Efficacy and safety of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup: a pooled analysis
Efficacy and safety of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup: a pooled analysis
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DOI：
10.1016/s2213-2600(16)30121-7
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发表时间：
2016-08-01
影响因子：
76.2
通讯作者：
Wainwright, Claire E.
中科院分区：
文献类型：
--
作者：
Elborn, J. Stuart;Ramsey, Bonnie W.;Wainwright, Claire E.
背景鲁玛卡托/依伐卡托联合治疗已在Phe 508 del CFTR突变纯合子囊性纤维化患者中显示出临床获益;然而，治疗前肺功能是一个潜在影响该治疗疗效和安全性的混杂因素。我们的目的是评估的疗效和安全性，在这些患者中，定义的特定类别的肺function.Methods两个试验（TRAFFIC和TRANSPORT）包括在这个汇总分析是多国，随机，双盲，安慰剂对照，平行组，3期研究。来自北美、澳大利亚和欧盟（两项试验）的187个参与中心的合格患者年龄为12岁或以上，确诊为囊性纤维化，Phe 508 del CFTR突变纯合子，筛选时预测FEV 1百分比（ppFEV（1））为40-90。患者被随机分配到交互式网络响应系统（1：1：1）接受安慰剂，lumacaftor（600 mg每日一次）+ivacaftor（250 mg每12小时），或lumacaftor（400 mg每12小时）+ivacaftor（250 mg每12小时），持续24周。对于基线时ppFEV（1）（≥ 40）和筛选时ppFEV（1）（≥ 70）的患者，按照肺功能（通过ppFEV（1）测量）对汇总疗效和安全性数据进行预先设定的亚组分析。主要终点是在所有接受至少一剂研究药物的随机化患者中分析的第24周ppFEV（1）相对于基线的绝对变化。这两项试验都在ClinicalTrials.gov上注册（TRAFFIC：NCT 01807923; TRANSPORT：NCT 01807949）。在纳入疗效分析的1108例患者中，81例患者的ppFEV（1）在筛选和基线之间降至40以下，1016例患者的ppFEV（1）在基线时为40或更高。筛选时，730人的ppFEV（1）小于70，342人的ppFEV（1）大于等于70。在基线ppFEV（1）水平低于40的亚组中，两种剂量的鲁玛卡托/依伐卡托均观察到ppFEV（1）相对于基线的绝对变化改善（与安慰剂相比的最小二乘平均差异为3.7个百分点[95% CI 0.5-6.9; p=0.024]和3.3个百分点[0.2-6.4; p=0.036]）。在基线ppFEV（1）水平为40或更高的亚组中，与安慰剂相比，ppFEV（1）也有改善（3.3个百分点[2.3-4.4; p
Background Lumacaftor/ivacaftor combination therapy has shown clinical benefits in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation; however, pretreatment lung function is a confounding factor that potentially affects the efficacy and safety of this therapy. We aimed to assess the efficacy and safety of lumacaftor/ivacaftor therapy in these patients, defined by specific categories of lung function.Methods Both trials (TRAFFIC and TRANSPORT) included in this pooled analysis were multinational, randomised, double-blind, placebo-controlled, parallel-group, phase 3 studies. Eligible patients from 187 participating centres in North America, Australia, and the European Union (both trials) were aged 12 years or older with a confirmed diagnosis of cystic fibrosis, homozygous for the Phe508del CFTR mutation, and with a percent predicted FEV1 (ppFEV(1)) of 40-90 at the time of screening. Patients were randomly assigned with an interactive web response system (1:1:1) to receive placebo, lumacaftor (600 mg once daily) plus ivacaftor (250 mg every 12 h), or lumacaftor (400 mg every 12 h) plus ivacaftor (250 mg every 12 h) for 24 weeks. Prespecified subgroup analyses of pooled efficacy and safety data by lung function, as measured by ppFEV(1), were done for patients with baseline ppFEV(1) (= 40) and screening ppFEV(1) (= 70). The primary endpoint was the absolute change from baseline in ppFEV(1) at week 24 analysed in all randomised patients who received at least one dose of study drug. Both trials are registered with ClinicalTrials.gov (TRAFFIC: NCT01807923; TRANSPORT: NCT01807949).Findings Both trials were done between April, 2013, and April, 2014. Of the 1108 patients included in the efficacy analysis, 81 patients had a ppFEV(1) that decreased to lower than 40 between screening and baseline and 1016 had a ppFEV(1) of 40 or higher at baseline. At screening, 730 had a ppFEV(1) of less than 70, and 342 had a ppFEV(1) of 70 or higher. Improvements in the absolute change from baseline at week 24 in ppFEV(1) were observed with both lumacaftor/ivacaftor doses in the subgroup with baseline ppFEV(1) levels lower than 40 (least-squares mean difference vs placebo was 3.7 percentage points [95% CI 0.5-6.9; p=0.024] in the lumacaftor [600 mg/day]-ivacaftor group and 3.3 percentage points [0.2-6.4; p=0.036] in the lumacaftor [400 mg/12 h]-ivacaftor group). Improvements in ppFEV(1) compared with placebo were also reported in the subgroup with baseline ppFEV(1) levels of 40 or higher (3.3 percentage points [2.3-4.4; p