Citation

Castro M, Rubin A, Laviolette M, Hanania NA, Armstrong B, and Cox G for the AIR2 Trial Study Group. Persistence of effectiveness of bronchial thermoplasty in patients with severe asthma.

Ann Allergy Asthma Immunol. 2011;107:65-70.

Objective

The objective of this study is to evaluate the safety and durability of effectiveness (beyond one year) of the Alair™ System in patients with severe persistent asthma.

Design

An international, multi-center, randomized, double-blind, sham-controlled trial conducted at 30 Investigational Sites in 6 countries comparing the effects of treatment with the Alair System plus conventional drug therapy of ICS LABA with sham bronchoscopy plus conventional drug therapy of ICS and LABA.

After 12 months after the last bronchoscopy procedure, subjects in the sham group exited the study and all BT group subjects entered an additional 4-year observation period. Durability of treatment effect was assessed by follow-up evaluations which included yearly physical examination and assessment of lung function as well as quarterly solicitation of all adverse events including respiratory adverse events resulting in treatment with oral corticosteroid pulses (severe exacerbation) and emergency department visits and hospitalizations for respiratory symptoms.

Blinding

None

Methods

All Alair treatment group subjects who completed one year in the AIR2 trial were eligible to participate in the extension part of the trial. Follow-up evaluation of the BT subjects included quarterly phone calls and annual follow-up visits.

Primary Endpoint

Comparison of proportion of BT group subjects experiencing severe exacerbations in Year 2 compared with Year 1.

Severe exacerbations were defined as exacerbations treated with oral or intravenous corticosteroids, or a doubling of the baseline inhaled corticosteroid dose for at least 3 days, or any temporary increase in the dosage of oral corticosteroids for a subject taking maintenance oral corticosteroids at entry into the AIR2 Trial.

Secondary Endpoints/Safety

• Severe exacerbation rates
• Respiratory adverse events
• Emergency department visits for respiratory symptoms
• Hospitalizations for respiratory symptoms
• Pre and post-bronchodilator forced expiratory volume in 1 second (FEV₁)

Results

Out of a total of 190 Subjects (18-65 years) randomized to the Alair group, 181 completed follow-up at 12 months and entered the extension phase of the study, and 166 (92%) completed the follow-up examinations at Year 2.

Effectiveness

• The proportion of subjects experiencing severe exacerbations in year 2 after BT was 23.0%, compared with 30.9% in year 1 and not statistically worse in year 2 compared with year as the upper 95% limit for difference in percent of subjects was within the pre-specified non-inferiority margin of <20%.
• No statistically significant differences between Year 1 and Year 2 severe exacerbation, asthma symptoms or healthcare utilization rates(events/subject/year [95% CI]):
  • Severe exacerbations (0.49 [0.39, 0.62] vs. 0.39 [0.30, 0.52], respectively)
  • Asthma (multiple symptoms) AEs (0.48 [0.38, 0.61] vs. 0.43 [0.33,0.56], respectively)
  • Emergency department visits for respiratory symptoms (0.07 [0.05, 0.10] vs. 0.08 [0.06, 0.12], respectively)
  • Hospitalizations for respiratory symptoms (0.04 [0.03, 0.06] vs. 0.06 [0.04, 0.09], respectively)
• The pre- and post-bronchodilator FEV1 values remained stable between Year 1 and Year 2 after BT. The pre-bronchodilator FEV1 (% predicted) values for Years 1 and 2 were 76.4 ± 17.8% (n=179) and 74.5 ± 19.3% (n=156), respectively. The post-bronchodilator FEV1 (% predicted) values for Years 1 and 2 were 83.4 ± 16.4% (n=178) and 80.8 ± 18.5% (n=155), respectively.

Safety

• Adverse events:
  • During the first year after BT, 369 respiratory-related adverse events were reported by 134 (71.7%) subjects, compared with 196 respiratory-related adverse events reported by 97 (58.4%) subjects in year 2
• Hospitalizations:
  • A total of 10 hospitalizations occurred for worsening of asthma symptoms in 7 subjects during year 2 after BT. All were treated with standard therapy. The median length of hospital stays was 2.5 days. Bronchial Thermoplasty resulted in a transient increase in respiratory adverse events peri-procedure.
• Changes in asthma maintenance medication dose at Year 2:
  • 15 subjects (9.0%) had a 50% or greater decrease in their ICS dose
  • 4 subjects (2.4%) had a 50% or more increase in their ICS dose.
  • 16 subjects (9.6%) had 50% or greater decrease in their long-acting-β2- agonists (LABA) dose
  • 3 subjects (1.8%) had a 50% or more increase in their LABA dose.
  • 7 subjects in the BT group entered the AIR2 trial with daily OCS as part of their maintenance asthma therapy.
    • 3 subjects had no change in their daily OCS usage, 1 subject had reduced their daily dosage, 2 subjects had stopped taking OCS altogether, and 1 subject had an increase in their dosage.
  • 3 subjects not previously on daily OCS initiated OCS usage as their maintenance asthma therapy.

Conclusions

Bronchial thermoplasty provides persistent asthma benefits in subjects with severe asthma to 2 years. The clinically meaningful improvements, combined with the consistent and stable safety data, confirm BT as an important treatment option for patients with severe asthma whose condition is poorly controlled despite using high-dose inhaled corticosteroids and long-acting bronchodilators.

Citation

Castro M, Rubin AS, Laviolette M, et al.

Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma. A multicenter, randomized, double-blind, sham-controlled clinical trial.

Am J Respir Crit Care Med. 2010;181:116-124.

Objective

The objective of this randomized, double blind, sham-controlled study was to demonstrate the safety and effectiveness of the Alair Bronchial Thermoplasty System in a population of subjects with severe asthma who are still symptomatic despite being managed on conventional therapy of high doses of inhaled corticosteroids (ICS — doses greater than 1000 mg per day beclomethasone or equivalent) and long-acting beta-agonists (LABA doses of at least 100 mg per day salmeterol or equivalent).

Design

An international, multi-center, randomized, double-blind, sham-controlled trial conducted at 30 Investigational Sites in 6 countries comparing the effects of treatment with the Alair Bronchial Thermoplasty System plus conventional drug therapy of ICS and LABA with sham bronchoscopy plus conventional drug therapy of ICS and LABA.

Subjects meeting the inclusion/exclusion criteria underwent baseline evaluations, followed by Bronchial Thermoplasty (BT) treatment or sham bronchoscopy procedures (depending upon randomization), and underwent follow-up evaluations at 3-, 6-, 9-, and 12-months post procedure.

Long-term follow up of BT-treated patients to include annual visits out to 5 years.

Blinding

Separate teams of study personnel were employed at each site in order to maintain blinding of the study. The unblinded team
(bronchoscopy team) performed both the sham and BT procedures. A separate blinded team (assessment team) conducted the baseline and post-procedure follow-up evaluations on the subjects.

All study subjects were blinded.

Methods

Subjects in the BT group received treatment with the Alair Bronchial Thermoplasty System during 3 separate bronchoscopy sessions while subjects in the sham group received 3 separate sham bronchoscopy procedures. All subjects continued on their prescribed maintenance asthma medications throughout the study. All subjects completed follow-up evaluations at 3 months, 6 months, 9 months, and 12 months after the last bronchoscopy session. Subjects were required to record in a diary their peak expiratory flow rates, asthma symptoms, and rescue medication usage for pre-specified periods throughout the study. Following the 12-month evaluation, Sham group subjects were exited from the study, while BT group subjects were scheduled to complete 4 subsequent annual follow-up evaluations for safety. The blind was broken at the 12-month visit.

Primary Endpoint

Difference between study groups in the change in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to the integrated score at 6, 9, and 12-month evaluations.

Secondary Endpoints

• Percent of symptom-free days
• Symptom scores
• Morning peak expiratory flow (am PEF)
• Asthma Control Questionnaire (ACQ) score
• Rescue medication use
• Severe exacerbations (rates and proportion of subjects having severe exacerbations)
• Time lost from work/school/other daily activities due to asthma symptoms
• Forced expiratory volume in 1 second (FEV₁) (safety endpoint)

Safety

Safety was assessed by comparing the incidence and types of adverse events reported for the subjects in each group during the treatment period (day of 1^st bronchoscopy till 6 weeks after the 3^rd bronchoscopy), and the post-treatment period (from 6 weeks after the 3^rd bronchoscopy till 12 months).

Safety was also assessed by comparing unscheduled physicians office visits for respiratory symptoms, emergency room visits for respiratory symptoms, and hospitalizations for respiratory symptoms.

Results

A total of 297 subjects (18-65 years) meeting study inclusion/exclusion criteria were randomized to the BT group (196) or a sham group (101) in a 2-to-1 randomization scheme.

288 subjects (190 BT group and 98 sham group) underwent the bronchoscopy procedures.

Effectiveness

Key findings for BT-treated patients versus sham during the post-treatment period:

• Mean change in the integrated AQLQ score was greater in the BT group than in the sham group. (Posterior probability of superiority was 96.0%)
  • Mean improvement over baseline in AQLQ Score was 1.35 in BT group
  • 79% of BT group achieved a 0.5 change in AQLQ score from baseline, compared to 64% in sham group
• 32% reduction in severe exacerbations
• 34% reduction in % of subjects with severe exacerbations
• 84% reduction in emergency room visits for respiratory symptoms
• 73% reduction in hospitalizations for respiratory symptoms
• 76% reduction in % of subjects with emergency room visits
• 66% reduction in time lost from work/school/other activities due to asthma
• 36% reduction in asthma (multiple symptoms) adverse events
• No deterioration in FEV₁ over time
• Secondary endpoints trended positively; differences were not statistically significant
• No subjects withdrawn from the study due to worsening of asthma.

Safety

Treatment Phase

• BT resulted in a transient increase in respiratory adverse events peri-procedure with more events reported in the BT (85% of subjects; 1.0 events/bronchoscopy) than in the sham group (76% of subjects; 0.7 events/bronchoscopy).
• The severity of respiratory adverse events for the BT and sham groups was as follows: mild, 43.6 versus 58.7%; moderate, 53.2 versus 39.8%; and severe, 3.1 versus 1.5%, respectively. The most common events were typical of airway irritation, including worsening asthma symptoms (wheezing, chest discomfort, cough, and chest pain), and upper respiratory tract infections.
• The majority of respiratory adverse events occurred within 1 day of the bronchoscopy and resolved within 7 days.

  In addition, there is a small possibility (3.4% per procedure) that the temporary worsening of asthma symptoms after a procedure may result in the patient being admitted to the hospital for management of asthma symptoms.

  • During the treatment period, 16 subjects (8.4%) in the BT group required 19 hospitalizations for respiratory symptoms (worsening of asthma, 12 in 10 subjects; segmental atelectasis, 3 in 2 subjects; lower respiratory tract infection, one subject; low FEV₁, one subject; hemoptysis, one subject; and aspirated prosthetic tooth; one subject) compared with two subjects (2.0%) in the sham group requiring two hospitalizations (both worsening of asthma).
  • Ten of the 19 hospitalizations in the BT group occurred on the day of the procedure. All these events resolved with standard therapy, including the hemoptysis, which was managed with bronchial artery embolization.
• There were more unscheduled physician office visits and hospitalizations for respiratory symptoms in the BT group compared to the sham group; however, there was no increase in ER visits for respiratory symptoms in the BT group compared to the sham group.

Post-Treatment Phase

• There was a lower incidence of asthma (multiple symptoms) in the BT group compared to the sham group.
  • 36% reduction in asthma (multiple symptoms) adverse events
  • 36% reduction in the proportion of subjects reporting asthma (multiple symptoms) adverse events
• There was a reduction in respiratory symptoms, ER visits and hospitalizations for respiratory symptoms
• No deterioration in either the pre-or post-bronchodilator FEV₁
• The mean doses of inhaled corticosteroids and long-acting beta-agonist were stable out to 1 year
• No radiological findings of clinical significance observed in
  high-resolution CT scans taken at 1 year.

Conclusions

BT delivered by the Alair System provides long-term asthma control in patients with severe asthma out to 1 year.

Bronchial Thermoplasty delivered by the Alair System is safe and effective for the treatment of severe asthma in adults.