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 |
Colangitis biliar primaria y disfunción hepática moderada o grave |
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E.1.1.1 | Medical condition in easily understood language |
Primary Biliary Cholangitis and Moderate to Severe Hepatic Impairment |
Colangitis biliar primaria y disfunción hepática moderada o grave |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
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 |
Evaluar la FC de OCA y sus conjugados, glyco-OCA y tauro-OCA, y glucurónido de metabolito de OCA en comparación con placebo. Evaluar la seguridad y tolerabilidad del tratamiento con OCA en comparación con 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), 7α-hydroxy-4-cholesten-3-one (C4), and plasma bile acids |
Evaluar el efecto del tratamiento con OCA en comparación con el placebo en: - La puntuación MELD y sus componentes - Puntuación CP y sus componentes - Bioquímica hepática que incluye bilirrubina total y directa, fosfatasa alcalina (ALP) y aminotransferasas (alanina aminotransferasa [ALT], aspartato aminotransferasa [AST] y gamma glutamil transaminasa [GGT]), índice internacional normalizado (INR), creatinina, albúmina, plaquetas - Biomarcadores de la síntesis y homeostasis de los ácidos biliares, incluido el factor de crecimiento fibroblástico 19 (FGF-19), 7α-hidroxi-4-colesten-3-ona (C4) y los ácidos biliares plasmático. |
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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 [Lindor 2009, EASL 2009]), 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 ≥16.9 kPa − 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 to 12) 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. Un diagnóstico claro o probable de CBP (coherente con la Asociación Americana para el Estudio de Enfermedades Hepáticas [AASLD] y las directrices sobre prácticas de la Asociación Europea para el Estudio del Hígado [EASL]), definida como tener ≥ 2 de los siguientes 3 factores de diagnóstico: • Antecedentes de niveles elevados de FA durante al menos 6 meses • Presencia de anticuerpos antimitocondriales positivos (AAM) o si los AAM son negativos o de baja titulación (≤ 1:80), anticuerpos específicos de la CBP (anti-GP210 y/o anti-SP100) y/o anticuerpos contra los principales componentes de M2 (PDC-E2, complejo ácido 2- oxoglutárico deshidrogenasa) • Biopsia hepática compatible con CBP (obtenida en cualquier momento antes de la selección) 2. Evidencia de cirrosis, que incluye al menos uno de los siguientes: • Resultados de la biopsia compatibles con el estadio 4 de la CBP • Rigidez hepática evaluada por un valor de TE ≥ 16,9 kPa • Evidencia clínica en ausencia de insuficiencia hepática aguda compatible con cirrosis, que incluye: varices gastroesofágicas, ascitis, indicios radiológicos de cirrosis (hígado nodular o agrandamiento de la vena porta y esplenomegalia) • Combinación de cifras bajas de plaquetas (< 140 000/mm3) con disminución persistente de la albúmina sérica, o elevación del tiempo de protrombina/INR (no debido al uso de fármacos antitrombóticos), o bilirrubina elevada (2 x LSN) 3. Cumplir los criterios de la clasificación CP modificada para la insuficiencia hepática durante la selección: • Moderado: CP-B (puntuaciones de 7 a 9) o • Grave: CP-C (puntuaciones de 10 a 12) 4. Puntuación MELD de 6 a 24 en la selección 5. Tomar UDCA durante al menos 12 meses (dosis estable durante ≥ 3 meses) antes del día 1 o incapacidad para tolerar o no responder a UDCA (sin UDCA durante ≥ 3 meses) |
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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 cirrótica o no cirrótica (leve; puntuación de 5 a 6) 2. Antecedentes de trasplante de hígado o trasplante de órganos 3. Antecedentes de alcoholismo o toxicomanía en los 12 meses anteriores a la selección. 4. Encefalopatía hepática actual (definida por una puntuación de West Haven ≥ 2) 5. Antecedentes o presencia de otra hepatopatía concomitante como las siguientes: • Infección por el virus de la hepatitis C y positivo para ARN • Infección activa por hepatitis B; sin embargo, los pacientes que han respondido (antígeno de superficie de la hepatitis B y antígeno e de hepatitis C negativo) pueden ser incluidos en este estudio después de consultarlo con el monitor médico. • Colangitis esclerosante primaria • Enfermedad alcohólica del hígado • Enfermedad hepática autoinmunitaria clara o hepatitis superpuesta • Síndrome de Gilbert 6. En opinión del investigador, fluctuaciones o deterioro rápido de la función hepática antes de la aleatorización |
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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 |
Objetivo primario: • Evaluar la farmacocinética (PK) de OCA y sus conjugados, glyco-OCA y tauro-OCA, y metabolito OCA glucurónido en comparación con placebo • Evaluar la seguridad y la tolerabilidad del tratamiento con OCA en comparación con 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) |
• 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), 7α-hydroxy-4-cholesten-3-one (C4), and plasma bile acids |
• Evaluar el efecto del tratamiento con OCA en comparación con el placebo en: - El modelo de puntuación de enfermedad hepática en etapa terminal (MELD) y sus componentes - Puntuación Child-Pugh (CP) y sus componentes - Bioquímica hepática que incluye bilirrubina total y directa, fosfatasa alcalina (ALP) y aminotransferasas (alanina aminotransferasa [ALT], aspartato aminotransferasa [AST] y gamma glutamil transaminasa [GGT]), índice internacional normalizado (INR), creatinina, albúmina, plaquetas - Biomarcadores de la síntesis y homeostasis de los ácidos biliares, incluido el factor de crecimiento fibroblástico 19 (FGF-19), 7α-hidroxi-4-colesten-3-ona (C4) y los ácidos biliares plasmáticos |
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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 | 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 |
Australia |
Brazil |
United States |
Belgium |
Estonia |
Germany |
Hungary |
Italy |
Lithuania |
Spain |
Switzerland |
United Kingdom |
Argentina |
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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 |
Última visita del ultimo 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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 7 |