Study of TVB 2640 in Subjects With Non-Alcoholic Steatohepatitis (NASH)

Study Overview
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Brief Summary
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This is a Phase 2 multi-center, randomized, single-blind, placebo-controlled study to evaluate the safety and efficacy of TVB-2640 in subjects with non-alcoholic steatohepatitis (NASH), a type of fatty liver disease. Subjects will be randomly assigned to 1 of 2 treatment groups (TVB- 2640 at one of three doses or placebo). Following randomization, subjects will begin the 12-week treatment period and will receive once daily TVB-2640 or placebo.

Official Title
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A Phase 2, Multi-Center, Single-Blind, Randomized, Placebo-Controlled Study of TVB 2640 in Subjects With Non-Alcoholic Steatohepatitis (FASCINATE-1)

Conditions
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Non-Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: TVB-2640
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥ 18 years with a body mass index (BMI) ≤40 kg/m2. Prior liver biopsy within 24 months of randomization with fibrosis Stage 1 to 3 and a non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of ≥ 4 with at least a score of 1 in each of the following NAS components: Steatosis Ballooning degeneration Lobular inflammation AND Confirmation of ≥ 8% liver fat content on MRI-PDFF. OR, if prior biopsy is not available: Either overweight or obese or diabetic or ALT ≥ 30 U/L or fatty liver on ultrasound and at least one more feature of metabolic syndrome by Adult Treatment Panel III (ATP III) criteria. AND Magnetic resonance elastography (MRE) ≥ 2.5 kPa and MRI-PDFF ≥ 8% during screening. Exclusion Criteria: Subjects meeting any of the following criteria are not eligible for enrollment in the study. History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening. Note: Significant alcohol consumption is defined as average of > 20 g/day in female subjects and > 30 g/day in male subjects. Type 1 diabetes. Uncontrolled Type 2 diabetes defined as: HbA1c ≥ 9.5% during screening. (Subjects with HbA1c ≥ 9.5% may be rescreened). Basal insulin dose adjustment > 10% within 60 days prior to enrollment. Requirement for glucagon-like peptide analogue or a complex oral anti-diabetic (OAD) regimen (3 or more OADs) within 6 months of screening. History of severe hypoglycemia (symptomatic hypoglycemia requiring outside assistance to regain normal neurologic status) within the previous year. Note: Individual diabetes regimens will be reviewed by Investigator and may be adjusted based on American Diabetes Association guidelines. Presence of cirrhosis on liver biopsy (Stage 4 fibrosis) or imaging.

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
Interventional Model Description: Subjects will be randomly assigned to experimental or placebo arms.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TVB-2640<br>Subjects randomly assigned to receive the study drug will take TVB-2640 tablet orally every day for 12 week treatment period. The dose is to be taken at the same time of the day, with each dose separated by 24 hours (±4 hours). | Drug: TVB-2640<br>* Oral dose, tablet, daily dosing<br>|
| Placebo Comparator: Placebo<br>Subjects randomly assigned to placebo will receive placebo tablets orally once a day under the same conditions and frequency as described for TVB-2640. | Other: Placebo<br>* Oral dose, tablet, daily dosing<br>|
| Experimental: Cross over to TVB-2640<br>At Catalina Research Institute, a subset of subjects who received placebo in the single-blind Cohorts 1 and 2 at that site will be recruited to an open label cross over Cohort 3 where they will receive the study drug (TVB-2640 tablet) orally every day for 12-week treatment period. Additional patients from outside the pool of previous placebo subjects may be needed to meet the enrollment target. | Drug: TVB-2640<br>* Oral dose, tablet, daily dosing<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of TVB-2640 versus placebo on the change in hepatic fat fraction from baseline in subjects with NASH by proton-density fat fraction by magnetic resonance imaging. | Proton-density Fat Fraction by Magnetic Resonance Imaging | 12 weeks | 
| The safety of TVB-2640 versus placebo in subjects with NASH, including changes in liver enzymes by monitoring adverse events. |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of TVB-2640 versus placebo on the change in triglycerides from baseline in subjects with NASH. |  | 12 weeks | 
| The effect of TVB-2640 versus placebo on the change in low-density lipoprotein cholesterol (LDL-C) from baseline in subjects with NASH. |  | 12 weeks | 
| The effect of TVB-2640 versus placebo on the change in high-density lipoprotein cholesterol (HDL-C) from baseline in subjects with NASH. |  | 12 weeks | 
| The effect of TVB-2640 versus placebo on the change in total cholesterol from baseline in subjects with NASH. |  | 12 weeks | 
| The effect of TVB-2640 versus placebo on the change in NASH and cytokeratin-18 (CK-18) from baseline in subjects with NASH. |  | 12 weeks | 
| The effect of TVB-2640 versus placebo on the change in NASH and fibrosis-4 (FIB-4) from baseline in subjects with NASH. |  | 12 weeks | 
| The effect of TVB-2640 versus placebo on the change in NASH and enhanced liver fibrosis score (ELF) from baseline in subjects with NASH. | The Enhanced Liver Fibrosis (ELF) score is a marker set consisting of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA) showing good correlations with fibrosis stages in chronic liver disease. There are three typical cut-off values: < 7.7 for exclusion of fibrosis, 9.8 for a high specificity identification of fibrosis and 11.3 to discriminate cirrhosis. | 12 weeks | 
| The effect of TVB-2640 versus placebo on the change in levels of eicosanoids from baseline in subjects with NASH. | Eicosanoids are lipid-derived signaling molecules including 5-LOX-derived leukotriene B4 (LTB4), COX-derived prostaglandin E2 (PGE2), and 15-LOX-derived 15-hydroxyeicosatetraenoic acid (15-HETE) and lipoxin A4 (LXA4). | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NASH, Non-Alcoholic Steatohepatitis, Fatty Liver Disease, Fatty Liver, Liver Diseases, FASN, Fatty Acid Synthase Inhibitor