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Abstract：
OBJECTIVE: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study.
RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings.
CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.
RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings.
CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.
摘要：
目的：Alagille综合征（ALGS）的特征是慢性胆汁淤积伴瘙痒和肝外异常。Maralixibat,回肠胆汁酸转运蛋白抑制剂，是ALGS中首次批准的胆汁淤积性瘙痒的药物治疗。由于长期安慰剂对照研究在患有罕见疾病的儿童中不可行或不符合道德标准，我们采用了一种新方法,将maralixibat试验的6年结局与全球ALagille联盟(GALA)研究的一致和统一的自然历史队列进行比较.
结果：Maralixibat试验包括84例ALGS患者，治疗时间≤6年。GALA包含来自1438名参与者的回顾性数据。对GALA进行了过滤，以符合关键的maralixibat资格标准，产生469名参与者。血清胆汁酸(sBA)不能包括在GALA过滤标准中,因为这些在临床实践中是常规进行的。通过最大似然估计确定指标时间，以使两个队列之间的疾病严重程度与maralixibat的开始保持一致。无事件生存（EFS），定义为门静脉高压症（静脉曲张破裂出血，需要治疗的腹水)，手术胆道改道,肝移植,或死亡，采用Cox比例风险法分析。应用敏感性分析和协变量调整。年龄,总胆红素（TB），γ-谷氨酰转移酶（GGT），谷丙转氨酶(ALT)平衡,组间差异无统计学意义。maralixibat队列中的EFS显著优于GALA队列(风险比0.305;95%CI,0.189-0.491;p<0.0001)。多重敏感性和亚组分析（包括sBA可用性）显示相似的结果。
结论：这项研究展示了一种新的应用，即在安慰剂比较不可行的长期干预研究中，一种可靠的统计方法来评估结果。为罕见疾病提供了广泛的应用。与现实世界自然历史数据的比较表明，maralixibat改善了ALGS患者的EFS。
结果：Maralixibat试验包括84例ALGS患者，治疗时间≤6年。GALA包含来自1438名参与者的回顾性数据。对GALA进行了过滤，以符合关键的maralixibat资格标准，产生469名参与者。血清胆汁酸(sBA)不能包括在GALA过滤标准中,因为这些在临床实践中是常规进行的。通过最大似然估计确定指标时间，以使两个队列之间的疾病严重程度与maralixibat的开始保持一致。无事件生存（EFS），定义为门静脉高压症（静脉曲张破裂出血，需要治疗的腹水)，手术胆道改道,肝移植,或死亡，采用Cox比例风险法分析。应用敏感性分析和协变量调整。年龄,总胆红素（TB），γ-谷氨酰转移酶（GGT），谷丙转氨酶(ALT)平衡,组间差异无统计学意义。maralixibat队列中的EFS显著优于GALA队列(风险比0.305;95%CI,0.189-0.491;p<0.0001)。多重敏感性和亚组分析（包括sBA可用性）显示相似的结果。
结论：这项研究展示了一种新的应用，即在安慰剂比较不可行的长期干预研究中，一种可靠的统计方法来评估结果。为罕见疾病提供了广泛的应用。与现实世界自然历史数据的比较表明，maralixibat改善了ALGS患者的EFS。
