Please select the eligibility criteria that correspond to the clinical trial below.
Title: AIR2 Extension Study to Demonstrate Longer-term (> 1 Year) Durability of Effectiveness
Brief Summary: The objective of this study is to evaluate durability of effectiveness (beyond one year) of the Alair System in patients with severe persistent asthma. The study will consist of Alair-group subjects who are currently in the follow-up phase (out to 5 years) of the AIR2 Trial (Protocol #04-02, clinicaltrials.gov number NCT00231114).

Durability of the treatment effect will be evaluated by comparing the proportion of subjects who experience severe exacerbations during the first year after Alair treatment with the proportion of subjects who experience severe exacerbations during subsequent 12 month periods out to 5 years.

All Alair group subjects in the AIR2 Trial are being followed out to 5 years as per the AIR2 Trial protocol. The data that are to be used to determine durability of effectiveness as described in the present protocol (Protocol #10-01) are being collected under the existing AIR2 Trial protocol (Protocol # 04-02).

Study Hypothesis: An empirical demonstration of the durability of the treatment effect will be used to show that the proportion of subjects experiencing severe exacerbations for the first year compared with the proportions of subjects experiencing severe exacerbations in subsequent years do not get substantially worse.

The primary statistical objective is to demonstrate that the proportion of subjects who experience severe exacerbations in the subsequent 12-month follow-up (for Year 2, Year 3, Year 4 and Year 5 \[in 12-month periods\]) is not statistically worse when compared with the proportion of first 12-months, which begins 6-weeks after the last Alair treatment. This objective will be met if the upper 95% confidence limit of the difference in proportions (i.e., the subsequent 12-month proportion minus the first 12-month proportion) is less than 20%.


Options:
A: Inclusion Criteria:

* All Alair group subjects who have participated in the AIR2 Trial (NCT00231114) and were not lost to follow-up at the end of the 12 month premarket visit, and those who are willing to comply with the study protocol and routine visits for the duration of the study will be included in the post-approval study

Exclusion Criteria:

* None.
B: 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.
C: Inclusion Criteria:

* Subject is an adult between the ages of 18 to 65 years.
* Subject has asthma and is taking regular maintenance medication that includes Inhaled corticosteroid (ICS) AND long acting ß2-agonist (LABA).
* Subject has a Pre-bronchodilator Forced Expiratory Volume in one second (FEV1) of greater than or equal to 60% of predicted after medication stabilization during the Baseline Period.
* Subject has a PC20 \< 8 mg/ml per methacholine inhalation test using standardized methods. PC20 is a provocative concentration of Provocholine® (a brand of methacholine chloride) resulting in a drop of FEV1 of 20% or more from Baseline.
* Subject has at least two days of asthma symptoms during the 4-weeks of the Baseline Diary Period.
* Subject is a non-smoker for 1 year or greater (if former smoker, less than 10 pack years total smoking history).

Exclusion Criteria:

* Subject has a Post-bronchodilator FEV1 of less than 65%.
* Subject has 3 or more hospitalizations for exacerbations of asthma in the previous year; OR a history of life-threatening asthma, defined by past intubations for asthma, or ICU admission for asthma within the prior 24 months.
* Subject has a history of recurrent lower respiratory tract infections requiring antibiotics (more than 3 in the past 12 months).
* Subject has a history of recurrent oral steroid use for asthma (4 or more pulses of oral steroids in the past 12 months).
* Subject has a known sensitivity to medications required to perform bronchoscopy (such as lidocaine, atropine and benzodiazepines).
* Subject has known systemic hypersensitivity or contraindication to Methacholine chloride or other parasympathomimetic agents.
* Subject has other medical criteria.
D: Inclusion Criteria:

* Ambulatory adult; age 18-65 years
* Asthma requiring regular maintenance medication that includes inhaled corticosteroid (at least 200 μg beclomethasone per day or equivalent) AND long acting ß2 agonist (LABA) (at least 100 mg salmeterol per day or equivalent)
* Pre-bronchodilator FEV1 60-85% (patients stabilized on inhaled corticosteroids and long acting β2 agonists)
* PC20 \< 8 mg/ml per methacholine inhalation test using standardized methods.
* Demonstration of worsening of asthma following 2-week withdrawal of LABA, as documented by either:
* an increase of at least 0.5 in the Juniper Asthma Control Questionnaire score, relative to the Questionnaire score in the 2 weeks preceding withdrawal of LABA, OR
* a decline of at least 5% in the average am Peak Expiratory Flow during the second week of LABA abstinence relative to the average am Peak Expiratory Flow during the week immediately preceding LABA withdrawal
* Non-smoker x 1 year or greater (if former smoker, less than 10 pack years total smoking history)
* 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, either within 6 weeks of the pretreatment evaluation, or during the study period
* Current or recent respiratory tract infection (resolved less than 6 weeks from pretreatment evaluation)
* History of recurrent (³ 3 infections/year) lower respiratory tract infection requiring antibiotics.
* With the exception of the use of a prophylactic bronchodilator for exercise, requirement for more than 4 puffs in a 24-hour period of a short-acting b2-adrenergic agonist such as albuterol or salbutamol 100 mg/puff or equivalent within the seven days immediately prior to commencement of Enrollment Testing, Part I.
* Unstable asthma as defined by the need for an extra visit to a healthcare provider, increase in or introduction of new maintenance or symptom relieving medications (including new requirement for IV or nebulized medications) within 6 weeks of enrollment
* Use of an internal or external pacemaker or internal cardiac defibrillator
* Significant co-morbid illness such as cancer, renal failure, liver disease or cerebral vascular disease
* POST-bronchodilator FEV1 of less than 65%.
* Known systemic hypersensitivity or contraindication to methacholine chloride or other parasympathomimetic agents
* Known sensitivity to medications required to perform bronchoscopy, including lidocaine, atropine and benzodiazepines
* Use of a systemic b-adrenergic blocking agent
* Pregnancy
* Nursing mother
* History of epilepsy
* Cardiovascular disease, including bradycardia, angina, cardiac dysrhythmia, conduction defect or cardiac myopathy
* Myocardial infarction or stroke within 6 months of the pretreatment evaluation
* Any active disease left untreated,
* Bleeding diathesis, platelet dysfunction, thrombocytopenia with platelet count less than 125,000/mm2 or known coagulopathy (INR \> 1.5)
* Use of anticoagulants
* Insulin-dependent diabetes
* Psychiatric disorder which in the judgement of the investigator could interfere with provision of informed consent, completion of tests, therapy, or follow-up
* Presence of segmental atelectasis, lobar consolidation, significant or unstable pulmonary infiltrate, or pneumothorax, confirmed on x-ray
* Interstitial lung disease
* Uncontrolled hypertension (\>200 mmHg systolic or \>100mmHg diastolic pressure)
* Known aortic aneurysm

Answer: A