Randomized Sham Controlled Trial of Targeted Lung Denervation in Patients with COPD (AIRFLOW-3)

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 COPD. Objective: Evaluate the impact of TLD on COPD exacerbations compared to optimal medical treatment. Methods: AIRFLOW-3 patients were symptomatic (CAT ≥10) with moderate to very severe airflow obstruction (25% ≤ FEV1 ≤ 80% predicted) and GOLD E status (≥2 moderate or ≥1 severe exacerbation over prior 12 months). The primary endpoint was comparison of time-to-first moderate or severe COPD exacerbation through 12 months between the Treatment (TLD + optimal medical treatment) and Sham Control groups (sham procedure + optimal medical treatment). Secondary endpoints included rate of severe COPD exacerbations, change in quality of life (SGRQ-C and SF-36), change in lung function (FVC, FEV1, RV), and change in CAT. Measurements and Main Results: 388 patients were randomized 1:1 at 32 sites. There was no difference between TLD compared to sham treatment in probability of participants having a moderate or severe COPD exacerbation, HR 1.268 (95% CI, 0.988 to 1.628). At 1 year, the TLD group had less dyspnea (> 1 point improvement in TDI 35.4 vs 24.1%, p 0.021) compared to sham. Post-hoc analyses revealed 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.