| Citation |
Pavord ID, Cox G, Thomson NC, Rubin AS, Corris PA, Niven RM, Chung KF, Laviolette M, and the RISA Trial Study Group
Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma.
Am J Respir Crit Care Med., 2007; 176: 1185-1191.
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| Objectives |
The primary objective of this Study was to demonstrate the safety of bronchial thermoplasty (BT) with the Alair® System in patients with severe asthma refractory to the current standard of care. Secondary objectives were to evaluate whether asthma symptoms or medication levels could be reduced in this population.
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| Design |
Multicenter, randomized, clinical trial conducted at 8 Investigational Sites in 3 countries (Canada, United Kingdom, and Brazil).
Enrollment was limited to asthmatic patients who remained symptomatic despite regular maintenance medication of high dose inhaled corticosteroids (greater than 750?g fluticasone per day or equivalent) and long acting ?2-agonist (LABA) (at least 100?g salmeterol per day or equivalent) with or without other asthma maintenance medications. Subjects could be taking oral prednisone ? 30 mg/day, leukotriene modifiers, theophylline or other asthma control drugs.
BT-treated patients have been followed out to 3 years post-BT to evaluate long-term safety.
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| Methods |
Eligible subjects were randomized 1:1 to the BT group (BT treatment plus standard-of-care therapy of high dose inhaled corticosteroids and long acting ?2-agonists with or without oral corticosteroids at a dose of ? 30mg/day) or Control group (Standard-of-care therapy of high dose inhaled corticosteroids and long acting ?2-agonists with or without oral corticosteroids at a dose of ? 30mg/day).
Subjects in the BT group were administered the BT treatment in 3 separate bronchoscopy sessions, while subjects in the Control group completed 3 “Control Visits” to the Physicians office, timed to coincide with the 3 treatment bronchoscopy sessions. All subjects remained on their maintenance asthma medications until they were 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 then underwent a 14 week period from 22 Weeks to 36 Weeks (termed the Steroid Wean Phase) during which an attempt was made to wean them off either their maintenance ICS or, if taking maintenance oral corticosteroids (OCS), their oral steroids. If a subject could not tolerate the steroid reduction at a particular level (as evidenced by loss of asthma control), they were stabilized on their last tolerable dose of steroid.
All subjects maintained 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). Subjects were consented to continue safety assessment out to 5 years.
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| Study Endpoints |
Safety: Safety was assessed by comparing the incidence and types of adverse events reported for the subjects in each group.
Effectiveness: Effectiveness was assessed by comparing differences between the BT and Control groups in the changes between Baseline and follow-up for the following parameters: Total Symptom Score, Nighttime Awakenings, Symptom-Free Days, Rescue Medication Use, Morning and Evening Peak Expiratory Flow Rates (PEF), Forced Expiratory Volume in 1 second (FEV1), Airway Hyperresponsiveness (methacholine PC20), Asthma Quality of Life Questionnaire (AQLQ) score, Asthma Control Questionnaire (ACQ) score, and Use of Corticosteroids for Asthma.
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| Results |
Effectiveness Results
Effectiveness parameters were assessed for the period when all subjects were in the Steroid Stable Phase, and after the Steroid Wean attempt during the Reduced Steroid Phase.
Steroid Stable Phase
Between Baseline and the end of the Steroid Stable Phase, the BT group demonstrated statistically significant improvements over the Control group in the following parameters:
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Use of Rescue Medication: The Alair group subjects experienced a reduction of 26.6 ± 40.1 puffs of rescue medication per 7 days compared to a reduction of 1.5 ± 11.7 puffs per 7 days in the Control group (p=0.046).
- Spirometry: The BT group subjects experienced a percent improvement in their pre-bronchodilator FEV1 (% predicted) of 14.9% ± 17.4% compared to a decrease of 0.9% ± 22.3% in the Control group (p=0.039).
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Asthma Quality of Life Questionnaire (AQLQ) Score: The AQLQ Score is measured on a 7-point scale from 1 to 7, with 7 representing the best quality of life. The mean increase in the AQLQ of the BT group was 1.21 ± 1.05 compared to an increase of 0.15 ± 0.75 in the Control group (p=0.003).
An increase of 0.5 in AQLQ score is considered to be a clinically meaningful within- subject improvement and a decrease of -0.5 or more is considered to be a clinically meaningful deterioration in asthma quality of life (Juniper et al, 19941). More BT subjects (77% of subjects) experienced an improvement from Baseline of 0.5 or more on the AQLQ Score than did Control subjects (35% of subjects). Fewer Alair subjects (8% of subjects) experienced a deterioration of -0.5 compared to Control subjects (18% of subjects).
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Asthma Control Questionnaire (ACQ) Score: The ACQ score is measured on a 7-point scale from 0 to 6, with 0 representing the highest level of asthma control. The mean improvement (i.e. decrease) in the ACQ of the BT group was -1.04 ± 1.03 compared to an improvement of -0.13 ± 1.00 for the Control group (p=0.020).
- Other measures were not significantly different between groups.
Steroid Wean Phase
The Study included a Steroid Wean Phase during which subjects attempted to wean off of either maintenance oral steroids or maintenance inhaled steroids. All 15 subjects in the BT group were able to initiate steroid reduction while only 14 out of the 17 subjects in the Control group were able to initiate steroid reduction. Three subjects in the Control group (two on oral corticosteroids and one on only ICS) did not attempt the steroid reduction due to unstable asthma.
- Maintenance Oral Steroid Use was reduced in BT subjects compared to Control subjects:
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Four of 8 (50%) BT subjects eliminated their oral steroid use while only one of 7 (15%) Control subjects eliminated oral steroid use.
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The 8 subjects in the BT group that were taking oral steroids as their maintenance asthma medication were able to reduce their average daily dose of oral steroids by 63.5% ± 45.4% by the end of the Steroid Wean Phase, while the 7 control subjects on oral steroids were able to reduce their daily dose by 26.2% ± 40.7% (p=0.12).
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Both groups experienced similar reductions in maintenance ICS use; the mean reduction in inhaled corticosteroid use was 28.6% ± 30.4% in the BT group and 20.0%+ 32.9% in the Control group (p=0.59).
Reduced Steroid Phase
During the Reduced Steroid Phase, both groups had completed their steroid wean attempts and were stabilized on their lowest tolerable maintenance doses of OCS and ICS. The BT group subjects were taking lower doses of OCS and ICS on average after the steroid wean than were Control group subjects. This apparent difference between groups in maintenance drugs should be considered while reviewing efficacy and safety data for the Reduced Steroid Phase.
Between Baseline and the end of the Reduced Steroid Phase, the BT group demonstrated statistically significant improvements over the Control group in the following parameters:
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Use of Rescue Medication: The BT group subjects experienced a reduction of 25.56 ± 31.19 puffs of rescue medication per 7 days compared to a reduction of 6.07 ± 12.43 puffs per 7 days in the Control group (p=0.046).
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Asthma Quality of Life Questionnaire (AQLQ) Score: The AQLQ (scale from 1-7, where 7 reflects a higher quality of life) is a validated instrument that measures quality of life in asthma. The mean increase in the AQLQ of the BT group was 1.53 ± 0.79 compared to an increase of 0.42 ± 0.82 in the Control group (p=0.001).
An increase of 0.5 in AQLQ score is considered to be a clinically meaningful within- subject improvement and a decrease of -0.5 or more is considered to be a clinically meaningful deterioration in asthma quality of life (Juniper et al, 19941). More BT subjects (80% of subjects) experienced an improvement from Baseline of 0.5 or more on the AQLQ Score than did Control subjects (59% of subjects). Fewer BT subjects (0% of subjects) experienced a deterioration of -0.5 compared to Control subjects (24% of subjects).
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Asthma Control Questionnaire (ACQ) Score: The mean improvement (decrease) in the ACQ of the BT group was -0.99 ± 0.83 compared to an improvement of -0.22 ± 0.78 for the Control group (p=0.011).
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Spirometry: Although not statistically significant, the mean percent changes in the pre-bronchodilator FEV1 (% predicted) for the BT group (7.97% ± 19.13%) continued to trend higher than those in the Control group (1.89% ± 15.00%) (p=0.322).
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Other measures, including Total Symptom Score, Symptom-Free Days, Nighttime Awakenings, amPEF, and pmPEF, were not significantly different between groups.
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| Safety Results |
Safety Results
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Transient Increase in Respiratory Adverse Events Peri-Procedure: Administration of the BT treatment in this group of subjects resulted in a transient increase in adverse events relative to the Control group.
There were 7 hospitalizations in 4 subjects for respiratory symptoms in the BT group and none in the Control group related to respiratory symptoms during the Treatment Phase of the Study. These types of adverse events, while of concern, are known to occur in this population of severe, refractory asthmatic patients undergoing bronchoscopy.
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From a qualitative perspective, the adverse events reported were of the type reported following a bronchoscopy procedure in a severe asthma patient. The most frequently observed adverse events in the BT group were (% of subjects reporting): wheezing (73%), cough (73%), dyspnea (60%), productive cough (53%), chest discomfort (40%), and sputum discolored (33%).
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Median time to onset of respiratory adverse events was within 1 day of bronchoscopy: The median time to onset for respiratory-related adverse events in the BT group was within 1 day of BT bronchoscopy (average within 6.5 days), and the median time to resolution after onset was 5 days (average 6.7 days).
Hospitalizations for Respiratory-related Adverse Events:
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In the post-treatment period, 5 hospitalizations occurred in 3 subjects in the BT group and 4 hospitalizations occurred in one subject in the control group. This difference was not statistically significant.
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No BT subjects required intubation or treatment in the intensive care unit (ICU); one control subject had an exacerbation on Day 42 that resulted in management in the ICU (respiratory failure).
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In addition, in the post-treatment period, 2 subjects in the BT group had 5 severe respiratory adverse events (increased wheeze, chest tightness, increased breathlessness, nocturnal wheeze, and chest infection) and one subject in the control group had one severe respiratory adverse event (flulike syndrome), all of which were medically treated and did not result in hospitalization.
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| Long-term Safety |
The absence of procedure-related clinical complications (based on AE reporting) and the maintenance of stable lung function (no deterioration of FEV1) over a 3-year period post-BT in patients with severe asthma refractory to the current standard of care suggest a stable long-term safety profile of the procedure out to 3 years.
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| Conclusions |
The results of this study show a stable long-term safety profile for BT out to 3 years with the Alair® System in this population of patients with severe, refractory asthma.
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