In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 μg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0–4) from baseline to weeks 21–24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on () and EudraCT (2020-004011-28), and is completed. Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat 3·0 [0·6] for placebo). Mean scratching scores at weeks 21–24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of –1·7 (95% CI –2·0 to –1·3) for odevixibat and –0·8 (–1·3 to –0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline –0·9 [95% CI –1·4 to –0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 μmol/L [SD 115] with odevixibat 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] 271 μmol/L [167]; LS mean change –90 μmol/L [95% CI –133 to –48] with odevixibat 22 μmol/L [–35 to 80] with placebo; difference in LS mean change –113 μmol/L [95% CI –179 to –47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group one [6%] of 17 in the placebo group) and pyrexia (eight [23%] four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. Albireo Pharma, an Ipsen company.

中文翻译：

---

odevixibat 对 Alagille 综合征患者的疗效和安全性 (ASSERT)：一项 3 期、双盲、随机、安慰剂对照试验


在阿拉吉勒综合征患者中，胆汁淤积相关的临床特征可能包括高血清胆汁酸和严重瘙痒，可能需要进行肝移植。我们的目的是评估回肠胆汁酸转运蛋白抑制剂 odevixibat 与安慰剂相比对 Alagille 综合征患者的疗效和安全性。 ASSERT 研究是一项双盲、随机、安慰剂对照 3 期试验，招募了 10 个国家（比利时、法国、德国、意大利、马来西亚、荷兰、波兰、土耳其、英国）21 个医疗中心或医院的患者和美国）。符合条件的患者具有阿拉吉尔综合征的基因诊断、明显瘙痒病史和血清胆汁酸升高。患者被随机分配 (2:1) 接受每日口服 odevixibat 120 μg/kg 或安慰剂治疗 24 周（以 6 为一组，按年龄分层：<10 岁和 ≥10 岁至 <18 岁）基于网络的系统。患者、临床医生、研究人员和数据分析人员对治疗分配情况不知情。主要疗效终点是护理人员报告的抓挠评分（PRUCISION 仪器；范围 0-4）从基线到第 21-24 周的变化。预先指定的关键次要疗效终点是血清胆汁酸浓度从基线到第 20 周和第 24 周平均值的变化。对接受至少一剂研究药物的患者进行结果分析（疗效结果的完整分析集和安全性分析）为安全结果而设置）。该试验在()和EudraCT (2020-004011-28)上注册，并已完成。 2021年2月26日至2022年9月9日期间，52名患者被随机分配接受odevixibat（n = 35）或安慰剂（n = 17），所有这些患者都包含在分析组中。 中位年龄为 5·5 岁（IQR 3·2 至 8·9）。 52 名患者中有 27 名（52%）为男性，25 名（48%）为女性。两组的平均抓挠评分在基线时均有所升高（odevixibat 为 2·8 [SD 0·5]，安慰剂为 3·0 [0·6]）。第 21-24 周时，odevixibat 的平均抓挠评分为 1·1 (0·9)，安慰剂为 2·2 (1·0)，代表最小二乘 (LS) 平均变化为 –1·7 (95% CI) odevixibat 为 –2·0 至 –1·3)，安慰剂为 –0·8 (–1·3 至 –0·3)，odevixibat 显着高于安慰剂（LS 平均变化与基线的差异 –0 ·9 [95% CI –1·4 至 –0·3]；p=0·0024)。与安慰剂相比，Odevixibat 还导致平均血清胆汁酸从基线（237 μmol/L [SD 115]，odevixibat 246 μmol/L [121]，安慰剂）显着降低至第 20 周和第 24 周的平均值（149 μmol/L） [102] 271 μmol/L [167]；与安慰剂相比，LS 平均变化为 –90 μmol/L [95% CI –133 至 –48]；与安慰剂相比，LS 平均变化为 22 μmol/L [–35 至 80]； 113 μmol/L [95% CI –179 至 –47]；p=0·0012)。最常见的治疗中出现的不良事件是腹泻（odevixibat 组 35 名患者中有 10 名患者 [29%]，安慰剂组 17 名患者中有 1 名患者 [6%]）和发热（8 名患者 [23%] 4 名患者 [24%]）。 7 名患者在治疗期间出现严重的治疗相关不良事件：odevixibat 组有 5 名患者（14%），安慰剂组有 2 名患者（12%）。没有患者停止治疗，也没有死亡病例。 Odevixibat 可能是一种有效的非手术干预措施，可改善 Alagille 综合征患者的瘙痒、降低血清胆汁酸并提高护理标准。正在进行的开放标签 ASSERT-EXT 研究正在等待 odevixibat 在该人群中的长期安全性和有效性数据。 Albireo Pharma，Ipsen 旗下公司。