一个雌性生殖道校正器(lumacaftor)和雌性生殖道电位器(ivacaftor)治疗囊性纤维化患者有CFTR phe508del检测突变:第二阶段随机对照试验。

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博伊尔MP,贝尔SC, Konstan MW, McColley SA罗SM, Rietschel E,黄X,华尔兹D, Patel NR,罗德曼D

一个雌性生殖道校正器(lumacaftor)和雌性生殖道电位器(ivacaftor)治疗囊性纤维化患者有CFTR phe508del检测突变:第二阶段随机对照试验。

柳叶刀和地中海。2014年7月,2 (7):527 - 38。doi: 10.1016 / s2213 - 2600 (14) 70132 - 8。Epub 2014年6月24日。

PubMed ID

24973281 (在PubMed

]

文摘

背景:CFTR phe508del检测突变导致囊性纤维化通过限制的雌性生殖道蛋白量到达上皮细胞表面。我们测试了lumacaftor联合治疗,临床实验的雌性生殖道校正器,增加贩卖phe508del雌性生殖道细胞表面,和雌性生殖道ivacaftor电位器提高氯运输的雌性生殖道细胞表面。方法:在这个2期临床试验,我们评估连续三组,每个组的结果通知剂量选择随后的队列。我们招募了来自24个囊性纤维化的病人中心在澳大利亚、比利时、德国、新西兰和美国。合格标准:证实诊断囊性纤维化,至少18岁,用力呼气量在1 s (FEV1)比预测的40%或更多。群1包括phe508del雌性生殖道纯合子患者随机分配到lumacaftor每天200毫克一次14天之后添加ivacaftor 150毫克和250毫克每12小时7天,或安慰剂的21天。在一起,组2和3包括phe508del雌性生殖道纯合子和杂合的患者,随机分配到56天的lumacaftor(组2:200毫克,400毫克,或每天600毫克一次,3组:400毫克每12小时)添加了ivacaftor 250毫克每12小时后28天,或安慰剂的56天。的主要结果军团都是汗水氯浓度变化联合治疗期间的意向处理人口和安全(实验室测量和不良事件)。这项研究是在ClinicalTrials.gov注册,NCT01225211数量,和EudraCT,数量2010-020413-90。结果:组1包括64名参与者。 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<0.001) during the combination treatment period in cohort 1. In cohorts 2 and 3, mean sweat chloride concentration did not decrease significantly during combination treatment in any group. Frequency and nature of adverse events were much the same in the treatment and placebo groups during the combination treatment period; the most commonly reported events were respiratory. 12 of 97 participants had chest tightness or dyspnoea during treatment with lumacaftor alone. In pre-planned secondary analyses, a significant decrease in sweat chloride concentration occurred in the treatment groups between day 1 and day 56 (lumacaftor 400 mg once per day group -9.1 mmol/L, p<0.001; lumacaftor 600 mg once per day group -8.9 mmol/L, p<0.001; lumacaftor 400 mg every 12 h group -10.3 mmol/L, p=0.002). These changes were significantly greater than the change in the placebo group. In cohort 2, the lumacaftor 600 mg once per day significantly improved FEV1 from day 1 to 56 (difference compared with placebo group: +5.6 percentage points, p=0.013), primarily during the combination period. In cohort 3, FEV1 did not change significantly across the entire study period compared with placebo (difference +4.2 percentage points, p=0.132), but did during the combination period (difference +7.7 percentage points, p=0.003). Phe508del CFTR heterozygous patients did not have a significant improvement in FEV1. INTERPRETATION: We provide evidence that combination lumacaftor and ivacaftor improves FEV1 for patients with cystic fibrosis who are homozygous for phe508del CFTR, with a modest effect on sweat chloride concentration. These results support the further exploration of combination lumacaftor and ivacaftor as a treatment in this setting. FUNDING: Vertex Pharmaceuticals, Cystic Fibrosis Foundation Therapeutics Development Network.

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药物

Lumacaftor