Design and rationale of the AIR-NET trial: a randomised, open-label, multifactorial, multicentre, adaptive platform trial using a range of repurposed anti-inflammatory treatments to improve outcomes in patients with bronchiectasis within the EMBARC clinical research network

Background Neutrophilic airway inflammation is associated with disease severity and exacerbation frequency in bronchiectasis. Neutrophil protease inhibition significantly reduced exacerbation rates in phase II and III trials in bronchiectasis, highlighting this disease feature as an important therapeutic target. Additional neutrophil targeting therapeutics are needed to reduce the burden of the disease. Herein, we describe the protocol for the AIR-NET trial, the first randomised, open-label, multifactorial, multicentre, adaptive platform trial for people with bronchiectasis, run via the EMBARC network, to investigate the safety and efficacy of several repurposed anti-inflammatory treatments. Methods and Analysis Participants with CT-confirmed bronchiectasis, daily sputum production and evidence of active airway neutrophilic inflammation (based on a positive lateral flow test for neutrophil elastase(NE) activity), across 10 sites in the UK, will be randomized to one of several repurposed drugs with published evidence of effects on neutrophilic inflammation and acceptable safety profile (oral dose: disulfiram 400 mg, once-daily; dipyridamole 200 mg twice-daily; doxycycline 100 mg once-daily. N=42/arm) or usual care, according to arm-specific eligibility criteria, and treated for 28-days. New arms will be added to the trial through an adaptive design. The primary endpoint is change from baseline in sputum NE activity (a validated biomarker and surrogate of exacerbation risk) at day 28. Key secondary endpoints include time-to-first exacerbation, quality of life questionnaires, neutrophil function, and safety. Summary AIR-NET will establish a multi-centre network with integrated clinical and translational capabilities for the investigation of therapies in bronchiectasis aiming to identify key anti-inflammatory mechanisms and effective re-purposed treatments.