Effect of Recombinant Human Pentraxin 2 vs Placebo on Change in Forced Vital Capacity in Patients With Idiopathic Pulmonary Fibrosis A Randomized Clinical Trial
Effect of Recombinant Human Pentraxin 2 vs Placebo on Change in Forced Vital Capacity in Patients With Idiopathic Pulmonary Fibrosis A Randomized Clinical Trial
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DOI：
10.1001/jama.2018.6129
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发表时间：
2018-06-12
影响因子：
120.7
通讯作者：
Richeldi, Luca
中科院分区：
文献类型：
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作者：
Raghu, Ganesh;van den Blink, Bernt;Richeldi, Luca
特发性肺纤维化（IPF）是一种预后不良的进行性纤维化肺病。目的确定重组人正五聚蛋白2与安慰剂对平均用力肺活量（FVC）占预测值百分比从基线至第28周变化的影响。设计、设置和参与者在7个国家的18个地点对符合条件的IPF患者进行的2期、随机、双盲、安慰剂对照试验（N = 117;年龄40 - 80岁; FVC>= 50%和>= 90%预测值;第一秒用力呼气量/FVC比值> 0.70;一氧化碳弥散量[DLCO]>= 25%和>= 90%预测值; 6分钟步行试验距离>= 150 m）。研究时间为2015年8月至2017年5月。干预患者随机接受重组人正五聚蛋白2（10 mg/kg静脉注射，每4周一次，n = 77）或安慰剂（n = 39），持续24周，并按并发IPF治疗状态分层。主要结果和指标主要终点是最低的-从基线至第28周FVC占预测值百分比的平方平均变化（最小临床重要差异，下降2%-6%）。次要终点包括肺容积的平均变化高分辨率计算机断层扫描（HRCT）和6分钟步行距离（总肺、正常肺和间质性肺异常）结果在117名随机化患者中，116名接受了至少1剂研究药物，（平均年龄：68.6岁; 81.0%为男性;自IPF诊断以来的平均时间：3.8年），111例（95.7%）完成研究。从基线到第28周，重组人正五聚蛋白2治疗组患者FVC占预测值百分比的最小二乘均值变化为-2.5，安慰剂组为-4.8（差异，+2.3 [90% CI，1.1 - 3.5]; P = 0.001）。在总肺容量方面未观察到显著的治疗差异（差异，93.5 mL [90% CI，-27.7至214.7]），HRCT上的定量实质特征（正常肺容积差异，-1.2%<$90% CI，-4.4至1.9];间质性肺异常差异，1.1%[90% CI，-2.2至4.3]）或DLCO测量值（差异，-0.4至90% CI，-2.6至1.7]）。用重组人正五聚蛋白2治疗的患者的6分钟步行距离的变化为-0.5米，而安慰剂组的患者为-31.8米（差异，+31.3米[90%CI，17.4至45.1]; P <0.001）。重组人正五聚蛋白2与安慰剂组最常见的不良事件是咳嗽（18%vs5%）、疲劳（17%vs10%）和鼻咽炎（16%vs23%hCLUSION AND RELEVANCE在这项初步研究中，重组人正五聚蛋白2与安慰剂相比，导致特发性肺纤维化患者在28周内肺功能下降较慢。进一步的研究应更全面地评估疗效和安全性。
IMPORTANCE Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression.OBJECTIVE To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value.DESIGN, SETTING, AND PARTICIPANTS Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N = 117; aged 40-80 years; FVC >= 50% and >= 90% predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [DLCO] >= 25% and >= 90% predicted; and distance of >= 150 m on the 6-minute walk test). Study period was August 2015-May 2017.INTERVENTIONS Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n = 77) or placebo (n = 39) for 24 weeks, and stratified by concurrent IPF treatment status.MAIN OUTCOMES AND MEASURES The primary end pointwas the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2%-6%). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m).RESULTS Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, + 2.3[90% CI, 1.1 to 3.5]; P =.001). No significant treatment differences were observed in total lung volume (difference, 93.5mL[90% CI, -27.7 to 214.7]), quantitative parenchymal features on HRCT (normal lung volume difference, -1.2%[90% CI, -4.4 to 1.9]; interstitial lung abnormalities difference, 1.1%[90% CI, -2.2 to 4.3]), or measurement of DLCO (difference, -0.4[90% CI, -2.6 to 1.7]). The change in 6-minute walk distance was -0.5m for patients treated with recombinant human pentraxin 2 vs -31.8 m for those in the placebo group (difference, + 31.3 m[90% CI, 17.4 to 45.1]; P < .001). The most common adverse events in the recombinant human pentraxin 2 vs placebo group were cough (18% vs 5%), fatigue (17% vs 10%), and nasopharyngitis (16% vs 23%).CONCLUSIONS AND RELEVANCE In this preliminary study, recombinant human pentraxin 2 vs placebo resulted in a slower decline in lung function over 28 weeks for patients with idiopathic pulmonary fibrosis. Further research should more fully assess efficacy and safety.