Two-Year Outcomes for the Double-Blind, Randomized, Sham-Controlled Study of Targeted Lung Denervation in Patients with Moderate to Severe COPD: AIRFLOW-2

Abstract

Purpose: COPD exacerbations are associated with worsening clinical outcomes and increased healthcare costs, despite use of optimal medical therapy. A novel bronchoscopic therapy, targeted lung denervation (TLD), which disrupts parasympathetic pulmonary innervation of the lung, has been developed to reduce clinical consequences of cholinergic hyperactivity and its impact on COPD exacerbations. The AIRFLOW-2 study assessed the durability of safety and efficacy of TLD additive to optimal drug therapy compared to sham bronchoscopy and optimal drug therapy alone in subjects with moderate-to-severe, symptomatic COPD two years post randomization.

Patients and methods: TLD was performed in COPD patients (FEV1 30-60% predicted, CAT≥10 or mMRC≥2) in a 1:1 randomized, sham-controlled, double-blinded multicenter study (AIRFLOW-2) using a novel lung denervation system (Nuvaira, Inc., USA). Subjects remained blinded until their 12.5-month follow-up visit when control subjects were offered the opportunity to undergo TLD. A time-to-first-event analysis on moderate and severe and severe exacerbations of COPD was performed.

Results: Eighty-two subjects (FEV1 41.6±7.4% predicted, 50.0% male, age 63.7±6.8 yrs, 24% with prior year respiratory hospitalization) were randomized. Time-to-first severe COPD exacerbation was significantly lengthened in the TLD arm (p=0.04, HR=0.38) at 2 years post-TLD therapy and trended towards similar attenuation for moderate and severe COPD exacerbations (p=0.18, HR=0.71). No significant changes in lung function or SGRQ-C were found 2 years post randomization between groups.

Conclusion: In a randomized trial, TLD demonstrated a durable effect of significantly lower risk of severe AECOPD over 2 years. Further, lung function and quality of life remained stable following TLD.

Clinical trial registration: NCT02058459.

Keywords: COPD; COPD exacerbation; bronchoscopy; targeted lung denervation.

Conflict of interest statement

DJS reports grant, consultancy fees paid to the institution, and nonfinancial support from Nuvaira, Inc. during the conduct of the study. HSN reports employment with Nuvaira, Inc. MM reports consultancy fees and employment with Nuvaira, Inc. during the conduct of the study. MM owns stock from Nuvaira, Inc in exchange for multiple patents with Nuvaira. AV reports speaker fees from Nuvaira during the conduct of the study. PLS reports personal fees from Nuvaira during the conduct of the study; personal fees for consultancy from Olympus, PneumRX/BTG, Creo Medical, and from CSA medical outside the submitted work. FJH reports personal fees for serving at the advisory board for Olympus, Pumonx, and Uptake outside the submitted work. Christophe Pison reports grants, personal fees, non-financial support, and fees to CHUGA to conduct RCT IPSII, AF2 and AF3 from Nuvaira during the conduct of the study; grants, personal fees, non-financial support in the field of COPD and Asthma from GSK France, Boehringer Ingelheim, Chiesi, and AstraZeneca outside the submitted work. PIB reports non-financial support from Nuvaira during the conduct of the study. RK reports grants, personal fees from Nuvaira during the conduct of the study. WG reports personal fees as speaker and receives travel supports from PulmonX and Astra Zeneca, and travel support from PneumRX outside the submitted work. TP reports costs of clinical trial from Holaira-Nuvaira during the conduct of the study; personal fees served in the COPD advisory board from Novartis, Chiesi, and Boehringer Ingelheim, grants for clinical research from Astra Zeneca outside the submitted work. GD reports personal fees from Nuvaira during the conduct of the study; personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, BTG-PneumRx, and Novartis outside the submitted work. RG was scientific advisory board member for Nuvaira until 2019; reports grants from Boehringer Ingelheim, Aquilo, Novartis, and Chiesi outside the submitted work. The authors report no other conflicts of interest in this work.

© 2020 Valipour et al.

Figures

Figure 1

AIRFLOW-2 Study Subject Flow at major study timepoints with sample size numbers denoted in parentheses. Subjects were unblinded at the 1-year follow-up appointment and those in the sham-control group were offered the opportunity to cross-over and undergo the TLD procedure. Cross-over subjects (n=20) underwent the TLD procedure between the 1st and 2nd year follow-up visits. All other sham-control patients completed the 2-year follow-up visit, creating the control group (n=14). *Three patients unable to participate in the in-person follow-up visit for the control group (n=11 for pulmonary function tests).

Figure 2

Percent (%) of patients experiencing a serious adverse event during the second year post-randomization for control (n=14; black bars) and TLD (n=36; diagonal stripe bars).

Figure 3

Time to first event analysis for severe chronic obstructive pulmonary disease (COPD) exacerbation. Cumulative incidence curve for the % of subjects that have had at least one severe COPD exacerbation over the course of follow-up (TLD = solid line, control = dashed line). Light gray vertical line indicates the start of the time period (417 days) when eligible patients could cross-over. Number of patients at risk includes patients still enrolled in the study who have not been censored out due to (1) a COPD event, (2) study exit, or (3) cross-over procedure.

Figure 4

Time to first event analysis for Moderate or Severe chronic obstructive pulmonary disease (COPD) exacerbations. Cumulative incidence curve for the % of subjects that have had at least one moderate or severe COPD exacerbation over the course of follow-up (TLD = solid line, control = dashed line). Light gray vertical line indicates the start of the time period (417 days) when eligible patients could cross-over. Number of patients at risk includes patients still enrolled in the study who have not been censored out due to (1) a COPD event, (2) study exit, or (3) cross-over procedure.