Randomized, Double-Blind Trial of the Efficacy and Safety of Pirfenidone in Patients with Fibrotic Hypersensitivity Pneumonitis

Abstract

Rationale: Fibrotic hypersensitivity pneumonitis (FHP) is an irreversible lung disease with high morbidity and mortality. We sought to evaluate the safety and effect of pirfenidone on disease progression in such patients.Methods: In a phase 2 double-blind, single-center trial, we randomly assigned, in a 2:1 ratio, adults with FHP to receive either oral pirfenidone (2403 mg/day) or placebo for 52 weeks. Patients had to have CT lung fibrotic abnormalities affecting ≥5%, worsening respiratory symptoms, and either an increase in the extent of fibrosis on CT or relative decline in the FVC% of ≥5% within the 24-months before screening. The primary endpoint was the mean change from baseline to week 52 in %FVC. Secondary endpoints included progression-free survival (PFS, time to the first occurrence of any one of the following: a relative decline of ≥10% in FVC and/or DLCO, acute exacerbation, a decrease of ≥50 m in the 6-minute walk distance, increase in background prednisone by ≥10 mg or introduction of corticosteroids and/or steroid-sparing drugs, or death), change from baseline to week 52 in FVC slope and mean %DLCO, all-cause hospitalizations, CT progression of lung fibrosis, and safety. Results: After 40 patients had been randomized (mean age 67.1 years, 42.5% males) the study was stopped due to slow recruitment due to the COVID-19 pandemic. At baseline, demographics, smoking and inciting antigen exposure history, lung function, 6-minute walk distance, extent of CT lung fibrosis, and immunosuppressive therapy were balanced in both groups. There was no significant difference between the pirfenidone and placebo groups after adjusting for baseline %FVC and concomitant immunosuppressive therapy (p=0.88) in mean change from baseline to week 52 in %FVC. Secondary endpoints showed no difference between groups in change from baseline to week 52 in FVC slope, mean %DLCO, all-cause hospitalization and CT progression of lung fibrosis. However, a decrease in PFS favored pirfenidone (Table). The percentages of patients with any adverse events (AE) were similar in both groups. Nausea and rash, respectively, led to transient dose reduction of study treatment in 2 patients in the pirfenidone group. There were no treatment-related serious AE or AE leading to discontinuation of study treatment. No death occurred in the pirfenidone group and one death (respiratory) occurred in the placebo group. Conclusions: The trial was under powered to detect a difference in the primary endpoint. Pirfenidone was found to be tolerable and safe and compared to placebo reduced PFS in patients with FHP.