A Randomized, Double-blind, Placebo-controlled, Phase 2/3 Study to Assess the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Obeticholic Acid Compared to Placebo in Pediatric Subjects With Biliary Atresia, Post-hepatoportoenterostomy
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 28
- 试验地点
- 31
- 主要终点
- Time to the First Occurrence of Composite Endpoint
研究概览
简要总结
This study will evaluate the efficacy, safety and tolerability, as well as PK/PD of OCA in eligible pediatric participants with biliary atresia with successful hepatoportoenterostomy (HPE, also known as a Kasai portoenterostomy). The double-blind period comprises of 2 phases: dose titration phase and age expansion treatment phase.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Care Provider)
入排标准
- 年龄范围
- 1 Day 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female pediatric participants from birth to <18 years old. Note: Participants aged <2 years old will not be enrolled until after review of safety data during the planned interim analysis and agreement from the Data Safety Monitoring Board (DSMB) that there is sufficient safety data to enroll this age group.
- •Diagnosis of non-syndromic biliary atresia.
- •Demonstrated successful HPE as defined by total bilirubin <2 milligrams per deciliter (mg/dL) (34.2 micromoles per liter [μmol/L]) at least 3 months post-HPE procedure.
排除标准
- •Prior liver transplant or active status on transplant list.
- •Participants diagnosed with biliary atresia splenic malformation (BASM).
- •Conjugated (direct) bilirubin ≥ upper limit of normal (ULN) of site-specific reference range. If conjugated bilirubin is not available: total bilirubin ≥2 mg/dL (34.2 mol/L).
- •Platelets <120,000/μL
- •International normalized ratio (INR) ≥1.
- •Current or history of complications of decompensated chronic liver disease including:
- •Gastroesophageal varices and/or variceal bleeding
- •Clinically evident ascites related to portal hypertension
- •Hepatic encephalopathy
- •Prior placement of portosystemic shunt
- •Hepatopulmonary syndrome or portopulmonary hypertension
- •Hepatorenal syndrome
- •Any evidence of portal hypertension based on imaging (e.g., cavernous transformation of portal vein, abdominal varices, etc.)
- •Hepatocellular carcinoma
- •Childs-Pugh B or C
- •Height and weight Z-score <-2 per site-specific reference ranges.
- •Acholic (pale) stools.
- •Aspartate aminotransferase (AST) >4x ULN.
- •Alanine aminotransferase >4x ULN
- •GGT >500 Units per Liter (U/L)
- •On anticoagulation therapy
- •Albumin <3.5 grams per deciliter (g/dL).
- •Inability to swallow tablets (i.e., tablet or mini-tablet formulations).
研究组 & 干预措施
Participants receiving OCA
Participants will be randomized to receive OCA (starting at 1.5 milligrams [mg] adult equivalent dose [AED]) orally, with water, once daily. Dose will be titrated every 2 weeks in a stepwise manner for the first 6 weeks, starting at 1.5 mg AED and titrating through 3 mg AED to a maximum of 5 mg AED, as tolerated; a discussion with the Medical Monitor is encouraged when determining uptitration if considerable signs or symptoms have arisen. Following the 6-week dose titration phase, participants will continue at the tolerated dose for approximately 24 months in Age Expansion Treatment Phase.
干预措施: OCA (Drug)
Participants receiving Matching placebo
Participants will be randomized to receive matching placebo orally, with water, once daily. Dose will be titrated every 2 weeks in a stepwise manner for the first 6 weeks, starting at 1.5 mg AED and titrating through 3 mg AED to a maximum of 5 mg AED, as tolerated; a discussion with the Medical Monitor is encouraged when determining uptitration if considerable signs or symptoms have arisen. Following the 6-week dose titration phase, participants will continue at the tolerated dose for approximately 24 months in Age Expansion Treatment Phase.
干预措施: Matching Placebo (Drug)
结局指标
主要结局
Time to the First Occurrence of Composite Endpoint
时间窗: Up to Week 64
To evaluate the effect of OCA compared to placebo in conjunction with established local standard of care on clinical outcomes in participants with biliary atresia who have had a successful Kasai procedure as measured by time to first occurrence of any of the following adjudicated events, derived as composite event endpoint of all-cause death, liver transplant, Pediatric end-stage liver disease (PELD) score ≥17/model of end-stage liver disease (MELD)≥15, Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of Variceal bleed, hepatic encephalopathy (as defined by a West Haven score of ≥2), Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) and Clinically evident ascites related to poral hypertension (diuretic-resistant ascites requiring therapeutic paracentesis at a frequency of at least twice in a month)
Number of Participants With Composite Liver-Related Clinical Events
时间窗: Up to Week 48
Number of participants experiencing any of the following: All-cause death; Liver transplantation; Hospitalization (≥24 hours) for variceal bleeding, hepatic encephalopathy, or spontaneous bacterial peritonitis; Clinically relevant ascites requiring therapeutic paracentesis have been presented. No clinical outcome events were reported at the time of the study termination; hence It was not possible to conduct the planned primary efficacy analysis.
Change From Baseline in Pediatric End-stage Liver Disease (PELD) Score
时间窗: Baseline and up to Week 48
The Pediatric End-stage Liver Disease (PELD) score is a scale used to assess the severity of chronic liver disease in pediatric participants younger than 12 years of age. The total PELD score ranges from negative values to positive values, with no absolute minimum or maximum, with higher scores indicating more severe liver disease and greater urgency for liver transplantation. The score is calculated using total bilirubin, international normalized ratio (INR), albumin, age at listing, and growth failure. Baseline was defined as the last assessment prior to first study drug administration. Change from baseline was calculated as the last post-baseline value minus the baseline value. A negative change from baseline indicates improvement, while a positive change indicates worsening.
Change From Baseline in Model of End-stage Liver Disease With Sodium (MELD-NA) Score
时间窗: Baseline and up to Week 48
The Model of End-stage Liver Disease with Sodium (MELD-Na) score is a scale used to assess the severity of chronic liver disease in participants 12 years of age and older, ranging from 6 (less ill) to 40 (gravely ill). Higher scores indicate more severe liver disease and greater urgency for liver transplantation. The score is derived from total bilirubin, serum creatinine, INR, and serum sodium. Baseline was defined as the last assessment prior to first study drug administration. Change from baseline was calculated as the last post-baseline value minus the baseline value. A negative change from baseline indicates improvement, while a positive change indicates worsening.
次要结局
- Plasma concentration of unconjugated OCA (parent), glyco-OCA, tauro-OCA, and total OCA (molar sum of OCA and its active conjugates)(Up to Week 64)
- Change from Baseline in Gamma Glutamyl Transferase (GGT)(Baseline and up to Week 64)
- Change from Baseline in total and direct (conjugated) bilirubin(Baseline and up to Week 64)
- Change from Baseline in Fibroblast Growth Factor-19 (FGF-19)(Baseline and up to Week 64)
- Change from Baseline in liver stiffness as assessed by transient elastography(Baseline and up to Week 64)
- Safety and tolerability as assessed by the incidence of treatment-emergent adverse events (TEAEs) including serious adverse events (SAEs)(Up to Week 64)
- Change from Baseline in 7-hydroxyl-4-cholesten-3-one (C4)(Baseline and up to Week 64)
- Change from Baseline in endogenous bile acids(Baseline and up to Week 64)
- Change from Baseline in plasma levels of fat-soluble vitamins (D and K)(Baseline and up to Week 64)
- Percentage of Participants With Improvement in GGT and Direct Bilirubin (Composite Responder Endpoint)(Up to Week 48)
- Change From Baseline in GGT(Baseline and up to Week 48)
- Change From Baseline in Total and Direct (Conjugated) Bilirubin(Baseline and up to Week 48)
- Change From Baseline in Endogenous Bile Acids(Baseline and up to Week 48)
- Change From Baseline in Liver Stiffness as Assessed by Transient Elastography(Baseline and up to Week 48)
- Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs(Up to Week 48)
- Change From Baseline in Plasma Levels of Fat-Soluble Vitamin D(Baseline and Week 48)
- Change From Baseline in Plasma Levels of Fat-Soluble Vitamin K(Baseline and Week 48)