A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial
A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial
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DOI：
10.1016/s2213-2600(14)70132-8
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发表时间：
2014-07-01
影响因子：
76.2
通讯作者：
Rodman, David
中科院分区：
文献类型：
--
作者：
Boyle, Michael P.;Bell, Scott C.;Rodman, David
背景：phe508del CFTR突变通过限制CFTR蛋白到达上皮细胞表面的数量导致囊性纤维化。我们测试了lumacaftor（一种正在研究的CFTR校正剂，可以增加phe508del CFTR到细胞表面的运输）和ivacaftor（一种CFTR增强剂，可以增强CFTR在细胞表面的氯化物运输）的联合治疗。在这项2期临床试验中，我们评估了三个连续的队列，每个队列的结果为后续队列的剂量选择提供信息。我们从澳大利亚、比利时、德国、新西兰和美国的24个囊性纤维化中心招募了患者。入选标准为：确诊囊性纤维化，年龄至少18岁，用力呼气量（FEV1）大于或等于预测值的40%。队列1包括phe508del CFTR纯合子患者，随机分配到每天一次200 mg的lumacaftor，持续14天，随后每12小时添加150 mg或250 mg的ivacaftor，持续7天，或21天的安慰剂。同时，队列2和3纳入了phe508del CFTR纯合子和杂合子患者，随机分配到56天的lumacaftor（队列2:200 mg， 400 mg或600 mg，每天一次，队列3:400 mg每12小时），28天后每12小时添加250 mg的ivacaftor，或56天的安慰剂。所有队列的主要结局是意向治疗人群在联合治疗期间汗液氯化物浓度的变化和安全性（实验室测量和不良事件）。该研究已在ClinicalTrials.gov注册，注册号为NCT01225211， eudraft注册号为2010-020413-90。队列1包括64名参与者。队列2和队列3共包含96例phe508del CFTR纯合子和28例复合杂合子。用lumacaftor 200mg每日一次，ivacaftor 250mg每12 h治疗，使平均汗液氯化物浓度降低9.1 mmol/L (p
Background The phe508del CFTR mutation causes cystic fibrosis by limiting the amount of CFTR protein that reaches the epithelial cell surface. We tested combination treatment with lumacaftor, an investigational CFTR corrector that increases trafficking of phe508del CFTR to the cell surface, and ivacaftor, a CFTR potentiator that enhances chloride transport of CFTR on the cell surface.Methods In this phase 2 clinical trial, we assessed three successive cohorts, with the results of each cohort informing dose selection for the subsequent cohort. We recruited patients from 24 cystic fibrosis centres in Australia, Belgium, Germany, New Zealand, and the USA. Eligibility criteria were: confirmed diagnosis of cystic fibrosis, age at least 18 years, and a forced expiratory volume in is (FEV1) of 40% or more than predicted. Cohort 1 included phe508del CFTR homozygous patients randomly assigned to either lumacaftor 200 mg once per day for 14 days followed by addition of ivacaftor 150 mg or 250 mg every 12 h for 7 days, or 21 days of placebo. Together, cohorts 2 and 3 induded phe508del CFTR homozygous and heterozygous patients, randomly assigned to either 56 days of lumacaftor (cohort 2: 200 mg, 400 mg, or 600 mg once per day, cohort 3: 400 mg every 12 h) with ivacaftor 250 mg every 12 h added after 28 days, or 56 days of placebo. The primary outcomes for all cohorts were change in sweat chloride concentration during the combination treatment period in the intention-to-treat population and safety (laboratory measurements and adverse events). The study is registered with ClinicalTrials.gov, number NCT01225211, and EudraCT, number 2010-020413-90.Findings Cohort 1 induded 64 participants. Cohort 2 and 3 combined contained 96 phe508del CFTR homozygous patients and 28 compound heterozygotes. Treatment with lumacaftor 200 mg once daily and ivacaftor 250 mg every 12 h decreased mean sweat chloride concentration by 9.1 mmol/L (p