CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab
CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab
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DOI：
10.1183/13993003.01558-2014
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发表时间：
2015-12-01
影响因子：
24.3
通讯作者：
Barnathan, Elliot S.
中科院分区：
文献类型：
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作者：
Raghu, Ganesh;Martinez, Fernando J.;Barnathan, Elliot S.
本研究的目的是确定Carlumab治疗特发性肺纤维化（IPF）的安全性和有效性，在IPF患者（n=126）中进行了一项2期、随机、双盲、安慰剂对照的剂量范围研究。患者被随机分配至carlumab（1 mg.kg（-1）、5 mg. kg（-1）或15 mg. kg（-1））或安慰剂组，每4周一次。主要终点是用力肺活量（FVC）的百分比变化率。次要终点为疾病进展时间、FVC的绝对变化、肺一氧化碳弥散量（DLCO）的相对变化和St乔治呼吸问卷（SGRQ）总评分。FVC的百分比变化率显示无治疗效应（安慰剂-0.582%，1 mg.kg（-1）-0.533%，5 mg.kg（-1）-0.799%，15 mg.kg（-1）-0.470%; p=0.261）。与安慰剂组（-130 mL）相比，所有活性药物治疗组的FVC下降幅度更大（1 mg.kg（-1）-290 mL、5 mg.kg（-1）-370 mL和15 mg.kg（-1）-320 mL）。未观察到对疾病进展、DLCO、感染率或死亡率的影响。SGRQ评分显示，活性治疗组的恶化趋势不显著。出乎意料的是，游离CC-趋化因子配体2水平在第24周和第52周均高于基线。在5 mg.kg（-1）组中观察到发生1起或多起严重不良事件的患者比例（53.1%）高于1 mg. kg（-1）（15.2%）、15 mg. kg（-1）（21.9%）和安慰剂组（46.4%），但未观察到非预期严重不良事件。尽管提前停止给药，但Carlumab不太可能为IPF患者提供获益。
The objective of this study was to determine the safety and efficacy of carlumab in the treatment of idiopathic pulmonary fibrosis (IPF).A phase 2, randomised, double-blind placebo-controlled dose-ranging study was conducted in patients with IPF (n=126). Patients were randomised to carlumab (1 mg.kg(-1), 5 mg.kg(-1), or 15 mg.kg(-1)) or placebo every 4 weeks. The primary endpoint was the rate of percentage change in forced vital capacity (FVC). Secondary endpoints were time to disease progression, absolute change in FVC, relative change in diffusing capacity of the lung for carbon monoxide (DLCO), and St George's Respiratory Questionnaire (SGRQ) total score.Due to a pre-planned, unfavourable interim benefit-risk analysis, dosing was suspended. The rate of percentage change in FVC showed no treatment effect (placebo -0.582%, 1 mg.kg(-1) -0.533%, 5 mg.kg(-1) -0.799% and 15 mg.kg(-1) -0.470%; p=0.261). All active treatment groups showed a greater decline in FVC (1 mg.kg(-1) -290 mL, 5 mg.kg(-1) -370 mL and 15 mg.kg(-1) -320 mL) compared with placebo (-130 mL). No effect on disease progression, DLCO, infection rates or mortality was observed. SGRQ scores showed a nonsignificant trend toward worsening with active treatment. Unexpectedly, free CC-chemokine ligand 2 levels were elevated above baseline at both 24 and 52 weeks. A higher proportion of patients with one or more serious adverse events was observed in the 5 mg.kg(-1) group (53.1%) compared with 1 mg.kg(-1) (15.2%), 15 mg.kg(-1) (21.9%) and placebo (46.4%), although no unexpected serious adverse events were noted.Although dosing was stopped prematurely, it is unlikely that carlumab provides benefit to IPF patients.