| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Biliary Cholangitis |
| Colangitis biliar primaria |
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary Biliary Cholangitis |
| Colangitis biliar primaria |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 | 10036680 |
| E.1.2 | Term | Primary biliary cirrhosis |
| E.1.2 | System Organ Class | 100000023866 |
|
| 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 efficacy of oral GKT137831 in comparison with placebo, in subjects with PBC receiving UDCA and with persistently elevated Alkaline Phosphatase (ALP). |
| Evaluar la eficacia de GKT137831 oral en comparación con placebo en sujetos con CBP tratados con AUDC y con fosfatasa alcalina (FA) persistentemente elevada. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety of oral GKT137831 in comparison with placebo, in subjects with PBC.
- To estimate the population pharmacokinetics (PK) of GKT137831 and explore any potential Pharmacokinetics-Pharmacodynamics (PK-PD) relationships in this subject population.
- To explore any relationship between genetic parameters and therapeutic responses in a subset of subjects. |
- Evaluar la seguridad de GKT137831 oral en comparación con placebo en sujetos con CBP.
- Calcular los parámetros farmacocinéticos (FC) de GKT137831 en la población y analizar cualquier posible relación entre la farmacocinética y la farmacodinámica (FC-FD) en esta población de sujetos.
- Analizar cualquier relación entre los parámetros genéticos y las repuestas terapéuticas en un subgrupo de sujetos. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria:
1. Male or female aged 18 to 80 years, inclusive.
2. Willing and able to give written informed consent and to comply with the requirements of the study.
3. PBC diagnosis as demonstrated by the presence of > or = 2 of the following 3 diagnostic factors:
-History of elevated ALP levels (> ULN) for at least 6 months
-Positive anti-mitochondrial antibody (AMA) titer or if AMA negative or in 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 (based on historic liver biopsy), including non-suppurative, destructive cholangitis affecting mainly the interlobular and septal bile ducts.
4. Serum ALP > or = 1.5 x ULN.
5. Serum GGT > or = 1.5 x ULN.
6. UDCA treatment for at least 6 months and stable dose for at least 3 months prior to Visit 1.
7. Subjects being treated for pruritus with colestyramine must be on a stable dose of colestyramine for at least 8 weeks prior to baseline/Day 1 (Visit 2). Subjects must be willing and able to take colestyramine at least 2 hours before or after study medication.
8. Female subjects of childbearing potential must use a highly effective method of contraception to prevent pregnancy for 4 weeks before randomization and must agree to continue strict contraception for 90 days after last administration of investigational medicinal product (IMP). Male participants with female partners of childbearing potential must be willing to use a condom and require their partner to use an additional form of adequate contraception as approved by the Investigator. This requirement begins at the time of informed consent and ends 90 days after the last administration of IMP. Male study participants must also not donate sperm from baseline until 90 days after the last administration of IMP. |
Criterios de inclusión:
1. Hombre o mujer de entre 18 y 80 años de edad, ambos incluidos.
2. Dispuesto y capaz de otorgar consentimiento informado escrito y de respetar las obligaciones del estudio.
3. Diagnóstico de CBP demostrado mediante la presencia de al menos dos de los tres factores de diagnóstico siguientes:
- Historial de niveles de FA elevados (superiores al LSN) durante al menos 6 meses.
- Nivel de anticuerpos antimicondriales (AMA) positivo o, en caso de que sea negativo o bajo (<1:80), anticuerpos específicos de CBP (anti-GP210 y/o anti-SP100 y/o anticuerpos contra los principales componentes M2 [PDC-E2, complejo ácido 2-oxoglutárico deshidrogenasa]).
- Biopsia hepática consistente con CBP (según historial de biopsias hepáticas), incluyendo colangitis destructiva no supurativa que afecte principalmente a los conductos biliares interlobulares y septales.
4. FA en suero > o = 1,5 veces el LSN.
5. GGT en suero > o = 1,5 veces el LSN.
6. Tratamiento con AUDC durante al menos 6 meses y dosis estable durante al menos 3 meses antes de la visita 1.
7. Los sujetos tratados de pruritos con colestiramina deberán mantener una dosis estable de colestiramina durante al menos 8 semanas antes de la visita inicial/día 1 (visita 2). Los sujetos deberán estar dispuestos a tomar colestiramina al menos 2 horas antes o después de la medicación del estudio.
8. Las participantes mujeres en edad fértil deberán utilizar métodos anticonceptivos altamente eficaces para evitar el embarazo durante 4 semanas antes de la aleatorización y deberán aceptar continuar con el uso estricto de anticonceptivos durante 90 días tras la última administración del producto médico en fase de investigación (PMI). Los participantes masculinos con parejas que sean mujeres en edad fértil deberán estar dispuestos a utilizar preservativos e instar a su pareja a utilizar un método adicional de anticoncepción adecuado y aprobado por el Investigador. Este requisito entrará en vigor desde el momento en que se entregue el consentimiento informado y finalizará 90 días después de la última administración del PMI. Asimismo, los hombres que participen en el estudio no deberán donar semen desde la visita inicial y hasta pasados 90 días tras la última administración del PMI. |
|
| E.4 | Principal exclusion criteria |
1. A positive pregnancy test or breast-feeding for female subjects.
2. Any hepatic decompensation, defined as a past or current history of hepatic encephalopathy, gastrointestinal tract bleeding due to esophageal varices, or ascites
3. International normalized ratio (INR) > 1.2 unless subject is on anticoagulant therapy.
4. ALT > 3 x ULN.
5. Total bilirubin > 1 x ULN.
6. Planned or current plasmapheresis or other extra-corporeal treatments (e.g., molecular adsorbent recirculation system (MARS)) for treatment-refractory pruritus.
7. History of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score > or = 15.
8. Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma.
9. Hepatorenal syndrome (type I or II) or Screening serum creatinine > ULN
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7. Subjects being treated for pruritus with colestyramine must be on a
stable dose of colestyramine for at least 8 weeks prior to baseline/Day 1
(Visit 2). Subjects must be willing and able to take colestyramine at
least 2 hours before or after study medication.
8. Female subjects of childbearing potential must use a highly effective
method of contraception to prevent pregnancy for 4 weeks before
randomization and must agree to continue strict contraception for up to
90 days after last administration of investigational medicinal product
(IMP). Male participants with female partners of childbearing potential
must be willing to use a condom and require their partner to use an
additional form of adequate contraception as approved by the
Investigator. This requirement begins at the time of informed consent
and ends 90 days after the last administration of IMP. Male study
participants must also not donate sperm from baseline until 90 days
after the last administration of IMP.
E.4 PRINCIPAL EXCLUSION CRITERIA (list the most important)
English 1. A positive pregnancy test or breast-feeding for female subjects.
2. Any hepatic decompensation, defined as a past or current history of
hepatic encephalopathy, gastrointestinal tract bleeding due to
esophageal varices, or ascites
3. International normalized ratio (INR) > 1.2 unless subject is on
anticoagulant therapy.
4. ALT > 3 x ULN.
5. Total bilirubin > 1 x ULN.
6. Planned or current plasmapheresis or other extra-corporeal
treatments (e.g., molecular adsorbent recirculation system (MARS)) for
treatment-refractory pruritus.
7. History of liver transplantation, current placement on a liver
transplant list or current Model for End Stage Liver Disease (MELD) score
≥ 15.
8. Cirrhosis with complications, including history or presence of:
spontaneous bacterial peritonitis, hepatocellular carcinoma.
9. Hepatorenal syndrome (type I or II) or Screening serum creatinine >
ULN.
10. Competing etiology for liver disease (e.g., hepatitis C, active
hepatitis B, non-alcoholic steatohepatitis (NASH), alcoholic liver disease
(ALD), autoimmune hepatitis, primary sclerosing cholangitis, Gilbert's
Syndrome).
11. Subjects receiving prohibited medications within 3 months of
Screening (Visit 1) according to the list (a, b and c) provided in Section
6.6.2.
12. Treatment with any investigational agent within 4 weeks of Visit 1 or
5 half-lives of the investigational medicinal product (whichever is
longer).
13. A history of long QT syndrome.
14. Evidence of any of the following cardiac conduction abnormalities
during the screening period:
- A QTc Fredericia interval >450 milliseconds for males and >470
milliseconds for females.
- A second or third degree atrioventricular block not successfully treated
with a pacemaker.
15. History of cancer in the preceding 5 years, except adequately treated
non-melanoma skin cancer, carcinoma in situ of the cervix, in situ
prostate cancer, in situ breast ductal carcinoma, or superficial bladder
cancer stage 0).
16. The occurrence of any acute infection requiring systemic antibiotic therapy within the 2 weeks prior the Screening Visit (Visit 1), or human
immunodeficiency virus (HIV) infection.
17. A history of bone marrow disorder including aplastic anemia, or
marked anemia defined as hemoglobin < 10.0 g/dL (or 6.2 mmol/L).
18. Any condition which, in the opinion of the Investigator, constitutes a
risk or contraindication for the participation of the subject in the study,
or which could interfere with the study objectives, conduct, or
evaluation. |
1. Para las mujeres, prueba de embarazo positiva o lactancia.
2. Cualquier descompensación hepática, definida como un historial anterior o actual de encefalopatía hepática, sangrado gastrointestinal debido a varices esofágicas o ascitis.
3. Índice internacional normalizado (IIN) >1,2 salvo que el sujeto esté en tratamiento anticoagulante.
4. ALT >3 veces el LSN.
5. Bilirrubina total >1 vez el LSN.
6. Plasmaféresis planificada o actual, u otros tratamientos extracorpóreos (por ejemplo, el sistema de recirculación molecular absorbente [MARS]) para el prurito resistente al tratamiento.
7. Historial de trasplante hepático, inclusión actual en una lista de trasplante hepático o puntuación actual > o = 15 en la escala MELD (modelo de enfermedad hepática terminal).
8. Cirrosis con complicaciones, incluyendo historial o presencia de: peritonitis bacteriana espontánea y carcinoma hepatocelular.
9. Síndrome hepatorrenal (tipo I o II) o creatinina en suero en la selección >LSN.
10. Etiología conflictiva con la enfermedad hepática (por ejemplo, hepatitis C, hepatitis B activa, esteatosis hepática no alcohólica [EHNA], hepatopatía alcohólica [HPA], hepatitis autoinmune, colangitis esclerosante primaria o síndrome de Gilbert).
11. Los sujetos que reciban medicamentos prohibidos a menos de 3 meses de la selección (visita 1) según la lista (a, b y c) provista en la sección 6.6.2.
12. Tratamiento con cualquier agente en investigación a menos de 4 semanas de la visita 1 o a 5 períodos de la semivida del producto médico en investigación (lo que sea mayor).
13. Historial de síndrome de QT largo.
14. Evidencia de cualquiera de las siguientes anomalías en la conducción cardíaca durante el período de selección:
• Un intervalo QTc de Fredericia de >450 milisegundos para los hombres y >470 milisegundos para las mujeres.
• Un bloqueo atrioventricular de segundo o tercer grado tratado sin éxito con un marcapasos.
15. Historial de cáncer en los 5 años anteriores, excepto cáncer de piel distinto al melanoma correctamente tratado, carcinoma in situ del cuello uterino, cáncer de próstata in situ, carcinoma ductal in situ de mama o cáncer superficial de vejiga en estadio 0.
16. La aparición de cualquier infección aguda que requiera tratamiento con antibióticos sistémicos en las dos semanas anteriores a la visita de selección (visita 1) o infección por virus de inmunodeficiencia humana (VIH).
17. Historial de trastorno de la médula ósea, incluyendo anemia aplásica o anemia marcada, definida como hemoglobina <10,0 g/dl (o 6,2 mmol/l).
18. Cualquier afección que, en opinión del Investigador, suponga un riesgo o una contraindicación para la participación del sujeto en el estudio o que pueda interferir en los objetivos, la realización o la evaluación del estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary:
- the percent change from baseline to Week 24 (Visit 7) in serum GGT. |
Primary:
- El cambio porcentual entre la visita basal y la semana 24 (visita 7) de la GGT en suero |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The percent change from baseline to Week 24 (Visit 7) in serum GGT.
Serum GGT will be assessed during every treatment visit. (visit's 2-7) |
| El cambio porcentual entre la visita basal y la semana 24 (visita 7) de la GGT en suero. Los niveles séricos de GGT se evaluarán en cada visita de tratamiento (visitas 2 a 7) |
|
| E.5.2 | Secondary end point(s) |
- Absolute and percent change in serum GGT from baseline to each assessment.
- Absolute change in Enhanced Liver Fibrosis (ELF) score from baseline to Weeks 12 and 24.
- Absolute and percent change in serum levels of highsensitivity C-reactive protein (hsCRP) and fibrinogen from baseline to each
assessment.
- Absolute and percent change in serum Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and conjugated and total bilirubin, from baseline to each assessment.
- Absolute and percent change in serum Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), conjugated and total bilirubin, and Cytokeratin-18 (CK-18), from baseline to each assessment.
- Absolute and percent change in the Fibrosis-4 (FIB-4) and AST to Platelet Ratio Index (APRI) scores, from baseline to each assessment (FIB-4: age (years) x AST (IU/L)/(platelet count (109/L) x (ALT (IU/L)1/2, APRI: AST (IU/L)/ upper normal limit AST)x100/platelet count (10E9/L).
- Absolute and percent change in liver stiffness as assessed by transient elastography (FibroScan or similar technology), from baseline to Week 24, in patients with values at baseline and Week 24.
- Absolute and percent change in serum levels of collagen fragments indicative of collagen formation and degradation from baseline to Weeks 12 and 24.
-Absolute and percent change in total bile acids from baseline to Week 12 and 24. |
- El cambio porcentual y absoluto de la GGT en suero entre la visita basal y cada evaluación.
- El cambio absoluto de los resultados de fibrosis hepática mejorada (FHM) entre la visita basal y las semanas 12 y 24.
- El cambio porcentual y absoluto de la FA en suero entre la visita basal y cada evaluación.
- El cambio porcentual y absoluto de los niveles en suero de proteína C reactiva de alta sensibilidad (PCR-as) y fibrinógeno entre la visita basal y cada evaluación.
- El cambio porcentual y absoluto de los niveles en suero de alanina aminotransferasa (ALT), aspartato aminotransferasa (AST), bilirrubina conjugada y total entre la visita basal y cada evaluación.
- El cambio porcentual y absoluto de los resultados de fibrosis-4 (FIB-4) y del índice de la relación AST/plaquetas (APRI) entre la visita basal y cada evaluación (FIB-4: edad [años] x AST [IU/l]/(recuento plaquetario [109/l] x ALT [IU/l]1/2), APRI: (AST [IU/l]/límite normal superior AST)x100/recuento plaquetario [10E9/l].
- El cambio porcentual y absoluto de la rigidez hepática evaluada mediante elastografía transitoria (FibroScan o tecnología similar) entre la visita basal y la semana 24 en pacientes con valores en la visita basal y la semana 24.
- El cambio porcentual absoluto de los niveles en suero de fragmentos de colágeno, que indiquen la formación y degradación de colágeno entre la visita basal y las semanas 12 y 24.
- El cambio porcentual y absoluto en el total de ácidos biliares entre la visita basal y las semanas 12 y 24. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints of the secondary endpoints are included within the secondary objective endpoints section E.5.2 (above)
Most secondary assessments will be assessed from baseline to each visit however the ELF score and collagen fragments will be assessed from baseline to week 12 and week 24.
The change in liver stiffness (FibroScan or similar technology) will be assessed from baseline to week 24. |
los puntos temporales de evaluación de los criterios de valoración secundarios se mencionan en la sección anterior
La mayoría de las evaluaciones secundarias se evaluarán desde basal en cada visita. Sin embargo, el indicador de fibrosis hepática mejorada (FHM) y los fragmentos de colágeno se evaluarán desde la visita basal hasta la semana 12 y semana 24
El cambio en la elastografía transitoria (FibroScan o tecnología similar) se evaluará desde basal hasta la semana 24 |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| Belgium |
| Canada |
| Germany |
| Greece |
| Israel |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| LVLS |
| Última visita del Último paciente |
|
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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