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

Non Alcoholic Steatohepatitis (NASH) Clinical Trial

— ELIVATE  

Official title:

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04065841
• Other study ID #: CLJN452D12201C
• Secondary ID: 2019-002324-32
• Status: Terminated
• Phase: Phase 2
• Start date: December 30, 2019
• Est. completion date: October 27, 2022

Study information

• Verified date: December 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 234
• Est. completion date: October 27, 2022
• Est. primary completion date: October 27, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

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

Related Conditions & MeSH terms

• Fatty Liver
• Liver Cirrhosis
• Non Alcoholic Steatohepatitis (NASH)
• Non-alcoholic Fatty Liver Disease

Intervention

Drug:
• Tropifexor
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
• Licogliflozin
30mg tablet of licoglifozin taken orally every day

Other:
• Placebo
licogliflozin placebo + tropifexor placebo

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Florencio Varela	Buenos Aires
Belgium	Novartis Investigative Site	Mechelen
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Salvador	BA
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Canada	Novartis Investigative Site	Montreal	Quebec
Chile	Novartis Investigative Site	Valdivia	Los Rios
Chile	Novartis Investigative Site	Vina del Mar	Valparaiso
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Medellin	Antioquia
Colombia	Novartis Investigative Site	Rionegro	Antioquia
Denmark	Novartis Investigative Site	Aarhus
Estonia	Novartis Investigative Site	Tallinn
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Mainz
India	Novartis Investigative Site	New Delhi	Delhi
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Padova	PD
Italy	Novartis Investigative Site	Palermo	PA
Italy	Novartis Investigative Site	Rozzano	MI
Japan	Novartis Investigative Site	Izumo-city	Shimane
Japan	Novartis Investigative Site	Saga-city	Saga
Japan	Novartis Investigative Site	Takamatsu city	Kagawa
Japan	Novartis Investigative Site	Yokohama-city	Kanagawa
Korea, Republic of	Novartis Investigative Site	Dongjak Gu	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Mexico	Novartis Investigative Site	Cuauhtemoc	Ciudad De Mexico
Mexico	Novartis Investigative Site	Guadalajara	Jalisco
Mexico	Novartis Investigative Site	Mexico
Mexico	Novartis Investigative Site	Monterrey	Nuevo Leon
Puerto Rico	Novartis Investigative Site	San Juan
Russian Federation	Novartis Investigative Site	Novosibirsk
Russian Federation	Novartis Investigative Site	Samara
Russian Federation	Novartis Investigative Site	St Petersburg
Russian Federation	Novartis Investigative Site	St Petersburg
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
South Africa	Novartis Investigative Site	Cape Town
South Africa	Novartis Investigative Site	Port Elizabeth	Eastern Cape
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Taiwan	Novartis Investigative Site	Kaohsiung
Taiwan	Novartis Investigative Site	Tainan
Turkey	Novartis Investigative Site	Istanbul	Topkapi
United Kingdom	Novartis Investigative Site	Aberdeen
United Kingdom	Novartis Investigative Site	London
United States	Novartis Investigative Site	Albuquerque	New Mexico
United States	Novartis Investigative Site	Arlington	Texas
United States	Novartis Investigative Site	Chesterfield	Missouri
United States	Novartis Investigative Site	Coronado	California
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Doral	Florida
United States	Novartis Investigative Site	Dothan	Alabama
United States	Novartis Investigative Site	Greenville	South Carolina
United States	Novartis Investigative Site	Greenwood	South Carolina
United States	Novartis Investigative Site	Hermitage	Tennessee
United States	Novartis Investigative Site	Jackson	Mississippi
United States	Novartis Investigative Site	Lehigh Acres	Florida
United States	Novartis Investigative Site	Lenoir	North Carolina
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Manhasset	New York
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Morehead City	North Carolina
United States	Novartis Investigative Site	Pasadena	California
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	South Bend	Indiana
United States	Novartis Investigative Site	Sugar Land	Texas
United States	Novartis Investigative Site	Summerville	South Carolina
United States	Novartis Investigative Site	Tulsa	Oklahoma
United States	Novartis Investigative Site	Van Nuys	California
United States	Novartis Investigative Site	Ventura	California

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Brazil,  Bulgaria,  Canada,  Chile,  Colombia,  Denmark,  Estonia,  Germany,  India,  Italy,  Japan,  Korea, Republic of,  Mexico,  Puerto Rico,  Russian Federation,  Singapore,  South Africa,  Spain,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)