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.

中文翻译：

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ataluren 对未接受长期吸入氨基糖苷类药物的无义突变囊性纤维化患者的疗效和安全性：国际、随机、双盲、安慰剂对照 Ataluren 囊性纤维化确认试验 (ACT CF)

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药物可能干扰了 ataluren 的作用。因此，随后的试验 (NCT02139306) 旨在评估 ataluren 对于未接受氨基糖苷类治疗的无义突变 CF 患者的疗效和安全性。方法 来自 16 个国家 75 个地点的符合条件的无义突变 CF 受试者（年龄≥6 岁；预测百分比 (pp) FEV1 ≥40 且≤90）以双盲方式随机分配，每天三次接受口服 ataluren 或匹配安慰剂治疗。 48 周。主要终点是平均 ppFEV1 从基线到第 40 周和第 48 周平均值的绝对变化。 结果 纳入了 279 名受试者；研究结果 ataluren 组中的 138 名受试者和安慰剂组中的 136 名受试者进行了疗效评估。在第 40 周（-0.8 与 -1.8）或第 48 周（-1.7 与 -2.4）时，ataluren 组和安慰剂组之间相对于基线的绝对 ppFEV1 变化没有显着差异。从基线到第 40 周和第 48 周的平均 ppFEV1 治疗差异为 0.6（95% CI -1.3，2.5；p = 0.54）。每 48 周的肺部恶化率没有显着差异（ataluren 0.95 对比安慰剂 1.13；比率 p = 0.40）。各组之间的安全性相似。没有危及生命的不良事件或死亡的报道。解释 ataluren 组和安慰剂组之间 48 周内 ppFEV1 变化和肺部恶化率均无统计学差异。无义突变 CF 疗法的开发仍然难以捉摸。