A European Multi‐Center, Randomized, Double‐Blind Trial of Pirfenidone in Bronchiolitis‐Obliterans‐Syndrome Grade 1‐3 in Lung Transplant Recipients (European Trial of Pirfenidone in BOS (EPOS))

Abstract

Bronchiolitis obliterans syndrome (BOS), the most common form of chronic lung allograft dysfunction (CLAD), and the major limitation to long-term survival after lung transplantation. BOS affects up to 50% of lung transplant recipients within 5 years after transplant, causing significant morbidity and mortality. BOS manifesting early after transplantation shows a poorer prognosis than late-onset BOS. There are only few studies assessing treatment efficacy, but only a minority of patients respond to current treatment options. From trans-bronchial surveillance biopsies and autopsies from diseased transplant recipients, the BOS lesions reveal interstitial fibrosis, which suggest the possible use of anti-fibrotic agent like Pirfenidone. We hypothesized that there is a statistically significant difference between randomized study groups in the change in FEV1 from baseline to 6 months. This trial is investigator-initiated and including nine European expert lung transplant centers. Patients with new onset progressive BOS were randomized in a 1:1 ratio to receive either Pirfenidone or the matching placebo treatment for 6 months. Progressive BOS was defined by the following: at least 3 FEV1-measurements in the last 6 months, each at least 3 weeks apart, a total decline of at least 200ml in FEV1, and a mean decline of at least 50 ml in the last two measurements, as well as the exclusion of other reasons for FEV1 decline by an expert panel. All patients had to be on at least 250mg Azithromycin 3 times a week for at least 4 weeks prior to inclusion. A total of 80 patients were planned included in the study 40 in each group. The primary endpoint is to evaluate the effect of Pirfenidone on the change in FEV1 (ml) over 6 months in lung transplant recipients with BOS, who are treated with Azithromycin. Secondary endpoints are as follows; Categorical percentage change in FEV1, Change in FVC, Change in TLC, Change in FEV1/FVC ratio, Number of patients with treatment failure, Change in BOS grade, Change in percent predicted diffusion capacity (DLco), Change in functional level as assessed by 6MWT, Hospital admission for any reason, Death or re-transplantation rates, Change in quality of life assessed by EQ5D.