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

Phase 2

Terminated

• Conditions: Non Alcoholic Steatohepatitis (NASH)
• Interventions: Other: Placebo; Drug: Tropifexor; Drug: Licogliflozin

• Registration Number: NCT04065841
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2019-08-19
• Study First Submitted QC: 2019-08-20
• Study First Posted: 2019-08-22
• Study Start: 2019-12-30
• Primary Completion: 2022-10-27
• Study Completion: 2022-10-27
• Results First Submitted: 2023-10-26
• Results First Submitted QC: 2023-12-07
• Results First Posted: 2023-12-26
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-17
• Last Update Posted: 2024-06-20

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 234

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:

1. NASH using NAFLD Activity Score (NAS) ≥ 4 with at least 1 point each in inflammation and ballooning and
2. Fibrosis stage 2 or 3 using NASH CRN fibrosis criteria

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm D: Placebo	Placebo	Placebo arm: placebo matching tropifexor capsule + placebo matching licogliflozin tablet, once daily
Arm A: combination therapy	Licogliflozin	Combination therapy arm: tropifexor 140 mcg capsule + licogliflozin 30 mg tablet, once daily orally
Arm A: combination therapy	Tropifexor	Combination therapy arm: tropifexor 140 mcg capsule + licogliflozin 30 mg tablet, once daily orally
Arm B: tropifexor monotherapy	Tropifexor	Tropifexor monotherapy arm: tropifexor 140 mcg capsule (+ placebo matching licogliflozin tablet), once daily orally
Arm C: licogliflozin monotherapy	Licogliflozin	Licogliflozin monotherapy arm: licogliflozin 30 mg tablet (+ placebo matching tropifexor capsule), once daily orally

Primary Outcome Measures

Name	Time	Method
Number and Percentage of Participants With Resolution of NASH and no Worsening of Fibrosis	48 weeks	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.
Histological Improvement: Number and Percentage of Participants Who Responded at Week 48 Compared With Baseline	Baseline, Week 48	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.

Secondary Outcome Measures

Name	Time	Method
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	48 weeks	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.
Number and Percentage of Participants With at Least Two Stage Improvement in Fibrosis Without Worsening of NASH	48 weeks	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.
Number and Percentage of Participants With at Least One Stage Improvement in Fibrosis	48 weeks	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.
Number and Percentage of Participants Achieving 5% or More Reduction in Body Weight at Week 48 Compared With Baseline	Baseline, Week 48	Whether the participants had 5% or more reduction in body weight.
Change From Baseline to Week 48 in Percent Liver Fat Content Based on Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI - PDFF)	Baseline, Week 48	Change in liver fat content based on MRI-PDFF.
Change From Baseline in Alanine Transaminase (ALT) Over Time	Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks)	To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH.
Change From Baseline in Aspartate Aminotransferase (AST) Over Time	Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks)	To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH.
Change From Baseline in Gamma-glutamyltransferase (GGT) Over Time	Baseline to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, follow-up (up to 62 weeks)	To determine the relationship of investigational treatment and markers of hepatic inflammation in NASH.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇬🇧 London, United Kingdom