Non-alcoholic Steatohepatitis (NASH) MedDRA version: 20.1 Level: PT Classification code 10053219 Term: Non-alcoholic steatohepatitis System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Interventions
Product Name: LJN452
Product Code: LJN452
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Not available yet
Current Sponsor code: LJN452
Other descriptive name: LJN452
Concentration unit: µg m
Sponsors
Novartis Pharma Services AG
Eligibility
Sex/Gender
All
Inclusion criteria
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) Diagnosis of NASH: Parts A&B: 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, (i.e. fibrosis in the absence of established cirrhosis) no diagnosis of alternative chronic liver diseases Part C (All patients): Adequate liver biopsy sample for evaluation by Central Reader to confirm Histologic evidence of NASH based on liver biopsy obtained during the Screening period or within 6 months before randomization with a diagnosis consistent with NASH, fibrosis level F2 or F3, and no diagnosis of alternative chronic liver diseases. Permitted therapy must be stable as outlined in Table 5-5 (from 1 month prior to biopsy up to and including screening) AND (all parts) ALT = 43 IU/L (males) or = 28 IU/L (females) OR (for Parts A and B only) Phenotypic diagnosis of NASH based on presence of ALL THREE of the following: o ALT = 43 IU/L (males) or = 28 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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 190 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 155
Exclusion criteria
Exclusion criteria: Previous exposure to an FXR agonist including tropifexor 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the study is to determine safety and tolerability of different doses of tropifexor by monitoring adverse events. Moreover, the study will determine the dose-response relationship of tropifexor on markers of hepatic inflammation in NASH by changes in ALT and AST from baseline to Week 12 The study will also determine the dose-response relationship of tropifexor on liver fat content by changes from baseline to week 12 in quantitative MRI determined fat;Secondary Objective: Effect of different doses of tropifexor on weight, BMI, waist-to-hip (WTH) ratio) To determine the dose-response relationship of tropifexor on - markers of target engagement - liver fibrosis markers - GGT - fasting lipid profile - PK of tropifexor - Effect of tropifexor vs PBO regarding occurrence of potential itch based on a visual analog scale (VAS) - Effects of LJN452 on primary endpoints in the subset of patients with historical biopsy data, both overall and by subsets defined by fibrosis score and/or NAS score as feasible Additional Secondary Endpoints for Part C: - safety / tolerability of different doses of tropifexor by monitoring AEs. - dose-response relationship of tropifexor on markers of hepatic inflammation in NASH (baseline to wk 48). - dose-response relationship of tropifexor on liver fat content (MRI) baseline to wk 48 - efficacy of tropifexor in NASH and F2/F3 fibrosis as assessed by histological improvement from baseline to wk 48 vs PBO;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 - Relative change from baseline to Week 12 in percentage of fat in the liver assessed using MRI;Timepoint(s) of evaluation of this end point: 12 weeks of treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 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 At least a one point improvement of fibrosis stage without worsening of steatohepatitis at Week 48 compared to baseline Proportion of patients who have at least a two point improvement in fibrosis without worsening of steatohepatitis at Week 48 compared to baseline Resolution of steatohepatitis without worsening of fibrosis stage at Week 48 compared to baseline Change of NAS from baseline to Week 48 Absolute and relative change from baseline to Week 48 in percentage of fat in the liver assessed using MRI Change from baseline to Week 48 of ALT and AST;Timepoint(s) of evaluation of this end point: 12 respectively 48 weeks of treatment | — |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Italy, Korea, Republic of, Netherlands, Singapore, Slovakia, Spain, Taiwan, United States
Contacts
Public ContactDRA information desk
Novartis Slovakia s.r.o.
Outcome results
None listed