RCT Abstract - Cyclophosphamide added to glucocorticoids in acute exacerbation of idiopathic pulmonary fibrosis (EXAFIP): a randomized, double-blind, placebo-controlled, phase 3 trial

Abstract

Background: The utility of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is unknown.

Objectives: Our study was designed to evaluate the efficacy and safety of cyclophosphamide pulses in addition to high dose methylprednisolone in this population.

Methods: The study is a double-blind, placebo-controlled trial conducted in 35 sites in France. Patients with AE-IPF were randomly assigned in a 1:1 ratio to receive intravenous pulses of cyclophosphamide at a dose of 600 mg/m2 or placebo at Days 0, 15, 30 and 60. The primary end point was 3-month all-cause mortality, analysed by a χ² test following an intention-to-treat principle.

Results: 120 patients were randomized and 119 patients received at least one dose of cyclophosphamide (n=60) or placebo (n=59). The 3-month all-cause mortality was 45% (27/60) in patients treated with cyclophosphamide compared to 31% (18/59) in the placebo group (p=0.10). The risk of death at 3 month increased with the severity of IPF (odds ratio, 2·62; 95% CI, 1·12 to 6·12) and decreased with the use of antifibrotic therapy at baseline (odds ratio, 0·33; 95% CI, 0·13 to 0·82). Adverse events were similar and their proportion, including infections, did not differ among cyclophosphamide and placebo groups. Overall infection was the main adverse event and occurred in 20 (33%) vs 21 (36%) patients.

Conclusion: In patients with AE-IPF, adding intravenous cyclophosphamide pulses to glucocorticoids numerically increased the 3-months mortality. These findings provide evidence against the use of intravenous cyclophosphamide in such patients.