Christiane Herzog Zentrum Berlin/Charité-Universitätsmedizin Berlin, Berlin, Germany.
Division of Cystic Fibrosis, Department of Pulmonary Medicine, Faculty of Medicine, Universitat Duisburg Essen-Ruhrlandklinik, Essen, Germany.
J Cyst Fibros. 2021 Mar;20(2):228-233. doi: 10.1016/j.jcf.2020.06.001. Epub 2020 Jun 23.
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 (ppFEV) 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.
Participants ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV of ≥25% and ≤90% were randomized 1:1 and treated with tezacaftor/ivacaftor or placebo for 56 days.
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) ppFEV 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 ppFEV from baseline to the average value of days 28 and 56 was 2.7 percentage points with tezacaftor/ivacaftor vs placebo.
Tezacaftor/ivacaftor was generally safe, well tolerated, and efficacious in people ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV of ≥25% and ≤90% who previously discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms.
在患有纯合子 Phe508del-CFTR 突变的囊性纤维化的 12 岁及以上人群中，使用 lumacaftor/ivacaftor 治疗后，观察到呼吸不良事件的发生率增加，特别是在预测用力呼气量百分比（ppFEV）<40%的患者中。我们评估了在因治疗相关呼吸系统症状或体征而停止使用 lumacaftor/ivacaftor 的纯合子 Phe508del-CFTR 囊性纤维化患者中，tezacaftor/ivacaftor 的安全性、耐受性和疗效。
纳入≥12 岁、ppFEV 为≥25%且≤90%的纯合子 Phe508del-CFTR 囊性纤维化患者，按 1:1 随机分组，接受 tezacaftor/ivacaftor 或安慰剂治疗 56 天。
97 例参与者中，94 例（96.9%）完成了研究。主要终点为预先设定的特殊关注的呼吸系统不良事件的发生率（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）：tezacaftor/ivacaftor 组为 14.0%，安慰剂组为 21.3%。这些不良事件的严重程度为轻度或中度。没有严重不良事件，也没有导致治疗中断或停止。总体而言，两组停药率相似。tezacaftor/ivacaftor 组的基线时平均（SD）ppFEV 为 44.6%（16.1%），安慰剂组为 48.0%（18.1%）。tezacaftor/ivacaftor 组与安慰剂组相比，从基线到第 28 天和第 56 天的平均绝对 ppFEV 变化的后验平均差值为 2.7 个百分点。
在 ppFEV 为≥25%且≤90%的因治疗相关呼吸系统症状或体征而停止使用 lumacaftor/ivacaftor 的纯合子 Phe508del-CFTR 囊性纤维化患者中，tezacaftor/ivacaftor 通常是安全的，耐受良好，且有效。
