Harpavat Sanjiv, Borovsky Kristin A, Scheurer Michael E, Cavallo Laurel, Erhiawarie Franca E, Vasudevan Sanjeev, Vogel Adam M, Cerminara Dana, Tessier Elizabeth M, Patel Kalyani R, Devaraj Sridevi, Shneider Benjamin L
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
Division of Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
Hepatol Commun. 2025 Jun 9;9(7). doi: 10.1097/HC9.0000000000000729. eCollection 2025 Jul 1.
For infants with biliary atresia, the only treatment that can establish bile flow and delay need for liver transplant is the Kasai portoenterostomy (KP). Unfortunately, the KP has variable success. In this study, we hypothesized that intravenous N-acetylcysteine (IV NAC) treatment following KP would improve bile flow.
This was a phase 2 study following the two-stage "minimax" trial design. Participants received IV NAC (150 mg/kg/day) for 7 days after KP, and the primary endpoint was achieving total serum bile acids (TSBA) ≤10 μmol/L within 24 weeks of KP. Secondary endpoints were clinical markers and the occurrence of sentinel events.
There were 12 participants in stage 1 who received treatment, with none achieving TSBAs ≤10 μmol/L within 24 weeks of KP. As a result, no participants were enrolled in stage 2. There were 32 adverse events in 11 participants, including 5 serious adverse events which were considered part of the participants' natural clinical course and not directly attributable to NAC treatment. Analyses of secondary outcomes demonstrated no difference in clinical markers or occurrence of sentinel events between study participants and matched historical controls.
This study demonstrates how the two-stage "minimax" trial design can be used to efficiently evaluate potential therapies for BA. Although the primary endpoint was not met, NAC therapy was generally well-tolerated. NAC therapy may prove efficacious in future trials with (i) a less stringent primary endpoint and/or (ii) a longer course of treatment (NCT03499249).
对于患有胆道闭锁的婴儿，唯一能够建立胆汁流动并延缓肝移植需求的治疗方法是Kasai肝门空肠吻合术（KP）。不幸的是，KP的成功率各不相同。在本研究中，我们假设KP术后静脉注射N-乙酰半胱氨酸（IV NAC）治疗可改善胆汁流动。
这是一项遵循两阶段“最小化-最大化”试验设计的2期研究。参与者在KP术后接受7天的IV NAC（150mg/kg/天）治疗，主要终点是在KP术后24周内实现总血清胆汁酸（TSBA）≤10μmol/L。次要终点是临床指标和哨兵事件的发生情况。
第1阶段有12名参与者接受了治疗，在KP术后24周内无人实现TSBA≤10μmol/L。因此，第2阶段没有参与者入组。11名参与者发生了32起不良事件，包括5起严重不良事件，这些被认为是参与者自然临床病程的一部分，并非直接归因于NAC治疗。次要结果分析表明，研究参与者与匹配的历史对照在临床指标或哨兵事件的发生方面没有差异。
本研究展示了两阶段“最小化-最大化”试验设计如何用于有效评估BA的潜在治疗方法。虽然未达到主要终点，但NAC治疗总体耐受性良好。在未来的试验中，（i）采用不太严格的主要终点和/或（ii）延长治疗疗程（NCT03499249），NAC治疗可能被证明是有效的。
