Shneider Benjamin L, Spino Cathie, Kamath Binita M, Magee John C, Bass Lee M, Setchell Kenneth D, Miethke Alexander, Molleston Jean P, Mack Cara L, Squires Robert H, Murray Karen F, Loomes Kathleen M, Rosenthal Philip, Karpen Saul J, Leung Daniel H, Guthery Stephen L, Thomas Danny, Sherker Averell H, Sokol Ronald J
Section of Pediatric Gastroenterology, Hepatology, and Nutrition Baylor College of Medicine Houston TX.
School of Public Health University of Michigan Ann Arbor MI.
Hepatol Commun. 2018 Sep 24;2(10):1184-1198. doi: 10.1002/hep4.1244. eCollection 2018 Oct.
Medically refractory, severe, cholestasis-induced pruritus in Alagille syndrome may be improved by surgical interruption of the enterohepatic circulation. This multicenter trial (NCT02057692) tested the hypothesis that the intestinal bile acid transport inhibitor maralixibat would similarly reduce pruritus in Alagille syndrome. Thirty-seven children with Alagille syndrome were randomly assigned to double-blinded administration of placebo, 70, 140, or 280 µg/kg/day of maralixibat for 13 weeks. Pruritus was assessed by caregiver (itch-reported outcome instrument [ItchRO]) and clinician report (range, 0-4 [severe]). Liver chemistries and serum bile acids were measured. The primary outcome was the change from baseline to week 13 in ItchRO relative to placebo. In the first analysis of the primary efficacy endpoint, the mean adjusted difference between participants receiving 140 or 280 µg/kg/day and placebo was -0.47 (95% confidence interval [CI], -1.14, 0.20; 0.16). Statistically significant decreases were observed with doses of 70 and 140 µg/kg/day (mean adjusted difference, -0.89; 95% CI, -1.70, -0.08; 0.032; and mean adjusted difference, -0.91; 95% CI, -1.62, -0.19; 0.014) but not 280 µg/kg/day (mean adjusted difference, -0.04; 95% CI, -0.94, 0.86; 0.44) or all doses combined (mean adjusted difference, -0.61; 95% CI, -1.24, 0.20; 0.055). A 1-point reduction in pruritus was more common in maralixibat-treated versus placebo-treated participants (caregiver ItchRO, 65% versus 25%; 0.06; clinician score, 76% versus 25%; 0.01). There were no significant changes in liver chemistries or bile acids relative to placebo. Adverse and serious adverse events were similar between maralixibat and placebo. Although the prespecified primary analyses of ItchRO were not all statistically significant, the data suggest that maralixibat is safe and may reduce pruritus in Alagille syndrome.
阿拉吉尔综合征中药物难治性、严重的胆汁淤积性瘙痒，可通过肠肝循环的手术阻断得到改善。这项多中心试验（NCT02057692）检验了以下假设：肠道胆汁酸转运抑制剂maralixibat同样能减轻阿拉吉尔综合征中的瘙痒。37名阿拉吉尔综合征患儿被随机分配，接受为期13周的安慰剂、70、140或280μg/kg/天的maralixibat双盲给药。瘙痒由照料者（瘙痒报告结局工具[ItchRO]）和临床医生报告评估（范围为0至4[严重]）。检测了肝功能和血清胆汁酸。主要结局是相对于安慰剂，从基线到第13周ItchRO的变化。在对主要疗效终点的首次分析中，接受140或280μg/kg/天治疗的参与者与接受安慰剂治疗的参与者之间的平均调整差异为-0.47（95%置信区间[CI]，-1.14，0.20；P=0.16）。70和140μg/kg/天剂量组观察到有统计学意义的降低（平均调整差异分别为-0.89；95%CI，-1.70，-0.08；P=0.032；以及平均调整差异为-0.91；95%CI，-1.62，-0.19；P=0.014），但280μg/kg/天剂量组未观察到（平均调整差异为-0.04；95%CI，-0.94，0.86；P=0.44），所有剂量合并组也未观察到（平均调整差异为-0.61；95%CI，-1.24，0.20；P=0.055）。接受maralixibat治疗的参与者瘙痒减轻1分比接受安慰剂治疗的参与者更常见（照料者ItchRO评分，65%对25%；P=0.06；临床医生评分，76%对25%；P=0.01）。相对于安慰剂，肝功能和胆汁酸无显著变化。maralixibat组和安慰剂组的不良事件和严重不良事件相似。虽然对ItchRO预先指定的主要分析并非都具有统计学意义，但数据表明maralixibat是安全的，可能会减轻阿拉吉尔综合征中的瘙痒。
