E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
liver condition with abnormal bile flow |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10004653 |
E.1.2 | Term | Biliary atresia |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10004654 |
E.1.2 | Term | Biliary atresia, congenital |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Single-Dose, Multiple-Dose (SD MD) Phase To assess the effects of OCA in eligible pediatric subjects with biliary atresia on: •Safety and tolerability •PK of OCA and its conjugates
Open-Label Extension (OLE) To assess the effects of long-term OCA treatment in eligible pediatric subjects with biliary atresia on: •Long-term safety and tolerability
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E.2.2 | Secondary objectives of the trial |
Single-Dose, Multiple-Dose (SD MD) Phase To assess the effects of OCA in eligible pediatric subjects with biliary atresia on: •Efficacy of OCA as measured by hepatobiliary indices of liver function •PD of OCA as measured by appropriate biomarkers •Exposure-response (PK/PD) and exposure-tolerability relationships
Open-Label Extension (OLE) To assess the effects of long-term OCA treatment in eligible pediatric subjects with biliary atresia on: •Durability of efficacy as measured by hepatobiliary indices of liver function •PK, PD as measured by appropriate biomarkers
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Male or female pediatric subjects, aged <18 years 2.Diagnosis of biliary atresia, with successful HPE (also known as Kasai portoenterostomy) as defined by total bilirubin <2 mg/dL (34.2 μmol/L) at least 3 months post-HPE procedure. 3.Gamma-glutamyl transferase (GGT) ≥2x ULN 4.Able to take medications orally (ie, prior to the availability of the suspension formulation, able to swallow tablet(s) whole) 5.Prior to the availability of the suspension formulation, this study will initially restrict subject enrollment by weight into the 3 OCA dose groups as follows (ie, subjects must meet these restrictions at Screening and Day 0): - Low Dose Group: ≥42 kg - Medium Dose Group: ≥20 kg - High Dose Group: ≥21 kg
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E.4 | Principal exclusion criteria |
Subjects with or experiencing: 1. Prior liver transplant or active status on transplant list 2.Complications of decompensated cirrhosis including: a. Total bilirubin ≥2 mg/dL (34.2 μmol/L) b. Platelets <40,000/µL c. INR ≥2 d. Presence of known or large esophageal varices e. Uncontrolled ascites (diuretic resistant) f. Prior placement of portosystemic shunt g. Diagnosis of hepatopulmonary syndrome or portopulmonary hypertension 3.Current intractable pruritus or those requiring systemic treatment for pruritus within 3 months (eg, with bile acid sequestrants or rifampicin)
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E.5 End points |
E.5.1 | Primary end point(s) |
SAFETY. Adverse events and laboratory values
PK. Plasma concentrations of OCA and its conjugates (glycine 6α-ethyl-chenodeoxycholic acid [glyco-OCA] and taurine 6α-ethyl-chenodeoxycholic acid [tauro-OCA]) after single- and multiple-doses
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
PK sampling on days 1, 2, 7, 42, 63, and 64 in the single dose and multi dose phases.
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E.5.2 | Secondary end point(s) |
EFFICACY. Alkaline phosphatase [ALP], aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transferase [GGT], total and conjugated bilirubin, albumin, and international normalized ratio [INR]).
PD. 7-hydroxy-4-cholesten-3-one [C4], and endogenous bile acids.
PK/PD. Relationship of total OCA exposure to PD parameters, efficacy measures, Child-Pugh Score and adverse events
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
C4 and endogenous bile acids taken on Days 1, 42 and 63.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
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E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |