E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Biliary atresia |
Atresia Biliare |
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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 malattia rara del fegato e dei dotti biliari che blocca la bile all'interno del fegato |
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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 | 20.1 |
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.1.2 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.1.3 | 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 oSingle 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 oMultiple dose (MD) Phase: To assess the steady-state PK of OCA and its conjugates for a range of OCA doses |
• Sicurezza e tollerabilità • PK di OCA e suoi coniugati o Fase SD PK: valutare la farmacocinetica di OCA e dei suoi coniugati dopo una singola dose bassa di OCA il Giorno 1 e determinare l'idoneità del soggetto per la fase MD o Fase MD: valutare la farmacocinetica allo stato stazionario di OCA e dei suoi coniugati per un intervallo di dosi di OCA |
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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 |
• Farmacodinamica (Pharmacodynamics, PD) di OCA misurata in base ai marcatori di attivazione del recettore X del farnesoide (farnesoid X receptor, FXR) e ai biomarcatori della funzione epatobiliare |
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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. Soggetti pediatrici di sesso maschile e femminile di età compresa tra =2 e <18 anni 2. Diagnosi di atresia biliare 3. HPE (o portoenterostomia secondo Kasai) con esito positivo dimostrato come definito da bilirubina totale <2 mg/dl (34,2 µmol/l) almeno 3 mesi dopo la procedura HPE. 4. In grado di deglutire compresse (formulazioni in compresse o mini-compresse) Fare riferimento al protocollo per l'intero elenco dei criteri di inclusione. |
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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. Pregresso trapianto di fegato o stato attivo nell'elenco dei trapianti 2. Bilirubina coniugata (diretta) =ULN dell'intervallo di riferimento specifico del centro 3. Se la bilirubina coniugata non è disponibile: bilirubina totale =2 mg/dl (34,2 µmol/l) 4. Piastrine <150.000/µl 5. INR =1,5 6. Complicanze attuali o pregresse dello scompenso epatico cronico, tra cui: a. varici gastroesofagee ad alto rischio e/o sanguinamento delle varici b. ascite clinicamente evidente correlata a ipertensione portale c. encefalopatia epatica d. precedente posizionamento di shunt portosistemico e. sindrome epatopolmonare o ipertensione portopolmonare f. sindrome epatorenale 7. Prurito intrattabile attuale o necessità di trattamento sistemico per il prurito entro 3 mesi dallo Screening (p. es., con sequestranti degli acidi biliari o rifampicina) 8. Punteggio Z di altezza e peso <-2 secondo gli intervalli di riferimento specifici del centro 9. Feci acoliche (chiare) 10. AST >4 x ULN 11. ALT >4 x ULN 12. Gamma-glutamil transferasi (GGT) >500 U/l 13. Terapia anticoagulante 14. Albumina <3,5 g/dl
Fare riferimento al protocollo per l'intero elenco dei criteri di esclusione. |
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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. |
Sicurezza e tollerabilità: Eventi avversi emergenti dal trattamento (Treatment-emergent adverse event, TEAE) inclusi eventi avversi gravi (serious adverse event, SAE), elettrocardiogramma (ECG), esame obiettivo, risultati clinici di laboratorio, segni vitali
PK Concentrazioni plasmatiche di OCA non coniugato, suoi coniugati (glicina coniugata di OCA [glico-OCA] e taurina coniugata di OCA [tauro-OCA]) e OCA totale nelle fasi SD e MD |
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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. |
Sicurezza e tollerabilità - TEAE presi in tutte le visite, dallo screening alla fine dello studio - ECG eseguito allo screening, giorno 57, settimana 4 del periodo di follow-up (F/U) e visita ET. - Esame fisico sostenuto allo screening, giorno -1, 7, 21, 28, 42, 56, settimana 4 del Periodo F/U e visita ET - Risultati clinici di laboratorio allo screening, giorno 1, 2, 7, 21, 35, 42, 56, settimana 4 del periodo F/U e visita ET - Segni vitali eseguiti in tutte le visite, dallo screening alla fine dello studio
PK Campionamento farmacocinetico nei giorni 1, 2 e 7 in fase SD; giorno 42, 56 e 57 in MD fase. |
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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. |
PD: biomarcatori della funzione epatobiliare -fosfatasi alcalina (ALP), aspartato aminotransferasi (AST), alanina aminotransferasi (ALT), gamma glutamil transferasi (GGT), totale e bilirubina diretta (coniugata), tempo di protrombina, INR, albumina, piastrine contare.
PD: Marcatori di attivazione FXR -Fattore di crescita dei fibroblasti (FGF-19), 7-idrossi-4-colesten-3-one (C4), e acidi biliari endogeni. |
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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: biomarcatori degli indici di funzione epatobiliare -ALP, AST, ALT, GGT, bilirubina totale e diretta (coniugata), protrombina tempo, INR, albumina, conta piastrinica, rilevata allo screening, giorno 1, 2, 7, 21, 35, 42, 56, settimana 4 del periodo F/U e visita ET.
PD: Marcatori di attivazione FXR -FGF-19, C4 e acidi biliari endogeni presi al giorno 1, 56 e visita ET. |
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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 | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
to add "open" due to the open label extension |
to add "open" due to the open label extension |
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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.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 4 |
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 | Information not present in EudraCT |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |