Seattle Children's Hospital, 4800 Sand Point Way NE, Seattle, WA 98105, USA.
University of Edinburgh Centre for Inflammation Research and NHS Lothian, Edinburgh, UK.
J Cyst Fibros. 2019 Nov;18(6):838-843. doi: 10.1016/j.jcf.2019.03.009. Epub 2019 Apr 30.
KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI.
Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function.
All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters.
Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.
KIWI（NCT01705145）是一项为期 24 周的、单臂、药代动力学、安全性和疗效研究，评估 ivacaftor 在 2 至 5 岁囊性纤维化（CF）和 CFTR 门控突变儿童中的应用。在此，我们报告了 KLIMB（NCT01946412）的研究结果，这是 KIWI 的一项 84 周开放性扩展研究。
儿童根据年龄和体重接受 ivacaftor 剂量治疗，持续 84 周。主要结局为安全性。其他结局包括汗液氯化物、生长参数和胰腺功能测量。
完成 KIWI 的 33 名儿童均入组 KLIMB；28 名儿童完成了 84 周的治疗。大多数不良事件与 KIWI 期间报告的一致。10 名（30%）儿童的转氨酶升高 >3×正常值上限（ULN），导致 1 名丙氨酸氨基转移酶 >8×ULN 的儿童停药。KIWI 期间观察到的汗液氯化物、体重和体重指数 z 评分和粪便弹性蛋白酶-1 的改善在 KLIMB 期间得以维持；这些参数没有进一步改善。
在 2 至 5 岁 CF 伴门控突变儿童中，ivacaftor 治疗长达 108 周通常具有良好的耐受性，安全性与 KIWI 研究一致。在最初 24 周的治疗中，汗液氯化物和生长参数的改善在另外 84 周的治疗中得以维持。在开放性扩展期间，随着暴露时间的延长，转氨酶升高的发生率保持稳定且没有增加。
