E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Biliary Cholangitis and Moderate to Severe Hepatic Impairment |
Colangite biliare primitiva e compromissione epatica da moderata a grave |
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E.1.1.1 | Medical condition in easily understood language |
Primary Biliary Cholangitis and Moderate to Severe Hepatic Impairment |
Colangite biliare primitiva e compromissione epatica da moderata a grave |
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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 | 10032965 |
E.1.2 | Term | Other symptoms involving digestive system |
E.1.2 | System Organ Class | 100000004856 |
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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 |
To evaluate the PK of OCA and its conjugates, glyco-OCA and tauro-OCA, and OCA metabolite glucuronide compared with placebo. To evaluate the safety and tolerability of OCA treatment compared with placebo |
Valutare la farmacocinetica (PK) di OCA e dei suoi coniugati, glico-OCA e tauro-OCA, e il metabolita glucuronide OCA rispetto al placebo. Valutare la sicurezza e la tollerabilità del trattamento con OCA rispetto al placebo |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of OCA treatment compared to placebo on: - The MELD score and its components - CP score and its components - Liver biochemistry including total and direct bilirubin, alkaline phosphatase (ALP), and aminotransferases (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma glutamyl transaminase [GGT]), international normalized ratio (INR), creatinine, albumin, platelets - Biomarkers of bile acid synthesis and homeostasis including fibroblast growth factor 19 (FGF-19), 7a-hydroxy-4-cholesten-3-one (C4), and plasma bile acids |
Valutare l’effetto del trattamento con OCA rispetto al placebo su: - Il modello di punteggio per la malattia epatica allo stadio terminale (MELD) e relativi componenti - Il punteggio di Child-Pugh (CP) e relativi componenti - Biochimica epatica, compresi bilirubina totale e diretta, fosfatasi alcalina (ALP) e aminotransferasi (alanina aminotransferasi [ALT], aspartato aminotransferasi [AST] e gamma-glutamil transaminasi [GGT]), rapporto internazionale normalizzato (INR), creatinina, albumina, piastrine - Biomarcatori della sintesi e dell’omeostasi dell'acido biliare, compresi il fattore di crescita dei fibroblasti 19 (FGF-19), il 7a-idrossi-4-colestene-3-one (C4) e gli acidi biliari plasmatici |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. A definite or probable diagnosis of PBC (consistent with American Association for the Study of Liver Diseases [AASLD] and European Association for the Study of the Liver [EASL] Practice Guidelines, defined as having =2 of the following 3 diagnostic factors: • History of elevated ALP levels for at least 6 months • Positive antimitochondrial antibody (AMA) titer or if AMA negative or low titer (=1:80), PBC specific antibodies (anti-GP210 and/or anti- SP100) and/or antibodies against the major M2 components (PDC E2, 2-oxo-glutaric acid dehydrogenase complex) • Liver biopsy consistent with PBC (collected at any time prior to Screening) 2. Evidence of cirrhosis including at least one of the following: • Biopsy results consistent with PBC Stage 4 • Liver stiffness as assessed by TE Value =16.9kPa • Clinical evidence in the absence of acute liver failure consistent with cirrhosis including: gastroesophageal varices, ascites, radiological evidence of cirrhosis (nodular liver or enlargement of portal vein and splenomegaly) • Combined low platelet count (<140 000/mm3) with - persistent decrease in serum albumin, or - elevation in prothrombin time/INR (not due to antithrombotic agent use), or - elevated bilirubin (2× ULN) 3. Satisfy the criteria of the modified CP classification for hepatic impairment during Screening: • Moderate: CP-B (Scores 7 to 9) or • Severe: CP-C (Scores 10 to12) 4. MELD score of 6 to 24 at Screening 5. Taking UDCA for at least 12 months (stable dose for =3 months) prior to Day 1, or unable to tolerate or unresponsive to UDCA (no UDCA for =3 months) |
1. Diagnosi definita o probabile di PBC (coerente con le linee guida dell’American Association for the Study of Liver Diseases [AASLD] e dell’Associazione europea per lo studio del fegato [EASL, European Association for the Study of the Liver], definita con la presenza di =2 dei 3 fattori diagnostici seguenti: • Anamnesi di livelli ALP elevati per almeno 6 mesi • Titolo positivo dell’anticorpo antimitocondrio (AMA) o, se AMA negativo o basso titolo (=1:80), anticorpi PBC specifici (anti-GP210 e/o anti-SP100) e/o anticorpi contro i principali componenti M2 (PDC-E2, complesso deidrogenasi dell’acido 2-osso-glutarico) • Biopsia epatica coerente con PBC (prelevata in qualsiasi momento prima dello screening) 2. Evidenza di cirrosi, compresa almeno una delle voci seguenti: • Risultati bioptici coerenti con PBC di stadio 4 • Rigidità epatica valutata da un valore TE =16,9 kPa • Evidenza clinica in assenza di insufficienza epatica acuta coerente con la cirrosi, tra cui: varici gastroesofagee, ascite, evidenza radiologica di cirrosi (fegato nodulare o ingrossamento della vena porta e splenomegalia) • Bassa conta piastrinica combinata (<140 000/mm3) con - riduzione persistente dell’albumina sierica o - aumento del tempo di protrombina/INR (non dovuto all’uso di agenti antitrombotici) o - bilirubina elevata (2× ULN) 3. Soddisfacimento dei criteri della classificazione CP modificata per la compromissione epatica durante lo screening: • Moderata: CP-B (punteggi da 7 a 9) o • Grave: CP-C (punteggi da 10 a 12) 4. Punteggio MELD compreso tra 6 e 24 allo screening 5. Assunzione di UDCA per almeno 12 mesi (dose stabile per =3 mesi) prima del Giorno 1, oppure impossibilità a tollerare o non responsivo a UDCA (nessun UDCA per =3 mesi) |
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E.4 | Principal exclusion criteria |
1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6) 2. History of liver transplant or organ transplant 3. History of alcohol or drug abuse within 12 months prior to Screening 4. Current hepatic encephalopathy (as defined by a West Haven score of =2) 5. History or presence of other concomitant liver diseases including: • Hepatitis C virus infection and RNA positive • Active hepatitis B infection; however, patients who have seroconverted (hepatitis B surface antigen and hepatitis B e antigen negative) may be included in this study after consultation with the Medical Monitor • Primary sclerosing cholangitis • Alcoholic liver disease • Definite autoimmune liver disease or overlap hepatitis • Gilbert's Syndrome 6. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function prior to randomization |
1. CP-A non cirrotico o cirrotico (lieve; punteggio da 5 a 6) 2. Anamnesi di trapianto di fegato o di organo 3. Anamnesi di abuso di alcol o droghe entro i 12 mesi precedenti allo screening 4. Encefalopatia epatica in corso (definita da un punteggio di West Haven di =2) 5. Anamnesi o presenza di altre malattie epatiche concomitanti, tra cui: • Infezione da virus dell’epatite C e RNA-positivo • Infezione da epatite B attiva; tuttavia, i pazienti sieroconvertiti (antigene di superficie dell’epatite B e negativi all’antigene dell’epatite B) possono essere inclusi nello studio previo consulto con il supervisore medico • Colangite sclerosante primitiva • Epatopatia alcolica • Epatopatia autoimmune o epatite sovrapposta definita • Sindrome di Gilbert 6. A giudizio dello sperimentatore, funzionalità epatica fluttuante o in rapido deterioramento prima della randomizzazione |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Objective: • To evaluate the pharmacokinetics (PK) of OCA and its conjugates, glyco-OCA and tauro-OCA, and metabolite OCA glucuronide compared with placebo • To evaluate the safety and tolerability of OCA treatment compared with placebo |
Obiettivo primario • Valutare la farmacocinetica (PK) di OCA e dei suoi coniugati, glico-OCA e tauro-OCA, e il metabolita glucuronide OCA rispetto al placebo • Valutare la sicurezza e la tollerabilità del trattamento con OCA rispetto al placebo |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary Objectives: • To evaluate the effect of OCA treatment compared to placebo on: - The model of end stage liver disease (MELD) score and its components - Child-Pugh (CP) score and its components - Liver biochemistry including total and direct bilirubin, alkaline phosphatase (ALP), and aminotransferases (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma glutamyl transaminase [GGT]), international normalized ratio (INR), creatinine, albumin, platelets - Biomarkers of bile acid synthesis and homeostasis including fibroblast growth factor 19 (FGF-19), 7a-hydroxy-4-cholesten-3-one (C4), and plasma bile acids |
Obiettivi secondari: • Valutare l’effetto del trattamento con OCA rispetto al placebo su: - Il modello di punteggio per la malattia epatica allo stadio terminale (MELD) e relativi componenti - Il punteggio di Child-Pugh (CP) e relativi componenti - Biochimica epatica, compresi bilirubina totale e diretta, fosfatasi alcalina (ALP) e aminotransferasi (alanina aminotransferasi [ALT], aspartato aminotransferasi [AST] e gamma-glutamil transaminasi [GGT]), rapporto internazionale normalizzato (INR), creatinina, albumina, piastrine - Biomarcatori della sintesi e dell’omeostasi dell'acido biliare, compresi il fattore di crescita dei fibroblasti 19 (FGF-19), il 7a-idrossi-4-colestene-3-one (C4) e gli acidi biliari plasmatici |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
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
| 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
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 |
Argentina |
Australia |
Brazil |
United States |
Belgium |
Estonia |
Germany |
Hungary |
Italy |
Lithuania |
Spain |
Switzerland |
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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Last Visit of Last Subject |
LVLS |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |