Background

The use of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF) is unknown. Our study was designed to evaluate the efficacy and safety of four cyclophosphamide pulses in addition to high-dose methylprednisolone in this population.

Methods

In this double-blind, placebo-controlled trial done in 35 departments across 31 hospitals in France, adult patients (≥18 years) with acute exacerbation of IPF and those with suspected acute exacerbation of IPF were randomly assigned in a 1:1 ratio using a web-based system to receive either intravenous pulses of cyclophosphamide (600 mg/m²) plus uromitexan as haemorrhagic cystitis prophylaxis (200 mg/m²) at the time of cyclophosphamide administration and then again, 4 h later, or placebo at days 0, 15, 30, and 60. Random assignment was stratified according to the severity of IPF and was block-balanced with variable block sizes of four or six patients. Patients receiving mechanical ventilation, with active infection, with active cancer, or who were registered on the lung transplant waiting list were excluded. All patients received standardised high-dose glucocorticoids. The investigators, patients, and the sponsor were masked to the treatment assignments. The primary endpoint was 3-month all-cause mortality, analysed by a χ² test adhering to an intention-to-treat principle. The trial is now complete and registered with ClinicalTrials.gov, NCT02460588.

Findings

Between Jan 22, 2016, and July 19, 2018, 183 patients were assessed for eligibility, of whom 120 patients were randomly assigned and 119 patients (62 [52%] with severe IPF) received at least one dose of cyclophosphamide (n=60) or placebo (n=59), all of whom were included in the intention-to-treat analysis. The 3-month all-cause mortality was 45% (27/60) in patients given cyclophosphamide compared with 31% (18/59) in the placebo group (difference 14·5% [95% CI −3·1 to 31·6]; p=0·10). Similar results were found after adjustment by IPF severity (odds ratio [OR] 1·89 [95% CI 0·89–4·04]). The risk of death at 3 months, independent of the treatment received, was higher with severe than non-severe IPF (OR 2·62 [1·12–6·12]) and was lower with the use of antifibrotic therapy (OR 0·33 [0·13–0·82]). Adverse events were similar between groups by 6 months (25 [42%] in the cyclophosphamide group vs 30 [51%] in the placebo group) and their proportion, including infections, did not differ. Overall infection was the main adverse event and occurred in 20 (33%) of 60 patients in the cyclophosphamide group versus 21 (36%) of 59 patients in the placebo group.

Interpretation

In patients with acute exacerbation of IPF, adding intravenous cyclophosphamide pulses to glucocorticoids increased 3-month mortality. These findings provide evidence against the use of intravenous cyclophosphamide in such patients.

Funding

Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC 2014–502), Roche Pharmaceuticals.

中文翻译：

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糖皮质激素联合环磷酰胺治疗特发性肺纤维化急性加重（EXAFIP）：一项随机、双盲、安慰剂对照的 3 期试验

背景

在特发性肺纤维化 (IPF) 急性加重患者中使用环磷酰胺尚不清楚。我们的研究旨在评估除大剂量甲基强的松龙外，四种环磷酰胺脉冲在该人群中的疗效和安全性。

方法

在这项在法国 31 家医院的 35 个科室进行的双盲、安慰剂对照试验中，IPF 急性加重的成年患者（≥18 岁）和疑似 IPF 急性加重的患者按照 1:1 的比例随机分配一个基于网络的系统，用于接受环磷酰胺 (600 mg/m ² ) 和 uromitexan 作为出血性膀胱炎预防措施 (200 mg/m ^{2 ) 的静脉脉冲}) 在环磷酰胺给药时，然后在 4 小时后再次给药，或在第 0、15、30 和 60 天服用安慰剂。随机分配根据 IPF 的严重程度进行分层，并使用 4 或 4 的可变块大小进行块平衡六个病人。接受机械通气、活动性感染、活动性癌症或登记在肺移植等候名单上的患者被排除在外。所有患者均接受标准化的大剂量糖皮质激素。研究人员、患者和申办者对治疗分配不知情。主要终点是 3 个月的全因死亡率，通过遵循意向治疗原则的 χ2 检验^{进行分析。}该试验现已完成并在 ClinicalTrials.gov 注册，NCT02460588。

发现

在 2016 年 1 月 22 日至 2018 年 7 月 19 日期间，对 183 名患者进行了资格评估，其中 120 名患者被随机分配，119 名患者（62 [52%] 患有严重 IPF）接受了至少一剂环磷酰胺（n=60 ) 或安慰剂 (n=59)，所有这些都被纳入意向治疗分析。给予环磷酰胺的患者 3 个月全因死亡率为 45% (27/60)，而安慰剂组为 31% (18/59)（差异 14·5% [95% CI -3·1 至 31· 6]；p=0·10)。在通过 IPF 严重程度调整后发现了类似的结果（优势比 [OR] 1·89 [95% CI 0·89–4·04]）。3 个月时的死亡风险与接受的治疗无关，重度 IPF 高于非重度 IPF（OR 2·62 [1·12-6·12]），而使用抗纤维化治疗则较低（OR 0 ·33 [0·13–0·82])。与安慰剂组中的 30 [51%]) 和他们的比例，包括感染，没有差异。总体感染是主要的不良事件，发生在环磷酰胺组 60 名患者中的 20 名（33%）和安慰剂组 59 名患者中的 21 名（36%）。

解释

在 IPF 急性加重的患者中，在糖皮质激素的基础上增加静脉注射环磷酰胺会增加 3 个月的死亡率。这些发现提供了反对在此类患者中使用静脉环磷酰胺的证据。

资金

法国卫生部计划 Hospitalier de Recherche Clinique (PHRC 2014–502)，罗氏制药。