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Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: The international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF).

Ataluren 治疗无义突变囊性纤维化患者的疗效和安全性: 国际,随机,双盲, 囊性纤维化的安慰剂对照 Ataluren 确证试验 (ACT CF)。

  • 影响因子:2.88
  • DOI:10.1016/j.jcf.2020.01.007
  • 作者列表:"Konstan MW","VanDevanter DR","Rowe SM","Wilschanski M","Kerem E","Sermet-Gaudelus I","DiMango E","Melotti P","McIntosh J","De Boeck K","ACT CF Study Group.
  • 发表时间:2020-01-23
Abstract

BACKGROUND:Ataluren was developed for potential treatment of nonsense-mutation cystic fibrosis (CF). A previous phase 3 ataluren study failed to meet its primary efficacy endpoint, but post-hoc analyses suggested that aminoglycosides may have interfered with ataluren's action. Thus, this subsequent trial (NCT02139306) was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation CF not receiving aminoglycosides. METHODS:Eligible subjects with nonsense-mutation CF (aged ≥6 years; percent predicted (pp) FEV1 ≥40 and ≤90) from 75 sites in 16 countries were randomly assigned in double-blinded fashion to receive oral ataluren or matching placebo thrice daily for 48 weeks. The primary endpoint was absolute change in average ppFEV1 from baseline to the average of Weeks 40 and 48. FINDINGS:279 subjects were enrolled; 138 subjects in the ataluren arm and 136 in the placebo arm were evaluable for efficacy. Absolute ppFEV1 change from baseline did not differ significantly between the ataluren and placebo groups at Week 40 (-0.8 vs -1.8) or Week 48 (-1.7 vs -2.4). Average ppFEV1 treatment difference from baseline to Weeks 40 and 48 was 0.6 (95% CI -1.3, 2.5; p = 0.54). Pulmonary exacerbation rate per 48 weeks was not significantly different (ataluren 0.95 vs placebo 1.13; rate ratio p = 0.40). Safety was similar between groups. No life-threatening adverse events or deaths were reported. INTERPRETATION:Neither ppFEV1 change nor pulmonary exacerbation rate over 48 weeks were statistically different between ataluren and placebo groups. Development of a nonsense-mutation CF therapy remains elusive.

摘要

背景: Ataluren 被开发用于无义突变囊性纤维化 (CF) 的潜在治疗。之前的 3 期 ataluren 研究未能达到其主要疗效终点,但事后分析表明氨基糖苷类可能干扰了 ataluren 的作用。因此,该后续试验 (NCT02139306) 旨在评估 ataluren 在无义突变 CF 未接受氨基糖苷类药物的患者中的疗效和安全性。 方法: 无义突变 CF (年龄 ≥ 6 岁; 预计百分比 (pp) FEV1 ≥ 40 且 ≤ 90) 的合格受试者从 16 个国家的 75 个地点以双盲方式随机分配接受口服 ataluren 或匹配安慰剂,每天 3 次,共 48 周。主要终点是从基线到第 40 周和第 48 周平均 ppFEV1 的绝对变化。 结果: 入组 279 例受试者; ataluren 组 138 例受试者和安慰剂组 136 例受试者可评价疗效。在 40 周 (-0.8 vs-1.8) 或 48 周 (-1.7 vs-2.4),ataluren 和安慰剂组与基线相比的绝对 ppFEV1 变化没有显著差异。从基线到 40 周和 48 周的平均 ppFEV1 治疗差异为 0.6 (95% CI-1.3,2.5; p = 0.54)。每 48 周肺恶化率无显著差异 (ataluren 0.95 vs 安慰剂 1.13; 率比 p = 0.40)。组间安全性相似。未报告危及生命的不良事件或死亡。 解读: 48 周 ppFEV1 变化和肺部恶化率在 ataluren 组和安慰剂组之间均无统计学差异。无义突变 CF 治疗的发展仍然难以捉摸。

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翻译标题与摘要 下载文献
影响因子:4.40
发表时间:2020-01-01
DOI:10.1007/s00262-019-02431-8
作者列表:["Shibaki, Ryota","Murakami, Shuji","Matsumoto, Yuji","Yoshida, Tatsuya","Goto, Yasushi","Kanda, Shintaro","Horinouchi, Hidehito","Fujiwara, Yutaka","Yamamoto, Nobuyuki","Kusumoto, Masahiko","Yamamoto, Noboru","Ohe, Yuichiro"]

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影响因子:4.04
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作者列表:["Sousa SA","Soares-Castro P","Seixas AMM","Feliciano JR","Balugas B","Barreto C","Pereira L","Santos PM","Leitão JH"]

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