Design for a multicenter, randomized, sham-controlled study to evaluate safety and efficacy after treatment with the Nuvaira® lung denervation system in subjects with chronic obstructive pulmonary disease (AIRFLOW-3)

Abstract

Background: Targeted lung denervation (TLD) is a bronchoscopically delivered ablation therapy that selectively interrupts pulmonary parasympathetic nerve signaling. The procedure has the potential to alter airway smooth muscle tone and reactivity, decrease mucous secretion, and reduce airway inflammation and reflex airway hyperresponsiveness. Secondary outcome analysis of a previous randomized, sham-controlled trial showed a reduction in moderate-to-severe exacerbations in patients with COPD after TLD treatment. A pivotal trial, AIRFLOW-3 has been designed to evaluate the safety and efficacy of TLD combined with optimal medical therapy to reduce moderate or severe exacerbations throughout 1 year, compared with optimal medical therapy alone.

Methods: The study design is a multicenter, randomized, full sham bronchoscopy controlled, double-blind trial that will enroll 400 patients (1:1 randomization). Key inclusion criteria are FEV₁/FVC < 0.7, FEV₁ 30 to 60% of predicted, post-bronchodilator, ≥ 2 moderate or 1 severe COPD exacerbations in the prior year, and COPD assessment test (CAT) ≥ 10. Primary objective will be the comparison of moderate or severe COPD exacerbations through 12 months of TLD therapy with optimal medical therapy versus optimal medical therapy alone. The sham group will be allowed to cross over at 1 year. Patients will be followed for up to 5 years.

Discussion: The multicenter, randomized, full sham bronchoscopy controlled, double-blind AIRFLOW-3 trial will evaluate the efficacy of TLD to reduce moderate or severe COPD exacerbations beyond optimal medical therapy alone. The target population are patients with COPD, who suffer persistent symptoms and exacerbations despite optimal treatment, defining an unmet medical need requiring novel therapeutic solutions. This trial is registered at clinicaltrials.gov: NCT03639051.

Keywords: Acetylcholine; Anticholinergic; Bronchoscopy; COPD; Nerves; Targeted lung denervation.

Fig. 1

Participant flow through the study

Fig. 2

Example of transverse and coronal slice CT airway measurements. The patient’s computed tomography scan of the chest is reviewed prior to the procedure to re-confirm proper airway sizes and geometry. The right mainstem bronchial length must be ≥10 mm to ensure an adequate location for electrode placement. The diameters measured on the transverse scan and coronal scan (diameter indicated by white dotted lines on CT images) must be averaged to determine the appropriate catheter size for both mainstem bronchi

Fig. 3

Image of the Nuvaira Console with the dNerva Catheter in bronchoscope and the expandable cooled balloon. a An image of the Nuvaira lung denervation system including the Nuvaira Console and dNerva Catheter. b The dNerva catheter is inserted through the working channel of a flexible bronchoscopes and inflated following positioning. Cooling fluid is circulated through the catheter by the console and provides the cooling that protects the airway wall during energy delivery (blue arrows indicate fluid flow). c During the procedure, the catheter is positioned in the mainstem bronchi and d visualization of the electrode positioning is confirmed by coupling the bronchoscope to the distal end of the catheter balloon

Fig. 4

Key steps of the targeted lung denervation procedure. All four steps are repeated until the entire circumference of the first bronchus is treated to ablate the nerves. This is typically achieved in 4 activations. The catheter is then retracted, and the opposite main bronchus treated