their oral steroids. If a subject cannot tolerate the steroid reduction at a particular level (as evidenced by loss of asthma control), they will be stabilized on their last tolerable dose of steroid. All subjects will maintain their reduced steroid dosage from the end of the Steroid Wean Phase at 36 weeks to their final evaluations at the end of the Study at 52 weeks (termed the Reduced Steroid Phase). All subjects will be exited from the study following completion of the 52 week evaluations.

Official Title
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Multicenter Randomized Clinical Trial of Bronchial Thermoplasty With the Alair System for the Treatment of Severe Asthma

Conditions
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Asthma

Intervention / Treatment
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* Procedure: Bronchial Thermoplasty with the Alair System
* Drug: Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ambulatory adult; age 18-65 years Asthma requiring regular maintenance medication that includes high dose inhaled corticosteroid AND long acting β2 agonist (LABA) with or without other asthma maintenance medications. Oral prednisone ≤30 mg/day, leukotriene modifiers, theophylline or other asthma control drugs may be prescribed at the physician's discretion. Pre-bronchodilator forced expiratory volume in one second (FEV1) ≥50% predicted (patients stabilized on inhaled corticosteroids (ICS) and long acting β2 agonists) PC20 < 4 mg/ml per methacholine inhalation test using standardized methods, for patients with pre-bronchodilator FEV1 ≥60% predicted (or FEV1 > lower limit defined by individual hospital protocol). PC20 is the provocative concentration of Provocholine® (a brand of methacholine chloride) resulting in a drop of FEV1 of 20% or more from Baseline Reversible bronchoconstriction during the 12 months prior to enrollment, as demonstrated by an increase in FEV1 of at least 12% 30 minutes after 4 puffs of short-acting β2 agonist, for patients with pre-bronchodilator FEV1 < 60% predicted (or FEV1 < lower limit defined by individual hospital protocol) Patient must be symptomatic, despite medication with high dose inhaled corticosteroids and LABA, by at least one of the following: Use of rescue medication (short-acting β2 agonist) at least 8 of the 14 days prior to enrollment OR Daytime symptoms at least 10 of the 14 days prior to enrollment Non-smoker x 1 year or greater (if former smoker, less than 10 pack years total smoking history) Patient must be suitable for bronchoscopy in the opinion of the investigator or per hospital guidelines Willingness and ability to give written Informed Consent Willingness and ability to comply with the study protocol, including requirements for taking and abstaining from medications Exclusion Criteria: Participation in another clinical trial involving respiratory intervention that could affect the outcome measures of this study, within 6 weeks prior to randomization. Patients will be disqualified from the study if they enter another study or fail to comply with prescribed asthma medications. Use of immunosuppressant therapy (e.g., methotrexate). Current or recent lower respiratory tract infection (resolved less than 6 weeks from enrollment testing) History of recurrent (no more than three in the last three months) lower respiratory tract infection requiring antibiotics Presence of other respiratory diseases including emphysema, cystic fibrosis, vocal cord dysfunction, mechanical upper airway obstruction, obstructive sleep apnea, Churg-Strauss syndrome, cardiac dysfunction, allergic bronchopulmonary aspergillosis DLCO (diffusion capacity) < 70% predicted Uncontrolled sinus disease Uncontrolled gastro-esophageal reflux disease Use of implanted electronic device such as a pacemaker or internal cardiac defibrillator Use of external pacemaker Significant co-morbid illness such as cancer, renal failure, liver disease or cerebral vascular disease Post-bronchodilator FEV1 of less than 55% predicted Known systemic hypersensitivity or contraindication to methacholine chloride or other parasympathomimetic agents Known sensitivity to medications required to perform bronchoscopy, including lidocaine, atropine, benzodiazepines and opioids Use of a systemic b-adrenergic blocking agent Other medical criteria.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Alair treatment plus standard-of-care therapy of high dose inhaled corticosteroids and long acting beta-agonists with or without oral corticosteroids at a dose of ≤ 30 mg/day. | Procedure: Bronchial Thermoplasty with the Alair System<br>* Alair treatment plus standard-of-care therapy of high dose inhaled corticosteroids and long acting beta-agonists with or without oral corticosteroids at a dose of ≤ 30 mg/day.<br>* Other names: Alair System;|
| Active Comparator: Control<br>Standard-of-care therapy of high dose inhaled corticosteroids and long acting beta-agonists with or without oral corticosteroids at a dose of ≤30 mg/day. | Drug: Control<br>* Standard-of-care therapy of high dose inhaled corticosteroids and long acting beta-agonists with or without oral corticosteroids at a dose of ≤30 mg/day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory Adverse Events Per Subject | Respiratory adverse events (AEs) per subject reported during the Treatment Period, and Post-Treatment Period (Steroid Stable Phase, and Steroid Wean and Reduced Steroid Phase). Results were calculated by dividing the number of respiratory adverse events during each time period by the number of subjects in each group. Statistics were not calculated. | Baseline, 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Use of Maintenance Medications (Change From Baseline) | Percent Change from Baseline at 12 Months (Steroid Wean and Reduced Steroid Phase) Follow-up Visit in dose of inhaled and/or oral corticosteroids. | Baseline, 12 Months | 
| Use of Rescue Medications (Change From Baseline) | Change from Baseline at 22-Weeks (Steroid Stable Phase) and 12 Months (Steroid Wean and Reduced Steroid Phase) Follow-up Visits in use of rescue medications. Rescue medications for asthma are short-acting beta-agonists that bring quick relief of asthma symptoms. | Baseline, 12 Months | 
| Total Symptom Score (Change From Baseline) | Change from Baseline at 22-Weeks (Steroid Stable Phase) and 12 Months (Steroid Wean and Reduced Steroid Phase) Follow-up Visits in Total Symptom Score. The Total Symptom Score comprises the sum of six asthma symptom measurements recorded in a Daily Diary. Each of these symptoms is scored on a scale of 0 to 3 each day by the subject. The sum of the scores for these 6 symptoms comprises the Total Symptom Score, which measures overall asthma symptoms. The maximum score possible is 18. A lower Total Symptom Score represents better asthma control. | Baseline, 12 Months | 
| Pre-Bronchodilator FEV1 (Percent Predicted) (Change From Baseline) | Change from Baseline at 22-Weeks (Steroid Stable Phase) and 12 Months (Steroid Wean and Reduced Steroid Phase) Follow-up Visits in forced expiratory volume in one second (FEV1). FEV1 is the volume of air expired during the first second of a maximal effort expiration started at total lung capacity. | Baseline, 12 Months | 
| Post-Bronchodilator FEV1 (Percent Predicted) (Change From Baseline) | Change from Baseline at 22-Weeks (Steroid Stable Phase) and 12 Months(Steroid Wean and Reduced Steroid Phase) Follow-up Visits in forced expiratory volume in one second (FEV1). FEV1 is the volume of air expired during the first second of a maximal effort expiration started at total lung capacity. | Baseline, 12 Months | 
| Asthma Control Questionnaire (ACQ) Score (Change From Baseline) | Change from Baseline at 22-Weeks (Steroid Stable Phase) and 12 Months (Steroid Wean and Reduced Steroid Phase) Follow-up Visits in Asthma Control Questionnaire (ACQ) score. The ACQ is a self-administered patient questionnaire that assesses individual subject asthma control. The ACQ comprises 6 questions that relate to the patient's asthma symptoms, activity limitations, and daily rescue bronchodilator use, and FEV1. Each question is scored from 0 (Better) to 6 (Worse). The ACQ is based on a one-week recall period. A decrease in the ACQ score indicates better asthma control. | Baseline, 12 Months | 
| Asthma Quality of Life Questionnaire (AQLQ) Score (Change From Baseline) | Change from Baseline at 22-Weeks (Steroid Stable Phase) and 12 Months(Steroid Wean and Reduced Steroid Phase) Follow-up Visits in Asthma Quality of Life Questionnaire (AQLQ) score. The AQLQ is a self-administered patient questionnaire that assesses four aspects or domains of daily life for patients with asthma: symptoms, emotional function, activity limitations, and environmental stimuli. The AQLQ is based on a 2-week recall period and consists of 32 questions, each scored from 1 (Worse) to 7 (Better). An increase in the AQLQ score indicates a better quality of life. | Baseline, 12 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Bronchial Thermoplasty