Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial
Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial
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DOI：
10.1016/s0140-6736(19)32597-8
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发表时间：
2019-11-23
期刊：
影响因子：
168.9
通讯作者：
Mccoy, Karen S.
中科院分区：
文献类型：
--
作者：
Heijerman, Harry G. M.;McKone, Edward F.;Mccoy, Karen S.
背景囊性纤维化跨膜电导调节因子(CFTR)调节剂可纠正CFTR突变引起的基本缺陷。在F508del突变纯合子的囊性纤维化患者中，通过CFTR校正子和增强子的组合，已经实现了健康结果的改善。在对F508del突变纯合子囊性纤维化患者进行的2期研究中，在tezacaftor+iVacaftor中添加下一代CFTR校正器elexaftor(VX-445)进一步改善了F508del-CFTR的功能和临床结果。方法这项3期多中心、随机、双盲、主动对照试验在4个国家的44个地点进行。符合条件的参与者为囊性纤维化F508del突变纯合子者，年龄12岁或以上，病情稳定，预测用力呼气量(PPFEV(1))为40-90%的S(1)，包括40-90%。试验结束后，受试者被随机分配(1：1)至4周，试验组口服替扎卡福200 mg，每日1次，替扎卡夫100 mg，每日1次，每12小时口服1次，对照组每天口服替扎卡夫100 mg，每12小时口服1次，每次150 mg。主要结果是第4周时ppFEV(1)较基线的绝对变化(在替扎卡福加异烟肼磨合结束时测量)。关键的次要结果是氯化汗和囊性纤维化问卷-修订呼吸域(CFQ-R-RD)评分的绝对变化。这项研究已在ClinicalTrials.gov注册，NCT03525548。研究结果在2018年8月3日至12月28日期间，共有113名参与者参加。在磨合之后，107名参与者被随机分配(elexaftor+tezacaftor+iVacaftor组55人，tezacaftor+iVacaftor组52人)，并完成为期4周的治疗。Elexaftor+tezacaftor+iVacaftor组在ppFEV(1)的主要结果方面有改善(最小二乘平均[LSM]治疗差异10.0个百分点[95%CI 7.4至12.6]，p
Background Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation.Methods This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV(1)) of 40-90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV(1) at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548.Findings Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV(1) (least squares mean [LSM] treatment difference of 10.0 percentage points [95% CI 7.4 to 12.6], p