E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-alcoholic Steatohepatitis (NASH) |
Steatosi non alcolica |
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E.1.1.1 | Medical condition in easily understood language |
Fatty liver disease not related to alcohol intake |
Malattia del fegato grasso non correlata all'assunzione di alcol |
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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 | 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. |
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. |
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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. |
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. |
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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. |
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. |
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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
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•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 |
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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. |
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. |
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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) |
•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
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•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 |
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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 | 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 |
Combination arm compared to monotherapy arms. Placebo in each treatment arm for blinding purpose |
Combination arm compared to monotherapy arms. Placebo in each treatment arm for blinding purpose |
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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 | 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 | 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 |
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 |
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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 | 3 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |