Abstract：
BACKGROUND: 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.
METHODS: 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 ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed.
RESULTS: 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 vs 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 vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change -90 μmol/L [95% CI -133 to -48] with odevixibat vs 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 vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs 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.
CONCLUSIONS: 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.
BACKGROUND: Albireo Pharma, an Ipsen company.
METHODS: 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 ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed.
RESULTS: 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 vs 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 vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change -90 μmol/L [95% CI -133 to -48] with odevixibat vs 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 vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs 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.
CONCLUSIONS: 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.
BACKGROUND: Albireo Pharma, an Ipsen company.
摘要：
背景：在Alagille综合征患者中，与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，需要进行肝移植。我们旨在评估回肠胆汁酸转运蛋白抑制剂odevixibat与安慰剂在Alagille综合征患者中的疗效和安全性。
方法：ASSERT研究是第3阶段，双盲，随机化，安慰剂对照试验，在10个国家的21个医疗中心或医院招募患者(比利时，法国,德国,意大利,马来西亚,荷兰,波兰,蒂尔基耶,英国,和美国）。符合条件的患者经基因证实诊断为Alagille综合征，有严重瘙痒的病史，血清胆汁酸升高.患者被随机分配（2：1）接受口服odevixibat每天120μg/kg或安慰剂24周（6个块大小，按年龄分层：<10岁和≥10岁至<18岁）通过基于网络的系统。患者,临床医生,研究人员，分析数据的人被掩盖了治疗分配。主要疗效终点是从基线到第21-24周，护理人员报告的抓挠评分（在PRUCISION仪器上；范围0-4）的变化。预设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周的平均值的变化。在接受至少一剂研究药物的患者中分析结果（疗效结果的完整分析集和安全性结果的安全性分析集）。该试验已在ClinicalTrials.gov（NCT04674761）和EudraCT（2020-004011-28）上注册，并且完成了。
结果：在2021年2月26日至2022年9月9日之间，52名患者被随机分配接受奥德维西巴特（n=35）或安慰剂（n=17），所有这些人都被纳入分析集.中位年龄为5·5岁（IQR3·2至8·9）。52例患者中27例(52%)为男性,25例(48%)为女性。两组基线时的平均刮伤评分均升高（奥德维希巴特为2·8[SD0·5]，安慰剂为3·0[0·6]）。在第21-24周，奥德维希巴特的平均抓挠评分为1·1（0·9），安慰剂的平均抓挠评分为2·2（1·0），代表奥德维西巴特的最小二乘(LS)平均变化为-1·7(95%CI-2·0至-1·3)，安慰剂为-0·8(-1·3至-0·3)，与安慰剂相比，奥德维希巴特的差异显著更大(LS平均从基线-0·9的差异[95%CI-1·4至-0·3];p=0·0024)。与安慰剂相比，Odevixibat的平均血清胆汁酸从基线水平的降低也显着（与安慰剂相比237μmol/L[SD115]与246μmol/L[121]相比）达到第20周和第24周的平均值（149μmol/L[102]与271μmol/L[167]；LS平均变化-90μmol/L[95％CI-133至-48]，安慰剂为47μ最常见的治疗引起的不良事件是腹泻（odevixibat组35例患者中有10例[29%]，安慰剂组17例患者中有1例[6%]）和发热（8例[23%]，4例[24%]）。在治疗期间，有7例患者出现了严重的因治疗引起的不良事件：odevixibat组5例（14％），安慰剂组2例（12％）。没有患者停止治疗，也没有死亡。
结论：Odevixibat可能是一种有效的非手术干预措施，以改善瘙痒，降低血清胆汁酸，并提高Alagille综合征患者的护理水平。Odevixibat在该人群中的长期安全性和有效性数据正在等待，开放标签ASSERT-EXT研究。
背景：AlbireoPharma，Ipsen公司.
方法：ASSERT研究是第3阶段，双盲，随机化，安慰剂对照试验，在10个国家的21个医疗中心或医院招募患者(比利时，法国,德国,意大利,马来西亚,荷兰,波兰,蒂尔基耶,英国,和美国）。符合条件的患者经基因证实诊断为Alagille综合征，有严重瘙痒的病史，血清胆汁酸升高.患者被随机分配（2：1）接受口服odevixibat每天120μg/kg或安慰剂24周（6个块大小，按年龄分层：<10岁和≥10岁至<18岁）通过基于网络的系统。患者,临床医生,研究人员，分析数据的人被掩盖了治疗分配。主要疗效终点是从基线到第21-24周，护理人员报告的抓挠评分（在PRUCISION仪器上；范围0-4）的变化。预设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周的平均值的变化。在接受至少一剂研究药物的患者中分析结果（疗效结果的完整分析集和安全性结果的安全性分析集）。该试验已在ClinicalTrials.gov（NCT04674761）和EudraCT（2020-004011-28）上注册，并且完成了。
结果：在2021年2月26日至2022年9月9日之间，52名患者被随机分配接受奥德维西巴特（n=35）或安慰剂（n=17），所有这些人都被纳入分析集.中位年龄为5·5岁（IQR3·2至8·9）。52例患者中27例(52%)为男性,25例(48%)为女性。两组基线时的平均刮伤评分均升高（奥德维希巴特为2·8[SD0·5]，安慰剂为3·0[0·6]）。在第21-24周，奥德维希巴特的平均抓挠评分为1·1（0·9），安慰剂的平均抓挠评分为2·2（1·0），代表奥德维西巴特的最小二乘(LS)平均变化为-1·7(95%CI-2·0至-1·3)，安慰剂为-0·8(-1·3至-0·3)，与安慰剂相比，奥德维希巴特的差异显著更大(LS平均从基线-0·9的差异[95%CI-1·4至-0·3];p=0·0024)。与安慰剂相比，Odevixibat的平均血清胆汁酸从基线水平的降低也显着（与安慰剂相比237μmol/L[SD115]与246μmol/L[121]相比）达到第20周和第24周的平均值（149μmol/L[102]与271μmol/L[167]；LS平均变化-90μmol/L[95％CI-133至-48]，安慰剂为47μ最常见的治疗引起的不良事件是腹泻（odevixibat组35例患者中有10例[29%]，安慰剂组17例患者中有1例[6%]）和发热（8例[23%]，4例[24%]）。在治疗期间，有7例患者出现了严重的因治疗引起的不良事件：odevixibat组5例（14％），安慰剂组2例（12％）。没有患者停止治疗，也没有死亡。
结论：Odevixibat可能是一种有效的非手术干预措施，以改善瘙痒，降低血清胆汁酸，并提高Alagille综合征患者的护理水平。Odevixibat在该人群中的长期安全性和有效性数据正在等待，开放标签ASSERT-EXT研究。
背景：AlbireoPharma，Ipsen公司.
