Research in Severe Asthma (RISA) Trial

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.