Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
Lancet Respir Med. 2021 Sep;9(9):977-988. doi: 10.1016/S2213-2600(21)00069-2. Epub 2021 May 6.
A previous phase 3 study showed that lumacaftor-ivacaftor was generally safe and well tolerated over 24 weeks of treatment in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation. In this study, we aimed to assess the long-term safety of lumacaftor-ivacaftor in a rollover study of children who participated in this previous phase 3 study.
In this multicentre, phase 3, open-label, extension study (study 116; VX16-809-116), we assessed safety of lumacaftor-ivacaftor in children included in a previous multicentre, phase 3, open-label study (study 115; VX15-809-115). The study was done at 20 cystic fibrosis care centres in the USA and Canada. Children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation who completed 24 weeks of lumacaftor-ivacaftor treatment in study 115 received weight-based and age-based doses of oral lumacaftor-ivacaftor: children weighing less than 14 kg and aged younger than 6 years at study 116 screening received lumacaftor 100 mg-ivacaftor 125 mg every 12 h; children weighing 14 kg or more and aged younger than 6 years at screening received lumacaftor 150 mg-ivacaftor 188 mg every 12 h; and children aged 6 years or older received lumacaftor 200 mg-ivacaftor 250 mg every 12 h. Children received treatment for up to 96 weeks, equivalent to up to 120 weeks of treatment in total from the start of study 115 to completion of study 116. The primary endpoint was the safety and tolerability of the study drug in all participants who had received lumacaftor-ivacaftor for 24 weeks in study 115 and had received at least one dose in study 116. Secondary endpoints included change from baseline in study 115 at week 96 of study 116 in sweat chloride concentration, growth parameters, markers of pancreatic function, and lung clearance index (LCI) parameters in all children who received at least one dose of lumacaftor-ivacaftor in study 116. This study is registered with ClinicalTrials.gov, NCT03125395.
This extension study ran from May 12, 2017, to July 17, 2019. Of 60 participants enrolled and who received lumacaftor-ivacaftor in study 115, 57 (95%) were included in study 116 and continued to receive the study drug. A total of 47 (82%) of 57 participants completed 96 weeks of treatment. Most participants (56 [98%] of 57) had at least one adverse event during study 116, most of which were mild (19 [33%] participants) or moderate (29 [51%] participants) in severity. The most common adverse events were cough (47 [82%] participants), nasal congestion (25 [44%] participants), pyrexia (23 [40%] participants), rhinorrhoea (18 [32%] participants), and vomiting (17 [30%] participants). A total of 15 (26%) participants had at least one serious adverse event; most were consistent with underlying cystic fibrosis or common childhood illnesses. Respiratory adverse events occurred in five (9%) participants, none of which were serious or led to treatment discontinuation. Elevated aminotransferase concentrations, most of which were mild or moderate in severity, occurred in ten (18%) participants. Three (5%) participants discontinued treatment due to adverse events (two due to increased aminotransferase concentrations [one of whom had concurrent pancreatitis], considered as possibly related to study drug; and one due to gastritis and metabolic acidosis, considered unlikely to be related to study drug). No clinically significant abnormalities or changes were seen in electrocardiograms, vital signs, pulse oximetry, ophthalmological examinations, or spirometry assessments. Improvements in secondary endpoints observed in study 115 were generally maintained up to week 96 of study 116, including improvements in sweat chloride concentration (mean absolute change from study 115 baseline at week 96 of study 116 -29·6 mmol/L [95% CI -33·7 to -25·5]), an increase in growth parameters and pancreatic function, and stable lung function relative to baseline, as measured by the LCI.
Lumacaftor-ivacaftor was generally safe and well tolerated, and treatment effects were generally maintained for the duration of the extension study. These findings support the use of lumacaftor-ivacaftor for up to 120 weeks in young children with cystic fibrosis aged 2 years and older homozygous for the F508del-CFTR mutation.
Vertex Pharmaceuticals Incorporated.
一项先前的 3 期研究表明，在囊性纤维化 2 至 5 岁儿童中，对于纯合子 F508del-CFTR 突变的患者，使用 lumacaftor-ivacaftor 治疗 24 周总体上是安全且耐受良好的。在这项研究中，我们旨在评估 lumacaftor-ivacaftor 在先前 3 期研究中参与的儿童的扩展研究中的长期安全性。
在这项多中心、3 期、开放性标签、扩展研究（研究 116；VX16-809-116）中，我们评估了 lumacaftor-ivacaftor 在先前的多中心、3 期、开放性标签研究（研究 115；VX15-809-115）中纳入的儿童中的安全性。该研究在美国和加拿大的 20 个囊性纤维化护理中心进行。在研究 115 中完成 24 周 lumacaftor-ivacaftor 治疗的囊性纤维化纯合子 F508del-CFTR 突变的 2 至 5 岁儿童，根据体重和年龄接受口服 lumacaftor-ivacaftor 剂量：在研究 116 筛查时体重小于 14 kg 且年龄小于 6 岁的儿童，每 12 小时接受 lumacaftor 100 mg-ivacaftor 125 mg；在筛查时体重为 14 kg 或以上且年龄小于 6 岁的儿童，每 12 小时接受 lumacaftor 150 mg-ivacaftor 188 mg；年龄为 6 岁或以上的儿童，每 12 小时接受 lumacaftor 200 mg-ivacaftor 250 mg。儿童接受治疗最长 96 周，相当于从研究 115 开始至研究 116 完成总共接受 120 周治疗。主要终点是在研究 115 中接受 lumacaftor-ivacaftor 治疗 24 周且在研究 116 中至少接受一剂治疗的所有参与者的研究药物的安全性和耐受性。次要终点包括在研究 116 的第 96 周时，所有至少接受过一剂 lumacaftor-ivacaftor 治疗的儿童的研究 115 的基线时汗氯浓度、生长参数、胰腺功能标志物和肺清除指数（LCI）参数的变化。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT03125395。
这项扩展研究于 2017 年 5 月 12 日至 2019 年 7 月 17 日进行。在入组并在研究 115 中接受 lumacaftor-ivacaftor 治疗的 60 名参与者中，有 57 名（95%）被纳入研究 116 并继续接受研究药物。共有 47 名（82%）参与者完成了 96 周的治疗。大多数参与者（57 名中的 56 名，98%）在研究 116 期间至少发生了一次不良事件，大多数不良事件的严重程度为轻度（33%的参与者）或中度（51%的参与者）。最常见的不良事件是咳嗽（82%的参与者）、鼻塞（44%的参与者）、发热（40%的参与者）、鼻漏（32%的参与者）和呕吐（30%的参与者）。共有 15 名（26%）参与者发生了至少一次严重不良事件；大多数与囊性纤维化或常见儿童疾病一致。发生了 5 例（9%）呼吸不良事件，没有一起严重或导致治疗中断。有 10 名（18%）参与者出现转氨酶浓度升高，大多数为轻度或中度。有 3 名（5%）参与者因不良事件停止治疗（2 名因转氨酶浓度升高[其中 1 名伴有胰腺炎]，认为可能与研究药物有关；1 名因胃炎和代谢性酸中毒，认为可能与研究药物无关）。心电图、生命体征、脉搏血氧饱和度、眼科检查或肺活量测定评估均未出现临床显著异常或改变。在研究 115 中观察到的次要终点的改善在研究 116 的第 96 周时通常得到维持，包括汗氯浓度的改善（从研究 115 的基线到研究 116 的第 96 周的绝对变化-29.6 mmol/L[95%CI-33.7 至-25.5]），生长参数和胰腺功能的增加，以及与基线相比相对稳定的肺功能，这是通过 LCI 来衡量的。
lumacaftor-ivacaftor 总体上是安全且耐受良好的，并且在扩展研究期间治疗效果通常得到维持。这些发现支持在 2 岁及以上纯合子 F508del-CFTR 突变的囊性纤维化儿童中使用 lumacaftor-ivacaftor 治疗长达 120 周。
Vertex 制药公司。
