Efficacy, Safety and Tolerability of the Combination of Tropifexor & Licogliflozin and Each Monotherapy, Compared With Placebo in Adult Patients With NASH and Liver Fibrosis.

Study Overview
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Brief Summary
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Randomized, double-blind, parallel-group, multicenter study to assess efficacy, safety, and tolerability of oral tropifexor & licogliflozin combination therapy and each monotherapy, compared with placebo for treatment of adult patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis.

Detailed Description
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The study consisted of 1) a screening period, 2) a treatment period starting from randomization on Day 0 and running to Week 48, and 3) a follow-up period of 4 weeks after the last dose of study treatment. The study duration from first dose of study medication was 52 weeks.

Official Title
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A Randomized, Double-blind, Parallel-group, Multicenter Study to Assess Efficacy, Safety, and Tolerability of Oral Tropifexor (LJN452) & Licogliflozin (LIK066) Combination Therapy and Each Monotherapy, Compared With Placebo for Treatment of Adult Patients With Nonalcoholic Steatohepatitis (NASH) and Liver Fibrosis.(ELIVATE)

Conditions
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Non Alcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: Tropifexor
* Drug: Licogliflozin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presence of NASH with fibrosis confirmed by central reader's evaluation of liver biopsy obtained no more than 6 months before randomization as demonstrated by the following: NASH using NAFLD Activity Score (NAS) ≥ 4 with at least 1 point each in inflammation and ballooning and Fibrosis stage 2 or 3 using NASH CRN fibrosis criteria Exclusion Criteria: Type 1 diabetes mellitus Uncontrolled type 2 diabetes defined as glycated hemoglobin (HbA1c) ≥ 9.0% 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: Platelet count < LLN (see Central laboratory manual). Serum albumin < LLN (see Central laboratory manual). International Normalized Ratio (INR) > ULN (see Central laboratory manual). ALT or AST > 5× ULN (confirmed by 2 values during screening). Total bilirubin > ULN (see Central laboratory manual) (confirmed by 2 values during screening), including Gilbert's syndrome. Alkaline phosphatase > 300 IU/L (confirmed by 2 values during screening). History of esophageal varices, ascites or hepatic encephalopathy Splenomegaly MELD score >12

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: combination therapy<br>Combination therapy arm: tropifexor 140 mcg capsule + licogliflozin 30 mg tablet, once daily orally | Drug: Tropifexor<br>* 100mcg+30mcg+10mcg capsules of tropifexor taken orally every day until the 140 mcg capsule of tropifexor taken orally every day is produced, then patients will switch to the single 140mcg capsule taken orally every day<br>* Other names: LJN452;Drug: Licogliflozin<br>* 30mg tablet of licoglifozin taken orally every day<br>* Other names: LIK066;|
| Experimental: Arm B: tropifexor monotherapy<br>Tropifexor monotherapy arm: tropifexor 140 mcg capsule (+ placebo matching licogliflozin tablet), once daily orally | Drug: Tropifexor<br>* 100mcg+30mcg+10mcg capsules of tropifexor taken orally every day until the 140 mcg capsule of tropifexor taken orally every day is produced, then patients will switch to the single 140mcg capsule taken orally every day<br>* Other names: LJN452;|
| Experimental: Arm C: licogliflozin monotherapy<br>Licogliflozin monotherapy arm: licogliflozin 30 mg tablet (+ placebo matching tropifexor capsule), once daily orally | Drug: Licogliflozin<br>* 30mg tablet of licoglifozin taken orally every day<br>* Other names: LIK066;|
| Placebo Comparator: Arm D: Placebo<br>Placebo arm: placebo matching tropifexor capsule + placebo matching licogliflozin tablet, once daily | Other: Placebo<br>* licogliflozin placebo + tropifexor placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histological Improvement: Number and Percentage of Participants Who Responded at Week 48 Compared With Baseline | Response was defined as at least a one-stage improvement in fibrosis without worsening of nonalcoholic steatohepatitis (NASH) Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis. | Baseline, Week 48 | 
| Number and Percentage of Participants With Resolution of NASH and no Worsening of Fibrosis | Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Participants Who Achieved Resolution of NASH and no Worsening of Fibrosis OR Improvement in Fibrosis by at Least One Stage Without Worsening of NASH | Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis. | 48 weeks | 
| Number and Percentage of Participants With at Least One Stage Improvement in Fibrosis | Fibrosis staging and Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis. | 48 weeks | 
| Number and Percentage of Participants With at Least Two Stage Improvement in Fibrosis Without Worsening of NASH | Fibrosis staging and Non-alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) based on steatosis, lobular inflammation, and hepatocyte ballooning assessment were determined by a Study Central Reader. NASH CRN fibrosis criteria: Stage 0 = no fibrosis; Stage 1 = centrilobular pericellular fibrosis (or periportal fibrosis in children); Stage 2 = centrilobular and periportal fibrosis; Stage 3 = bridging fibrosis; and Stage 4 = cirrhosis. | 48 weeks | 
| Number and Percentage of Participants Achieving 5% or More Reduction in Body Weight at Week 48 Compared With Baseline | Whether the participants had 5% or more reduction in body weight. | Baseline, Week 48 | 
| Change From Baseline to Week 48 in Percent Liver Fat Content Based on Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI - PDFF) | Change in liver fat content based on MRI-PDFF. | Baseline, Week 48 | 
| Change From Baseline in Alanine Transaminase (ALT) Over Time | To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH. | Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks) | 
| Change From Baseline in Aspartate Aminotransferase (AST) Over Time | To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH. | Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks) | 
| Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time | To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH. | Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Placebo, NASH, Non alcoholic steatohepatitis, Tropifexor, LJN452, Licogliflozin, LIK066