E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Biliary atresia |
Atresia biliar |
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E.1.1.1 | Medical condition in easily understood language |
A rare disease of the liver and bile ducts that causes the bile to be trapped inside the liver |
Una enfermedad rara del hígado y las vías biliares que hace que la bilis quede atrapada dentro del hígado. |
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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 | 20.0 |
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 | 20.1 |
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 |
- Safety and tolerability - Pharmacokinetics (PK) of OCA and its conjugates o Single dose (SD) PK Phase: To assess the PK of OCA and its conjugates after a single low dose of OCA on Day1 and determine subject eligibility for the Multiple-Dose (MD) Phase o Multiple dose (MD) Phase: To assess the steady-state PK of OCA and its conjugates for a range of OCA doses |
- Seguridad y tolerabilidad - FC del AOC y sus conjugados o Fase para FC de DU: evaluar la FC del AOC y sus conjugados después de una única dosis baja de AOC el día 1 y determinar la idoneidad del sujeto para la fase de DM. o Fase de DM: evaluar la farmacocinética en estado de equilibrio del AOC y sus conjugados para un rango de dosis de AOC. |
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E.2.2 | Secondary objectives of the trial |
- Pharmacodynamics (PD) of OCA as measured by markers of farnesoid X receptor (FXR) activation and biomarkers of hepatobiliary function |
- Farmacodinámica (FD) del AOC determinada por los marcadores de activación del receptor X farnesoide (farnesoid X receptor, FXR) y los biomarcadores de la función hepatobiliar. |
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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 ≥2 to <18 years old 2. Diagnosis of biliary atresia 3. Demonstrated successful HPE (also known as a Kasai portoenterostomy) as defined by total bilirubin <2 mg/dL (34.2 μmol/L) at least 3 months post-HPE procedure. 4. Able to swallow tablets (ie, tablet or mini-tablet formulation)
Please refer to the protocol for the entire list of inclusion criteria. |
1. Sujetos pediátricos de sexo masculino o femenino de ≥ 2 a < 18 años. 2. Diagnóstico de la atresia biliar. 3. HPE satisfactoria demostrada (también conocida como portoenterostomía de Kasai) definida por una bilirrubina total < 2 mg/dl (34,2 μmol/l) al menos 3 meses después del procedimiento de HPE. 4.Capacidad para tragar comprimidos (es decir, formulaciones de comprimidos o minicomprimidos).
Véase lista completa de los criterios de inclusión en el protocolo del estudio. |
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E.4 | Principal exclusion criteria |
1.Prior liver transplant or active status on transplant list 2.Conjugated (direct) bilirubin ≥ULN of site specific reference range 3.If conjugated bilirubin is not available: total bilirubin ≥2 mg/dL (34.2 μmol/L) 4.Platelets <150,000/μL 5.INR ≥1.5 6.Current or history of complications of decompensated chronic liver disease including: a)High-risk gastroesophageal varices and/or varcieal bleeding b)Clinically evident ascites related to portal hypertension c)Hepatic encephalopathy d)Prior placement of portosystemic shunt e)Hepatopulmonary syndrome or portopulmonary hypertension f)Hepatorenal syndrome 7.Current intractable pruritus or those requires systemic treatment for pruritus within 3 months of Screening (eg, with bile acid sequestrants or rifampicin) 8.Height and weight Z-score <-2 per site specific reference ranges 9.Acholic (pale) stools 10.AST >4x ULN 11.ALT > 4X ULN 12.GGT > 500 U/L 13.Anticoagulation therapy 14.Albumin < 3.5 g/Dl 15.Ongoing current cholangitis 16.Choledochal cystic disease 17.Renal disease defined as serum creatinine >ULN for subject's age, prior to enrollment
Please refer to the protocol for the entire list of exclusion criteria. |
1. Trasplante hepático previo o estado activo en lista de trasplantes. 2. Bilirrubina conjugada (directa) ≥ LSN del rango de referencia específico del centro. 3. Si la bilirrubina conjugada no está disponible: bilirrubina total ≥ 2 mg/dl (34,2 μmol/l). 4. Plaquetas < 150 000/µl. 5. INR > 1,5. 6. Complicaciones actuales o antecedentes de enfermedad hepática crónica descompensada, que incluyen: a)varices gastroesofágicas de alto riesgo y/o hemorragia varicosa b)ascitis clínicamente evidente relacionada con hipertensión portal c)encefalopatía hepática d)colocación previa de derivación portosistémica e)síndrome hepatopulmonar o hipertensión portopulmonar f)síndrome hepatorrenal 7)Prurito intratable actual o que requiera tratamiento sistémico para el prurito en los 3 meses anteriores a la selección (por ejemplo, con secuestrantes de ácidos biliares o rifampicina). 8. Puntuación Z de la altura y el peso ≤2 según los rangos de referencia específicos del centro. 9. Heces acólicas (pálidas) 10. AST > 4 veces el LSN 11. ALT > 4 veces el LSN 12. Gammaglutamiltransferasa (GGT) > 500 U/l 13. Terapia anticoagulante 14. Albúmina < 3,5 g/dl
Véase lista completa de los criterios de exclusión en el protocolo del estudio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability - Treatment-emergent adverse events (TEAEs) including serious AEs (SAEs), electrocardiogram (ECG), physical exam, clinical laboratory results, vital signs.
PK - Plasma concentrations of unconjugated OCA, its conjugates (glycine conjugate of OCA [glyco-OCA] and taurine conjugate of OCA [tauro-OCA]) and total OCA in the SD and MD Phases. |
Seguridad y tolerabilidad - AA aparecidos durante el tratamiento (AADT), incluidos AA graves (AAG), electrocardiograma (ECG), exploración física, resultados analíticos, constantes vitales
FC - Concentraciones plasmáticas de AOC no conjugado, sus conjugados (conjugado de glicina de AOC [gluco-AOC] y conjugado de taurina de AOC [tauro-AOC]), y AOC total en las fases de DU y DM |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety and tolerability - TEAEs taken in all visits, from Screening to end of study - ECG taken at screening, day 57, week 4 of follow up (F/U) period, and ET visit. - Physical exam taken at screening, day -1, 7, 21, 28, 42, 56, week 4 of F/U period, and ET visit - Clinical laboratory results at screening, day 1, 2, 7, 21, 35, 42, 56, week 4 of F/U period, and ET visit - Vital signs performed in all visits, from Screening to End of study PK PK sampling on days 1, 2 and 7 in SD phase; day 42, 56 and 57 in MD phase. |
Seguridad y tolerabilidad - AADT realizados en visita de selección, día 57, semana 4 del periodo de seguimiento, y visita de terminación anticipada. - ECG realizados en visita de selección, día 57, semana 4 del periodo de seguimiento, y visita de terminación anticipada. - Examen físico realizado en visita de selección, día -1, 7, 21, 28, 42, 56, semana 4 del periodo de seguimiento, y visita de terminación anticipada. - Resultados de laboratorio clínico en visita de selección, día 1, 2, 7, 21, 35, 42, 56, semana 4 del periodo de seguimiento, y visita de terminación anticipada. - Signos vitales realizados en todas las visitas desde la de selección hasta la de fin de estudio. FC Muestras de FC en los días 1, 2 y 7 en la fase DU; día 42, 56 y 57 en la fase DM. |
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E.5.2 | Secondary end point(s) |
PD: Biomarkers of hepatobiliary function -Alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), total and direct (conjugated) bilirubin, prothrombin time, INR, albumin, platelet count.
PD: Markers of FXR activation -Fibroblast growth factor (FGF-19), 7-hydroxy-4-cholesten-3-one (C4), and endogenous bile acids. |
FD: Biomarcadores de función hepatobiliar - Fosfatasa alcalina (FA), AST, ALT, GGT, bilirrubina total y directa (conjugada), tiempo de protrombina, INR, albúmina, cifra de plaquetas.
FD: Marcadores de activación de FXR -Factor de crecimiento de fibroblastos-19 (FGF-19), 7-hidroxi-4-colesten-3-ona (C4) y ácidos biliares endógenos. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PD: Biomarkers of hepatobiliary function indices -ALP, AST, ALT, GGT, total and direct (conjugated) bilirubin, prothrombin time, INR, albumin, platelet count, taken at screening, day 1, 2, 7, 21, 35, 42, 56, week 4 of F/U period, and ET visit.
PD: Markers of FXR activation -FGF-19, C4, and endogenous bile acids taken at day 1, 56, and ET visit. |
PD: Biomarkers of hepatobiliary function indices -ALP, AST, ALT, GGT, total and direct (conjugated) bilirubin, prothrombin time, INR, albumin, platelet count, taken at screening, day 1, 2, 7, 21, 35, 42, 56, semana 4 del periodo de seguimiento, y visita de terminación anticipada.
FD: Marcadores de activación de FXR -FGF-19, C4 y ácidos biliares endógenos realizados el día 1, 56, y visita de terminación anticipada. |
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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 | No |
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 | No |
E.8.1.1 | Randomised | No |
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 | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
Israel |
France |
Poland |
Netherlands |
Spain |
Germany |
Italy |
Belgium |
United Kingdom |
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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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LVLS |
Última Visita del último paciente |
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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 | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 8 |