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

Study Overview
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Brief Summary
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This is a Phase 2, multi-center, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy on TVB-2640 in subjects with non-alcoholic steatohepatitis (NASH). Subjects will be randomly assigned toTVB-2640 or matching placebo PO QD for 52 weeks, with the first dose administered on Day 1.

Official Title
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A Phase 2B, Multi-Center, Double-Blind, Randomized, Placebo-Controlled Study of the Safety and Efficacy of TVB-2640 in Subjects With Nonalcoholic Steatohepatitis (FASCINATE-2)

Conditions
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Nonalcoholic 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: Must be willing and able to participate in the study and provide written informed consent. Male and female adults ≥18 years of age on the date that written informed consent to take part in the study is provided. Body mass index (BMI) ≥23 kg/m2 for Asians and ≥25 kg/m2 for other races. Female subjects must be either: Not of childbearing potential OR Women of childbearing potential (WOCBP) must have a negative serum pregnancy (beta-human chorionic gonadotropin [β-HCG]) test during Screening, a negative urine pregnancy test within 24 hours before the first dose of study drug on Day 1, and must agree to perform urine home pregnancy tests monthly between study visits. WOCBP must not be breastfeeding, not plan to become pregnant during the study, and must use birth control. Must have liver stiffness measurement ≥8.5 kPa measured by FibroScan and CAP score measured by FibroScan ≥280 dB/m during the Screening period. Histologic confirmation of NASH: must have had prior liver biopsy within 180 days before randomization (randomization is within 24 hours of Baseline [Day1]) with fibrosis stage F2-F3 and a NAS of ≥4 with at least a score of 1 in each of the following NAS components: steatosis, ballooning degeneration, and lobular inflammation. Exclusion Criteria: History of harmful alcohol intake for a period of more than 3 consecutive months within 1 year prior to Screening in the judgement of the Investigator. Active substance abuse. Gain or loss of >5% of body weight in the 6 months prior to Baseline (Day 1) or >10% of body weight in the 12 months prior to Screening. Type 1 diabetes mellitus by history. Positive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) polymerase chain reaction (PCR) test within 30 days before Baseline, history of hospitalization for coronavirus disease-2019 (COVID-19) ), or history of use of oxygen due to COVID-19) <6 months prior to the Screening visit date. Note that previous COVID-19 infection alone is not exclusionary and vaccination against SARS-CoV-2 is allowed. Infection and/or vaccination must be documented. Uncontrolled T2DM, defined as HbA1c ≥9.5% at Screening. Presence of cirrhosis on liver histology (stage 4 fibrosis), according to the judgement of the central reader, and/or cross sectional imaging evidence consistent with cirrhosis and/or portal hypertension. Use of glucagon-like peptide-1 (GLP-1) agonists or a sodium-glucose co-transporter-2 (SGLT2) inhibitor, unless on a stable daily dose for at least 6 months prior to the Screening visit date, or on a complex oral anti-diabetic (OAD) regimen (3 or more OADs [except for a GLP-1 agonist or an SGLT2 inhibitor]), unless on a stable dose for at least 3 months prior to the Screening visit date. Subjects with active or quiescent chronic liver disease of etiologies other than NASH (eg, viral or autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, and 'autoimmune hepatitis-overlap' syndromes, hemochromatosis, Wilson's disease, alpha 1 antitrypsin deficiency, alcohol-related liver disease, drug-induced liver disease, and/or infiltrative conditions [eg, sarcoidosis]). Current or historic clinically evident hepatic decompensation event (eg, ascites formation, variceal hemorrhage, hepatic encephalopathy). Any subject who has sustained a clinically evident cardiovascular, cerebrovascular, and/or peripheral vascular event during the 12 months prior to anticipated Baseline (Day 1) visit date is not eligible for study participation.

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 with liver fibrosis stage F2-F3, will be enrolled and randomized in a 2:1 ratio to receive TVB-2640, or placebo PO QD
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TVB-2640 50 mg<br>Subjects will receive TVB-2640 PO QD for 52 weeks, with the first dose administered on Day 1. | Drug: TVB-2640<br>* Oral dose, tablet<br>|
| Placebo Comparator: Placebo<br>Subjects will receive matching placebo PO QD for 52 weeks, with the first dose administered on Day 1. | Other: Placebo<br>* Oral dose, tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histological improvement in nonalcoholic fatty liver disease (NAFLD) activity score (NAS) without worsening of fibrosis (by NASH Clinical Research Network [CRN] fibrosis score) at Week 52 | Histological improvement is defined as ≥2 points improvement in NAS with ≥1 point improvement in ballooning or inflammation | 12 months | 
| Resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN fibrosis score). | Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for ballooning, and any value for steatosis | 12 months | 
| Safety and tolerability of PO QD doses of TVB-2640 in subjects with confirmed NASH and liver fibrosis evaluated by incidence of treatment emergent adverse events (TEAEs) |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NASH, Nonalcoholic Steatohepatitis, Fatty Liver Disease, Biopsy Confirmed, FASN, Liver Disease, Fatty Liver, Digestive System Diseases