Efficacy, Safety and Tolerability of the Combination of Tropifexor & Licogliflozin and Each Monotherapy, Compared With Placebo in Adult Patients With NASH and Liver Fibrosis.
- Conditions
- Non Alcoholic Steatohepatitis (NASH)
- Interventions
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 234
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
-
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- 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 (30)
Gut PC Digestive Health Specialist
🇺🇸Dothan, Alabama, United States
Integrity Clinical Rsh LLC
🇺🇸Doral, Florida, United States
Novartis Investigative Site
🇬🇧London, United Kingdom
FDI Clinical Research
🇵🇷San Juan, Puerto Rico
Southern California Research Center
🇺🇸Coronado, California, United States
Velocity Clinical Trials
🇺🇸Los Angeles, California, United States
California Liver Research Institute
🇺🇸Pasadena, California, United States
Galenus Group
🇺🇸Lehigh Acres, Florida, United States
Genoma Research Group Inc
🇺🇸Miami, Florida, United States
Dallas Diabetes and Endocrine Center
🇺🇸Dallas, Texas, United States
Medical Associates Research Group
🇺🇸San Diego, California, United States
San fernando Valley Health Institute
🇺🇸Van Nuys, California, United States
Island View Gastroenterology Associates
🇺🇸Ventura, California, United States
Digestive Res Alliance of Michiana
🇺🇸South Bend, Indiana, United States
Southern Therapy and Adv Res LLC
🇺🇸Jackson, Mississippi, United States
Clinical Research Professionals Inc
🇺🇸Chesterfield, Missouri, United States
Northwell Health
🇺🇸Manhasset, New York, United States
Diabetes And Endocrinology Conslt
🇺🇸Morehead City, North Carolina, United States
Options Health Research
🇺🇸Tulsa, Oklahoma, United States
Texas Clinical Research Institute
🇺🇸Arlington, Texas, United States
American Research Corporation at Texas Liver Institute
🇺🇸San Antonio, Texas, United States
Clinical Trials of Texas
🇺🇸San Antonio, Texas, United States
Endeavor Clinical Trials
🇺🇸San Antonio, Texas, United States
Pioneer Research Solutions
🇺🇸Sugar Land, Texas, United States
Southwest Gastroenterology Associates
🇺🇸Albuquerque, New Mexico, United States
Clinical Trials Of America LLC
🇺🇸Lenoir, North Carolina, United States
Prisma Health
🇺🇸Greenville, South Carolina, United States
Digestive Disease Research
🇺🇸Greenwood, South Carolina, United States
Palmetto Clinical Research
🇺🇸Summerville, South Carolina, United States
Summit Medical Care
🇺🇸Hermitage, Tennessee, United States