A European multi-center, randomized controlled trial of Pirfenidone in bronchiolitis obliterans syndrome after bilateral lung transplantation

Background Chronic Lung Allograft Dysfunction (CLAD) is a major obstacle to improving outcomes after lung transplantation. Bronchiolitis Obliterans Syndrome (BOS), characterized by progressive decline in FEV1 due to fibrotic scarring of the small airways, accounts for most CLAD cases. Pirfenidone, an antifibrotic agent used for idiopathic pulmonary fibrosis (IPF), was assessed for treating progressive BOS. Methods An investigator initiated, international, multicenter, randomized, double-blind, placebo controlled phase II trial was conducted in 9 European Lung Transplant centers. Adults with bilateral lung transplants and progressive BOS were randomized (1:1) to receive Pirfenidone 2403 mg·day −1 or placebo with standard care for 26 weeks. The primary endpoint was change in FEV1 from baseline to week 26, with imputation for missing values. (ClinicalTrials.gov, NCT02262299 ). Findings From May 1, 2015, to December 1, 2019, 477 patients were screened, and 90 were randomized to Pirfenidone (n=48) or placebo (n=42). Both groups showed continued decline in FEV1 from baseline to week 26, with no significant difference in intention to treat (ITT), ITT with imputation, or per-protocol (PP) analyses. Secondary endpoints (graft loss, death, re-transplantation) were similar between groups. Treatment related serious adverse events were equally distributed. 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.