BACKGROUND Increased rates of respiratory adverse events have been observed in people ≥12 years of age with cystic fibrosis homozygous for the Phe508del-CFTR mutation treated with lumacaftor/ivacaftor, particularly in those with percent predicted forced expiratory volume in 1 s (ppFEV1) of <40%. We evaluated the safety, tolerability, and efficacy of tezacaftor/ivacaftor in people with cystic fibrosis homozygous for Phe508del-CFTR who discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms. METHODS Participants ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV1 of ≥25% and ≤90% were randomized 1:1 and treated with tezacaftor/ivacaftor or placebo for 56 days. RESULTS Of 97 participants, 94 (96.9%) completed the study. The primary endpoint was incidence of predefined respiratory adverse events of special interest (chest discomfort, dyspnea, respiration abnormal, asthma, bronchial hyperreactivity, bronchospasm, and wheezing): tezacaftor/ivacaftor, 14.0%; placebo, 21.3%. The adverse events were mild or moderate in severity. None were serious or led to treatment interruption or discontinuation. Overall, the discontinuation rate was similar between groups. The mean (SD) ppFEV1 at baseline was 44.6% (16.1%) with tezacaftor/ivacaftor and 48.0% (18.1%) with placebo. The posterior mean difference in absolute change in ppFEV1 from baseline to the average value of days 28 and 56 was 2.7 percentage points with tezacaftor/ivacaftor vs placebo. CONCLUSIONS Tezacaftor/ivacaftor was generally safe, well tolerated, and efficacious in people ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV1 of ≥25% and ≤90% who previously discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.

中文翻译：

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Tezacaftor/ivacaftor 用于因呼吸道不良事件而停用 lumacaftor/ivacaftor 的囊性纤维化患者

背景 在接受 lumacaftor/ivacaftor 治疗的 12 岁以上患有 Phe508del-CFTR 突变纯合子囊性纤维化患者中观察到呼吸不良事件的发生率增加，特别是在 1 秒内用力呼气量百分比预测值 (ppFEV1) < 40%。我们评估了 tezacaftor/ivacaftor 在 Phe508del-CFTR 纯合子囊性纤维化患者中的安全性、耐受性和有效性，这些患者因治疗相关的呼吸道症状或体征而停用 lumacaftor/ivacaftor。方法 ≥12 岁的 Phe508del-CFTR 纯合子囊性纤维化参与者，ppFEV1 ≥25% 和≤90%，按 1:1 随机分配，接受 tezacaftor/ivacaftor 或安慰剂治疗 56 天。结果 在 97 名参与者中，94 名 (96.9%) 完成了研究。主要终点是预先定义的特别关注的呼吸道不良事件（胸部不适、呼吸困难、呼吸异常、哮喘、支气管高反应性、支气管痉挛和喘息）的发生率：tezacaftor/ivacaftor，14.0%；安慰剂，21.3%。不良事件的严重程度为轻度或中度。没有一个是严重的或导致治疗中断或中断。总体而言，组间的停药率相似。tezacaftor/ivacaftor 基线时的平均 (SD) ppFEV1 为 44.6% (16.1%)，安慰剂组为 48.0% (18.1%)。与安慰剂相比，tezacaftor/ivacaftor 从基线到第 28 天和第 56 天平均值的 ppFEV1 绝对变化的后验平均差异为 2.7 个百分点。结论 Tezacaftor/ivacaftor 通常是安全的，耐受性良好，