Abstract
BACKGROUND: Chronic lung allograft dysfunction (CLAD) is a major obstacle to improving outcomes after lung transplantation. Bronchiolitis obliterans syndrome (BOS), characterised by progressive decline in forced expiratory volume in 1 s (FEV(1)) due to fibrotic scarring of the small airways, accounts for most CLAD cases. Pirfenidone, an antifibrotic agent used for idiopathic pulmonary fibrosis, was assessed for treating progressive BOS. METHODS: An investigator-initiated, international, multicentre, randomised, double-blind, placebo-controlled phase II trial was conducted in nine European lung transplant centres. Adults with bilateral lung transplants and progressive BOS were randomised (1:1) to receive pirfenidone 2403 mg·day(-1) or placebo with standard care for 26 weeks. The primary end-point was change in FEV(1) from baseline to week 26, with imputation for missing values. FINDINGS: From 1 May 2015 to 1 December 2019, 477 patients were screened, and 90 were randomised to pirfenidone (n=48) or placebo (n=42). Both groups showed continued decline in FEV(1) from baseline to week 26, with no significant difference in intention to treat (ITT), ITT with imputation, or per-protocol analyses. Secondary end-points (graft loss, death, re-transplantation) were similar between groups. Treatment-related serious adverse events were distributed equally. INTERPRETATION: Pirfenidone did not show superiority over placebo and standard care in this exploratory trial. It cannot be recommended for treating BOS. Further research is needed to explore other treatments for CLAD to improve long-term outcomes after lung transplantation.