National Jewish Health, 1400 Jackson St., J318, Denver, CO 80206, USA.
Feinberg School of Medicine, Northwestern University, 420 E Superior St., Chicago, IL 60611, USA.
J Cyst Fibros. 2018 Mar;17(2):228-235. doi: 10.1016/j.jcf.2017.09.012. Epub 2017 Nov 8.
Evaluation of the safety, tolerability, and efficacy of lumacaftor/ivacaftor in patients with cystic fibrosis (CF) with severe lung disease.
Patients with CF 12 years of age and older, homozygous for F508del-CFTR, with percent predicted forced expiratory volume in 1 second (ppFEV) <40 received lumacaftor 400 mg/ivacaftor 250mg every 12h (full dose) for 24weeks in an open-label, prospective study (NCT02390219). Dose modification to half dose for 1-2weeks (including at initiation) was permitted. Safety and tolerability were the primary outcome measures; clinical outcomes were also assessed.
Of 46 patients (initiated on full dose: n=28; initiated on half dose: n=18), 35 (76%) completed 24weeks of treatment. The most common adverse events included infective pulmonary exacerbation, abnormal respiration, cough, and dyspnea. Compared with patients initiating on full dose, patients initiating at half dose had less frequent respiratory events (56% vs 71%) of shorter median duration (4 vs 9days). No dose modifications or discontinuations as a result of respiratory events occurred in patients initiating on half dose who were then increased to the full dose over 2weeks (versus three each for patients on full dose). Following an initial reduction, ppFEV was similar to baseline from week 4 throughout the remainder of the study (least squares mean [95% confidence interval] at week 24: -0.4 [-1.9, 1.1]; p=0.6249). Compared with the 24weeks prior to study, the annualized hospitalization rate was lower (rate ratio: 0.41; p=0.00026) and the duration of intravenous antibiotics was shorter (mean [standard deviation] difference: -8.52 [24.91] days; p=0.0369) through study week 24.
Compared with patients with higher lung function, respiratory events were more common in patients with ppFEV<40; aside from these events, the lumacaftor/ivacaftor safety profile was consistent with previous studies. Results suggest that patients with ppFEV<40 may benefit from treatment initiation at a lower dose with augmented monitoring before increasing to the full dose.
评估在伴有严重肺部疾病的囊性纤维化（CF）患者中，使用 lumacaftor/ivacaftor 的安全性、耐受性和疗效。
这项开放标签、前瞻性研究（NCT02390219）纳入了年龄 12 岁及以上、纯合子 F508del-CFTR 突变、第 1 秒用力呼气量预计值（ppFEV）＜40%的 CF 患者，他们接受 lumacaftor 400mg/ivacaftor 250mg 每 12 小时一次（全剂量）治疗 24 周。允许剂量减至半剂量（包括起始时）持续 1-2 周。安全性和耐受性是主要的观察终点；同时评估临床结局。
46 例患者（全剂量起始：n=28；半剂量起始：n=18）中，35 例（76%）完成了 24 周的治疗。最常见的不良事件包括感染性肺部恶化、呼吸异常、咳嗽和呼吸困难。与全剂量起始的患者相比，半剂量起始的患者呼吸事件的发生频率较低（56%比 71%），且中位持续时间较短（4 天比 9 天）。在半剂量起始并在 2 周内增加至全剂量的患者中，没有因呼吸事件而调整剂量或停药（而全剂量起始的患者各有 3 例）。初始降低后，ppFEV 从第 4 周开始直至研究结束时与基线相似（第 24 周的最小二乘均值[95%置信区间]：-0.4[-1.9, 1.1]；p=0.6249）。与研究前 24 周相比，住院率的年化率更低（比率比：0.41；p=0.00026），静脉用抗生素的持续时间更短（平均[标准偏差]差值：-8.52[24.91]天；p=0.0369），直至第 24 周研究结束。
与肺功能较高的患者相比，ppFEV＜40 的患者更常见发生呼吸事件；除了这些事件之外，lumacaftor/ivacaftor 的安全性与之前的研究一致。结果表明，ppFEV＜40 的患者可能受益于起始剂量较低，并在增加至全剂量之前进行强化监测。
