Background:The efficacy of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF) is still unknown. The study evaluated the efficacy and safety of receiving 4 doses of cyclophosphamide pulse therapy in addition to high-dose methylprednisolone therapy. Methods: A double-blind placebo-controlled trial was conducted in 35 departments of 31 French hospitals in which patients with acute exacerbation of IPF and suspected acute exacerbation of IPF (≥18 years old) were randomly assigned 1:1 to receive intravenous impulse therapy or placebo-controlled groups via a network system. The treatment group was treated with cyclophosphamide (600 mg/m2Mesna (200 mg/m) was administered at dosing time and 4 h after dosing2) to prevent hemorrhagic cystitis, the control group was treated with placebo on days 0, 15, 30, and 60. Randomization was stratified according to the severity of IPF and balanced between blocks with variable block sizes of 4 or 6 patients. Patients who underwent mechanical ventilation, had an active infection, had an active stage of cancer, and were enrolled on a waiting list for lung transplantation were excluded from this study. All patients received standardized high-dose glucocorticoid therapy. The patient's treatment grouping was unknown to the investigator, the patient, and the program funder. The primary endpoint of the study was 3-month all-cause mortality, which was analyzed according to the intention-to-treat principle by the X² test.Results:From January 22, 2016 to July 19, 2018, 183 patients were enrolled for pre-enrollment assessment and 120 were enrolled. One hundred and nineteen patients [62 (52%) with severe IPF] who received at least one dose of cyclophosphamide (60) or placebo (59) were included in the intention analysis. The 3-month all-cause mortality rate was 45% (27/60) in the treatment group and 31% (18/59) in the placebo group, with a difference of 14.5% (95%CI：-3.1，31.6；P=0.10）。 Results were similar adjusted for IPF severity (OR=1.89，95%CI：0.89，4.04）。 The risk of death at 3 months was not associated with treatment and was higher in patients with severe IPF than in patients with non-severe IPF [OR=2.62 (1.12, 6.12)], patients with antifibrotic therapy had a lower risk of death [OR0.33（0.13，0.82）］。 Adverse reactions at 6 months were similar in the two groups [25 (42%) in the cyclophosphamide group vs 30 (51%) in the placebo group], and there was no difference in the incidence of various adverse reactions, including infection. The main adverse event was infection, which occurred in 20 (33%) in the cyclophosphamide group and 21 (36%) in the placebo group.Conclusion:In patients with acute exacerbations of IPF, the addition of intravenous cyclophosphamide pulse therapy to glucocorticoid therapy increased mortality at 3 months. These findings provide evidence against intravenous use of cyclophosphamide in such patients.
