Research in Severe Asthma (RISA) Trial

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).

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.

Eligibility Criteria:
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:

  1. Use of rescue medication (short-acting β2 agonist) at least 8 of the 14 days prior to enrollment OR
  2. 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.