Patients with severe asthma suffer significant morbidity and disability despite the use of multiple medications (20
). The Asthma Intervention Research (AIR2) Trial is the largest sham-controlled trial to test a new device for the treatment of severe asthma in adults. This study evaluated the effectiveness and safety of BT in subjects with severe asthma who were symptomatic despite treatment with high doses of ICS and LABA, the current standard of care (18
). These results validate the findings of two previous randomized, controlled studies that compared BT with usual care without a sham control (5
The use of a patient-centered subjective endpoint, AQLQ, required that the study be sham-controlled and that subjects remain blinded throughout the study to adequately assess the added benefit of BT beyond the current standard of care. The use of sham control subjects for interventional procedures poses risks to research subjects without the prospect of direct benefit from participation in trials (21
). However, as previously demonstrated (22
), a well-conducted sham-controlled study, in which subjects have been adequately informed, is justified (24
). Proper execution of this double-blind, sham-controlled study required investigational sites to have separate teams to deliver the treatment and perform follow-up assessments. The sham procedure successfully duplicated the BT procedure except for delivery of RF energy. Analysis of blinding assessments indicated that during the posttreatment follow-up period, Assessment physicians were unaware of treatment assignments, and subject beliefs, specifically in the BT group, were unlikely to affect outcome assessments (data not shown).
An important goal of asthma management strategies is to improve health-related quality of life (25
). The AQLQ is a validated tool for assessing the impact of asthma and evaluating outcomes of various therapies (27
). This study demonstrates a clear effect of BT on improving the asthma-specific quality of life over 1 year despite a larger-than-expected improvement in the sham group. The improvement in the AQLQ score of 1.35 ± 1.10 in the BT group is consistent with changes that were previously observed after BT in patients with moderate to severe asthma (5
) and in patients with severe-persistent asthma (6
). This improvement occurred in subjects who were already taking high doses of ICS and LABA and yet is of similar magnitude to that seen in previous asthma studies where subjects were taking less medication (28
We observed a substantial mean improvement of 1.16 in AQLQ in the sham group despite the a priori
expectation of approximately 0.5. This expectation was based on literature reports of typical placebo responses of 40 to 60% (30
) compared with AQLQ changes after BT in prior clinical trials (5
). Some improvement in a control group of patients with asthma can be expected from participation in a clinical trial (31
), most likely due to the regression effect. We believe that in the present study, the preconceived expectations about this promising therapy, together with the care and attention provided by the study staff, contributed to the substantial sham effect. Furthermore, the anticipation of an upcoming study visit may have heightened expectations in both groups related to the electronic diary data collected for 1 month before the 6- and 12-month study visits. The augmentation of the placebo effect in this study is consistent with the findings of another recent study showing that an optimistic presentation of a drug (or device in this case) can enhance the placebo effect for patient-centered outcomes, such as questionnaire scores (32
). However, a larger proportion of BT subjects compared with sham group subjects experienced a clinically meaningful within-subject improvement in AQLQ score of 0.5 or greater. This improvement in the quality of life demonstrates the superiority of BT over sham treatment.
Consistent with an improved quality of life, subjects in the BT group had significantly fewer severe exacerbations and emergent use of healthcare. The improvement in quality of life after BT in these patients with severe asthma is associated with a subsequent reduction in ED visits, as has been demonstrated in other asthma studies (33
). Individuals with severe, uncontrolled asthma account for a large proportion of health care use and costs (34
). Asthma is also the fourth leading cause of work absenteeism for adults, resulting in nearly 15 million missed or “less productive” workdays each year (37
). In the current study, the improved quality of life and reduced exacerbations in BT-treated subjects likely led to a decrease in lost work/school days, consistent with these measures being interrelated.
BT-treated subjects had a substantial decrease in severe exacerbations and ED visits, whereas the BT and sham groups had similar respiratory tract infection rates during the posttreatment period. These findings suggest that treatment with BT may result in less bronchoconstriction in the setting of a known trigger of asthma exacerbation. The mechanisms underlying the modified host response to respiratory tract infections after BT could be an important area of future investigation.
Bronchoscopy in asthma is known to worsen symptoms and potentially induce complications, even more so in severe asthma (38
). Data from this trial suggest that treatment with BT may further aggravate the airways in the short term. The adverse events after BT in this study were short in duration, as in previous trials (5
), and patients responded well to therapy. Although there was an increase in respiratory adverse events in the BT group compared with the sham group in the treatment period, fewer subjects in the BT group reported respiratory adverse events in the posttreatment period. Furthermore, subjects in the BT group reported fewer exacerbations and better quality of life scores in this posttreatment period.
In summary, this study demonstrates that BT provides clinically meaningful improvements in severe exacerbations requiring corticosteroids, ED visits, and time lost from work/school during the posttreatment period in patients with severe and inadequately controlled asthma, together with improvements in quality of life. We conclude that the increased risk of adverse events in the short-term after BT is outweighed by the benefit of BT that persists for at least 1 year. BT offers clinicians a novel, procedure-based, add-on therapy beyond the current use of high-dose ICS and LABA to decrease the morbidity of severe asthma.