E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-alcoholic Steatohepatitis (NASH) |
|
E.1.1.1 | Medical condition in easily understood language |
Fatty liver disease not related to alcohol intake |
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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 | 19.0 |
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 |
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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 determine safety and tolerability of different doses of LJN452 by monitoring adverse events up to the end of the study.
Moreover, the study will determine the dose-response relationship of LJN452 on markers of hepatic inflammation in NASH by changes in ALT and AST from baseline to Week 12 |
|
E.2.2 | Secondary objectives of the trial |
To determine the dose-response relationship of LJN452 on liver fat content by quantitative MRI
To determine the effect of different doses of LJN452 on weight, BMI, waist-to-hip (WTH) ratio) after 12 weeks of treatment
To determine the dose-response relationship of LJN452 on markers of target engagement
To determine the dose-response relationship of LJN452 on markers of liver fibrosis
To determine the dose-response relationship of LJN452 on GGT, a cholestasis marker
To determine the effect of LJN452 on fasting lipid profile
To determine the pharmacokinetics of LJN452
To determine the effect of LJN452 compared to placebo with respect to occurrence of potential itch based on a visual analog scale (VAS) rating scale
To determine effects of LJN452 on primary endpoints in the subset of patients who have historical biopsy data, both overall and by subsets defined by fibrosis score and/or NAS score as feasible (based on extent of available data) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Written informed consent must be obtained before any assessment is performed
Male and female patients 18 years or older (at the time of the screening visit)
Presence of NASH as demonstrated by ONE of the following:
- Histologic evidence of NASH based on liver biopsy obtained 2 years or less before randomization with a diagnosis consistent with NASH, fibrosis level F1, F2 or F3, no diagnosis of alternative chronic liver diseases
AND
ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females)
OR
Phenotypic diagnosis of NASH based on presence of ALL THREE of the following:
o ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females) AND
o BMI ≥ 27 kg/m2 (in patients with a self-identified race other than Asian) or ≥23 kg/m2 (in patients with a self-identified Asian race)
AND
o Diagnosis of Type 2 diabetes mellitus by having either:
- HbA1C ≥ 6.5% or
- Drug therapy for Type 2 diabetes mellitus
Liver fat ≥ 10% at screening as determined by the central MRI laboratory
Patients must weigh at least 40 kg (88 lb) and no more than 150 kg (330 lb) to participate in the study |
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E.4 | Principal exclusion criteria |
Previous exposure to obeticholic acid (OCA)
Patients taking medications prohibited by the protocol
Pregnant or nursing (lactating) women
Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening (significant alcohol consumption is defined as more than 20 g/day in females and more than 30 g/day in males, on average) and/or a score on the AUDIT questionnaire ≥8
Uncontrolled diabetes defined as HbA1c ≥ 9.5% within 60 days prior to enrollment
Presence of cirrhosis on liver biopsy or clinical diagnosis
Clinical evidence of hepatic decompensation or severe liver impairment
Previous diagnosis of other forms of chronic liver disease
Patients with contraindications to MRI imaging |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Safety (to be assessed in the SAF):
- Occurrence of SAE
- Occurrence of AE resulting in permanent discontinuation or dose reduction of study treatment
- Occurrence of AE of special interest
Efficacy (to be assessed in the FAS):
- Change from baseline to Week 12 in ALT
- Change from baseline to Week 12 in AST |
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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) |
Relative change from baseline to Week 12 in percentage of fat in the liver assessed using MRI
Absolute change from baseline to Week 12 in percentage of fat in the liver assessed using MRI
Weight, BMI, waist-to-hip (WTH) ratio
FGF19, C4
Liver stiffness (in kPa) by Fibroscan®, enhanced liver fibrosis panel (ELF) score, and score of fibrosis biomarker test (originally known as Fibrotest®/ FibroSure®)
GGT
Fasting lipids (total cholesterol, trigylcerides, LDL and HDL cholesterol, free glycerol, free fatty acids)
Itch VAS |
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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 | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 29 |
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 |
Austria |
Belgium |
Canada |
France |
Germany |
Italy |
Korea, Republic of |
Netherlands |
Slovakia |
Spain |
Taiwan |
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
|
Last Visit Last Patient Last Site (LPLVLS) |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 3 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 3 |