Children's Respiratory and Critical Care Specialists, Children's Minnesota, Minneapolis, MN, USA.
Ann and Robert H Lurie Children's Hospital of Chicago and Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Lancet Respir Med. 2019 Apr;7(4):325-335. doi: 10.1016/S2213-2600(18)30460-0. Epub 2019 Jan 24.
The efficacy, safety, and tolerability of lumacaftor and ivacaftor are established in patients aged 6 years and older with cystic fibrosis, homozygous for the F508del-CFTR mutation. We assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of lumacaftor and ivacaftor in children aged 2-5 years.
In this multicentre, phase 3, open-label, two-part study, we enrolled children aged 2-5 years, weighing at least 8 kg at enrolment, with a confirmed diagnosis of cystic fibrosis who were homozygous for the F508del-CFTR mutation. Children received lumacaftor 100 mg and ivacaftor 125 mg (bodyweight <14 kg) or lumacaftor 150 mg and ivacaftor 188 mg (bodyweight ≥14 kg) orally every 12 h for 15 days in part A (to assess pharmacokinetics and safety) and for 24 weeks in part B (to assess safety, pharmacokinetics, pharmacodynamics, and efficacy). Children could participate in part A, part B, or both. Children were enrolled into part A at five sites in the USA and into part B at 20 sites in North America (USA, 17 sites; Canada, three sites). The primary endpoints of the study were the pharmacokinetics (part A) and safety (part B) of lumacaftor and ivacaftor; all analyses were done in children who received at least one dose of lumacaftor and ivacaftor. Secondary endpoints in part A were safety and pharmacokinetics of the metabolites of lumacaftor and ivacaftor, and in part B included pharmacokinetics in children who received at least one dose of lumacaftor and ivacaftor and absolute changes from baseline in sweat chloride concentration, growth parameters, and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02797132.
The study was done from May 13, 2016, to Sept 8, 2017. 12 children enrolled in part A, 11 of whom completed the 15-day treatment period and enrolled in part B. 60 children enrolled in part B, 56 of whom completed the 24-week treatment period. Safety and pharmacokinetics were consistent with the well characterised safety profile of lumacaftor and ivacaftor. In part B, most children (59 [98%] of 60 children) had one or more treatment-emergent adverse events; most events were mild to moderate in severity. The most common adverse events were cough (38 [63%] of 60), vomiting (17 [28%]), pyrexia (17 [28%]), and rhinorrhoea (15 [25%]). Serious adverse events occurred in four children: infective pulmonary exacerbation of cystic fibrosis (n=2), gastroenteritis viral (n=1), and constipation (n=1). Three (5%) of 60 children discontinued treatment because of elevated serum aminotransferase concentrations. Mean sweat chloride concentrations decreased by 31·7 mmol/L, biomarkers of pancreatic function improved (fecal elastase-1 concentrations increased and serum immunoreactive trypsinogen concentrations decreased), and growth parameters increased at week 24.
Lumacaftor and ivacaftor were generally safe and well tolerated in children aged 2-5 years with cystic fibrosis for 24 weeks. Efficacy findings also suggest that early intervention with lumacaftor and ivacaftor has the potential to modify the course of disease.
Vertex Pharmaceuticals Incorporated.
在 6 岁及以上的囊性纤维化纯合子 F508del-CFTR 突变患者中， lumacaftor 和 ivacaftor 的疗效、安全性和耐受性已得到证实。我们评估了 lumacaftor 和 ivacaftor 在 2-5 岁儿童中的安全性、药代动力学、药效学和疗效。
在这项多中心、3 期、开放标签、两部分研究中，我们招募了体重至少为 8 公斤且确诊为囊性纤维化的 2-5 岁儿童，且均为纯合子 F508del-CFTR 突变。儿童每 12 小时口服 lumacaftor 100mg 和 ivacaftor 125mg（体重 <14kg）或 lumacaftor 150mg 和 ivacaftor 188mg（体重≥14kg），在第 1 部分（评估药代动力学和安全性）治疗 15 天，在第 2 部分（评估安全性、药代动力学、药效学和疗效）治疗 24 周。儿童可以参加第 1 部分、第 2 部分或同时参加两部分。儿童在五个美国地点参加第 1 部分，在北美（美国 17 个地点，加拿大 3 个地点）的 20 个地点参加第 2 部分。该研究的主要终点是 lumacaftor 和 ivacaftor 的药代动力学（第 1 部分）和安全性（第 2 部分）；所有分析均在至少接受一次 lumacaftor 和 ivacaftor 治疗的儿童中进行。第 1 部分的次要终点是 lumacaftor 和 ivacaftor 代谢物的安全性和药代动力学，第 2 部分包括至少接受一次 lumacaftor 和 ivacaftor 治疗的儿童的药代动力学，以及从基线绝对变化的汗氯化物浓度、生长参数和胰腺功能标志物。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT02797132。
该研究于 2016 年 5 月 13 日至 2017 年 9 月 8 日进行。12 名儿童参加了第 1 部分，其中 11 名儿童完成了 15 天的治疗期，并参加了第 2 部分。60 名儿童参加了第 2 部分，其中 56 名儿童完成了 24 周的治疗期。安全性和药代动力学与 lumacaftor 和 ivacaftor 的特征性安全性特征一致。在第 2 部分中，大多数儿童（60 名儿童中的 59 名，98%）有一个或多个治疗出现的不良事件；大多数事件的严重程度为轻度至中度。最常见的不良事件是咳嗽（60 名儿童中的 38 名，63%）、呕吐（17 名，28%）、发热（17 名，28%）和鼻漏（15 名，25%）。4 名儿童发生严重不良事件：囊性纤维化感染性肺恶化（n=2）、病毒性胃肠炎（n=1）和便秘（n=1）。由于血清转氨酶浓度升高，3 名（5%）儿童停止治疗。平均汗氯化物浓度降低 31.7mmol/L，胰腺功能的生物标志物改善（粪便弹性蛋白酶-1 浓度增加，血清免疫反应性胰蛋白酶原浓度降低），生长参数在第 24 周增加。
在 24 周内， lumacaftor 和 ivacaftor 在 2-5 岁的囊性纤维化儿童中总体上是安全的，耐受性良好。疗效发现还表明，早期干预 lumacaftor 和 ivacaftor 有可能改变疾病进程。
Vertex 制药公司。
