| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-alcoholic Steatohepatitis (NASH) |
| Esteatohepatitis no alcohólica (EHNA) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Fatty liver disease not related to alcohol intake |
| Enfermedad del hígado graso no relacionada con la ingesta de alcohol. |
|
| 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 | 22.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10053219 |
| E.1.2 | Term | Non-alcoholic steatohepatitis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to demonstrate the efficacy of tropifexor + licogliflozin as assessed by histologic improvement after 48 weeks of combination treatment compared to each mono treatment in patients with NASH and stage 2 or 3 fibrosis. |
| El objetivo principal del estudio es demostrar la eficacia de tropifexor y licogliflozina según la evaluación de la mejoría histológica después de 48 semanas del tratamiento de combinación frente a cada uno de ellos en monoterapia en pacientes con EHNA y fibrosis en estadio 2 o 3. |
|
| E.2.2 | Secondary objectives of the trial |
Improvement in fibrosis by at least one stage with no worsening of NASH after 48 weeks of treatment.
Resolution of NASH with no worsening of fibrosis after 48 weeks of treatment.
Improvement in fibrosis by at least one stage.
Improvement in fibrosis by at least two stages with no worsening of NASH after 48 weeks treatment.
Reduction in body weight from baseline after 48 weeks of treatment.
Change in liver fat content after 48 weeks of treatment.
To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH (ALT and AST).
To determine the relationship of investigational treatment and GGT, a marker of cholestasis and oxidative stress.
To evaluate the safety and tolerability of tropifexor in combination with licogliflozin, compared to monotherapy of each compound. |
Mejoría de al menos un estadio de la fibrosis, sin empeoramiento de la EHNA después de 48 semanas de tratamiento.
Resolución de la EHNA sin empeoramiento de la fibrosis después de 48 semanas de tratamiento.
Mejora de al menos un estadio de la fibrosis.
Mejora de al menos dos estadios de la fibrosis, sin empeoramiento de la EHNA después de 48 semanas de tratamiento.
Disminución del peso corporal respecto a la basal después de 48 semanas de tratamiento.
Cambio en el contenido de grasa en el hígado después de 48 semanas de tratamiento.
Determinar la relación del tratamiento en investigación y los marcadores de inflamación hepática en EHNA (ALT y AST).
Determinar la relación del tratamiento en investigación y la GGT, un marcador de colestasis y estrés oxidativo.
Evaluar la seguridad y tolerabilidad de tropifexor en combinación con licogliflozina, en comparación con respectivas monoterapias. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Presence of NASH as demonstrated by the following: NASH with fibrosis stage 2 or 3 confirmed by central reader's evaluation using NAFLD Activity Score (NAS) and NASH CRN criteria, of liver biopsy obtained no more than 6 months before randomization. |
| Presencia de EHNA demostrada por los siguientes:EHNA con fibrosis en estadio 2 o 3 confirmada mediante la evaluación de un lector central, según la puntuación de la actividad de EHGNA (NAS) y los criterios de EHNA de la CRN, de biopsia hepática obtenida menos de 6 meses antes de la aleatorización. |
|
| E.4 | Principal exclusion criteria |
•Type 1 diabetes mellitus
•Uncontrolled type 2 diabetes defined as glycated hemoglobin (HbA1c) ≥ 9.5% at screening
•HbA1c < 6.5% at screening in Type 2 diabetics currently treated with insulin or sulfonylureas
•Clinical evidence of liver impairment as defined by the presence of any of the following abnormalities:
◦Abnormal platelet count
◦Serum albumin < 3.2g/dL
◦International Normalized Radio (INR) > 1.3
◦ALT or AST > 5xULN
◦Total bilirubin >1.3 mg/dL (22 µmol/L) (including Gilbert's syndrome)
◦Alkaline phosphatase > 300 IU/L
◦History of esophageal varices, ascites or hepatic encephalopathy
◦Splenomegaly |
•Diabetes mellitus de tipo 1.
•Diabetes tipo 2 no controlada definida como hemoglobina glicosilada
(HbA1c) >/=9,5 % en la selección.
•HbA1c <6,5 % en la selección en diabéticos tipo 2 tratados actualmente con
insulina o sulfonilureas.
•Signos clínicos de deterioro hepático definido por la presencia de cualquiera de las anomalías siguientes:
◦Recuento anómalo de plaquetas
◦Albúmina sérica <3,2 g/dl.
◦Índice internacional normalizado (INR) >1,3.
◦ALT o AST >5 x LSN.
◦Bilirrubina total >1,3 mg/dl (22 μmol/l) (incluyendo el síndrome de Gilbert).
◦Fosfatasa alcalina >300 × UI/L.
◦Antecedentes de varices esofágicas, ascitis o encefalopatía hepática.
◦Esplenomegalia. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of patients with resolution of NASH and no worsening of fibrosis OR improvement in fibrosis by at least one stage without worsening of NASH at Week 48 compared with baseline.
To demonstrate the efficacy of tropifexor + licogliflozin as assessed by histologic improvement after 48 weeks of combination treatment compared to each monotherapy treatment in patients with NASH and stage 2 or 3 fibrosis. |
Proporción de pacientes con resolución de la EHNA y sin empeoramiento de la fibrosis o mejora de la fibrosis en al menos un grado sin empeoramiento de la EHNA en la semana 48 comparado con la basal.
Demostrar la eficacia de la combinación de tropifexor+licogliflozina evaluada según la mejora histológica después de 48 semanas de tratamiento comparado con cada tratamiento en monoterapia en pacientes con EHNA y fibrosis de grado 2 o 3 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
•Proportion of patients who have at least one stage improvement in fibrosis without worsening of NASH at Week 48 compared with baseline
•Proportion of patients with resolution of NASH and no worsening of fibrosis at Week 48 compared with baseline
•Proportion of patients who have at least one stage improvement in fibrosis at Week 48 compared with baseline
•Proportion of patients who have at least two stage improvement in fibrosis without worsening of NASH at Week 48 compared with baseline
•Proportion of patients with 5% or more reduction in body weight at Week 48 compared to baseline
•Change in liver fat content based on MRI - PDFF (in 60% of patients) over time up to Week 48 compared with baseline
•Change in ALT and AST over time up to Week 48 compared with baseline
To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH (ALT and AST)
•Change in GGT over time up to Week 48 compared with baseline
To determine the relationship of investigational treatment and GGT, a marker of cholestasis and oxidative stress
•Number of participants with adverse events
To evaluate the safety and tolerability of tropifexor (LJN452) in combination with licogliflozin (LIK066), compared to monotherapy of each compound from baseline |
•Proporción de pacientes que presentan una mejora de al menos un grado de fibrosis sin empeoramiento de la EHNA en semana 48 comparado con la basal.
•Proporción de pacientes con resolución de la EHNA y sin empeoramiento de la fibrosis en semana 48 comparado con la basal.
•Proporción de pacientes que presentan una mejora de al menos un grado de fibrosis en la semana 48 comparado con la basal.
•Proporción de pacientes que presentan una mejora de al menos dos grados de fibrosis sin empeoramiento de la EHNA en semana 48 comparado con la basal.
•Proporción de pacientes con una reducción del 5% o más de su peso corporal en semana 48 comparado con la basal.
•Cambio en el contenido de grasa hepática basado en la RMN-PDFF (en el 60% de los pacientes) a lo largo del tiempo hasta semana 48 comparado con la basal
•Cambio en la ALT y la AST a lo largo del tiempo hasta semana 48 comparado con la basal.Determinar la relación del tratamiento en investigación y los marcadores de inflamación hepáticos en EHNA (ALT y AST)
•Cambio en la GGT a lo largo del tiempo hasta semana 48 comparado con la basal.Determinar la relación del tratamiento en investigación y la GGT, un marcador de colestasis y estrés oxidativo.
•Número de participantes con efectos adversos.
Evaluar la seguridad y tolerabilidad de tropifexor (LJN452) en combinación con licogliflozina (LIK066), comparado con la monoterapia de cada componente desde la basal. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Brazo de combinación comparado con los brazos en monoterapia. Placebo en cada brazo de tratamiento p |
| Combination arm compared to monotherapy arms. Placebo in each treatment arm for blinding purpose |
|
| 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 | 3 |
| 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 |
| Argentina |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| China |
| Colombia |
| Denmark |
| Egypt |
| Estonia |
| France |
| Germany |
| India |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Saudi Arabia |
| Singapore |
| South Africa |
| Spain |
| Taiwan |
| Turkey |
| 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
|
| LPLV |
| Último paciente última visita |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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 |
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