Randomized Sham-controlled Trial of Targeted Lung Denervation in Patients with Chronic Obstructive Pulmonary Disease (AIRFLOW-3)

Abstract

Rationale: AIRFLOW-3 was a 1:1 randomized, double-blind, sham-controlled trial of the D'Nerva targeted lung denervation (TLD) system in patients with chronic obstructive pulmonary disease (COPD). Objective: To evaluate the impact of TLD on COPD exacerbations compared with optimal medical treatment. Methods: AIRFLOW-3 patients were symptomatic (COPD Assessment Test score ⩾10) with moderate to very severe airflow obstruction (FEV₁ ≥25% but ⩽80% predicted) and Global Initiative for Chronic Obstructive Lung Disease E status (at least two moderate or one severe exacerbation during the previous 12 mo). The primary endpoint was a comparison of time to the first moderate or severe COPD exacerbation through 12 months between the treatment (TLD plus optimal medical treatment) and sham control groups (sham procedure plus optimal medical treatment). Secondary endpoints included the rate of severe COPD exacerbations, change in quality of life (St. George's Respiratory Questionnaire for COPD and Short Form-36 questionnaire), change in lung function (FVC, FEV₁, residual volume), and change in COPD Assessment Test score. Measurements and Main Results: 388 patients were randomized at a 1:1 ratio at 32 sites. There was no difference between treatment and the sham procedure in terms of the probability of participants having a moderate or severe COPD exacerbation (hazard ratio, 1.268; 95% confidence interval, 0.988-1.628). At 1 year, the TLD group had less dyspnea (>1-point improvement in Transitional Dyspnea Index, 35.4 vs. 24.1%; P = 0.021) compared with the sham group. Post hoc analyses suggests that failure to reach the primary endpoint was driven by an insufficient number of patients exhibiting an airway-predominant phenotype (lung hyperinflation without significant emphysema). Conclusions: AIRFLOW-3 failed to meet its primary endpoint. However, post hoc analyses identified a responder profile; a prospective multicenter randomized controlled trial is being designed to confirm these findings. Clinical trial registered with www.clinicaltrials.gov (NCT03639051).

Keywords: COPD; acetylcholine; anticholinergic; bronchoscopy; targeted lung denervation.

Figure 1.

Consolidated Standards of Reporting Trials flow chart. AE = adverse event; TLD = targeted lung denervation.

Figure 2.

Moderate and severe chronic obstructive pulmonary disease (COPD) exacerbation (intention-to-treat population). (A) The time-to-first-event analysis with a primary endpoint window of 0–12 months of follow-up. (B) The time-to-first-event analysis with a primary endpoint window of 3–12 months of follow-up. (C) Annualized rate of moderate and severe COPD exacerbations with an endpoint window of 0–12 months of follow up. (D) Annualized rate of moderate and severe COPD exacerbations with an endpoint window of 3–12 months of follow-up. Error bars indicate 95% confidence intervals.

Figure 3.

Severe chronic obstructive pulmonary disease (COPD) exacerbation (intention-to-treat population). (A) The time-to-first-event analysis with a primary endpoint window of 0–12 months of follow-up. (B) The time-to-first-event analysis with a primary endpoint window of 3–12 months of follow-up. (C) Annualized rate of severe COPD exacerbations with an endpoint window of 0–12 months of follow-up. (D) Annualized rate of severe COPD exacerbations with an endpoint window of 3–12 months of follow-up. Error bars indicate 95% confidence intervals.

Figure 4.

AIRFLOW-3 post hoc responder analysis: (A) difference in change in FEV₁ between targeted lung denervation (TLD) treatment and sham groups at 12 months after randomization as a function of baseline levels of hyperinflation (residual volume percent predicted [RV% pred]) and emphysema (percent low-attenuation area <−950 HU). (B) Percent reduction in moderate and severe chronic obstructive pulmonary disease (exacerbations in the TLD treatment group vs. the sham group as a function of baseline levels of hyperinflation [RV% pred] and emphysema [percent low-attenuation area <−950 HU; *P < 0.05, TLD group vs. sham group). AECOPD = acute exacerbation of chronic obstructive pulmonary disease.