HTD1801 in Adults With Nonalcoholic Steatohepatitis and Liver Fibrosis Who Have Type 2 Diabetes or Pre-Diabetes

Study Overview
=================
Brief Summary
-----------------
A phase 2b, multicenter, randomized, double-blind, placebo-controlled study of HTD1801 in adult subjects with non-alcoholic steatohepatitis and liver fibrosis who have type 2 diabetes mellitus or pre-diabetes.

Detailed Description
-----------------
This phase 2b, double-blind, randomized, placebo-controlled, multicenter study will evaluate the effect of HTD1801, 1250 mg twice daily (BID) compared to placebo BID on histologic improvements in adult subjects with non-alcoholic steatohepatitis and liver fibrosis who have type 2 diabetes mellitus or pre-diabetes. The study will enroll approximately 210 subjects with biopsy-confirmed non-alcoholic steatohepatitis and evidence of stage 2 or stage 3 liver fibrosis. Subjects will receive investigational product for up to 60 weeks.

Official Title
-----------------
A Phase 2b, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of HTD1801 in Adult Subjects With Nonalcoholic Steatohepatitis (NASH) and Liver Fibrosis Who Have Type 2 Diabetes (T2DM) or Pre-Diabetes

Conditions
-----------------
Nonalcoholic Steatohepatitis (NASH), Type 2 Diabetes

Intervention / Treatment
-----------------
* Drug: HTD1801
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion criteria: Clinical diagnosis of non-alcoholic steatohepatitis (NASH) upon central read of a liver biopsy obtained no more than 6 months before Day 0. Histologic evidence of fibrosis stage 2 or stage 3 as defined by the non-alcoholic steatohepatitis (NASH) clinical research network (CRN) scoring of fibrosis. Clinically documented diagnosis of type 2 diabetes mellitus for at least 6 months prior to screening or prediabetes at screening. BMI >25 kilograms/meters squared (>23 kilograms/meters squared if Asian). Key Exclusion criteria: Fibrosis stage 4. History of alcohol or substance abuse or dependence. Liver disease unrelated to non-alcoholic steatohepatitis. History of significant cardiovascular disease. History of type 1 diabetes. Inability or unwillingness to undergo 2 planned liver biopsies OR 1 planned biopsy if historical liver biopsy was used to confirm eligibility at entry.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This phase 2b, double-blind, placebo-controlled, multicenter study will evaluate the effect of HTD1801 on histologic improvements in adult subjects with non-alcoholic steatohepatitis (NASH) and liver fibrosis who have type 2 diabetes mellitus or pre-diabetes. Approximately 210 subjects with biopsy-confirmed NASH and evidence of stage 2 or stage 3 liver fibrosis will be randomized 2:1 to receive HTD1801 1250 mg twice daily (BID) or placebo BID. Subjects will receive investigational product for up to 60 weeks.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HTD1801<br>HTD1801,1250 mg, BID | Drug: HTD1801<br>* HTD1801,1250 mg, BID<br>* Other names: HTD1801 capsules;|
| Placebo Comparator: placebo<br>placebo, BID | Drug: Placebo<br>* Placebo, BID<br>* Other names: placebo capsules;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Endpoint | A decrease of ≥2-points in non-alcoholic fatty liver disease activity score (NAS) with ≥1-point decrease of either lobular inflammation or ballooning and no worsening of fibrosis; OR Resolution of non-alcoholic steatohepatitis (NASH) (defined as the overall histopathologic interpretation of 1) no fatty liver disease or 2) fatty liver disease (simple or isolated steatosis) without steatohepatitis AND a non-alcoholic fatty liver disease activity score (NAS) of 0 for ballooning and 0-1 for inflammation and no worsening of fibrosis. Nonalcoholic fatty liver disease activity score (NAS) is a histological scoring system that assesses a liver biopsy and gives scores for steatosis (0-3), lobular inflammation (0-3), and hepatocyte ballooning (0-2). The higher the score the more severe the disease. The total range for non-alcoholic fatty liver disease activity score (NAS) is between 0 to 8. The lower the score the better the outcome. | Up to 60 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endpoint 1 | Percentage of subjects with resolution of non-alcoholic steatohepatitis (NASH) on overall histopathological reading | Up to 60 Weeks | 
| Endpoint 2 | Percentage of subjects with resolution of non-alcoholic steatohepatitis hepatitis (NASH) and at least a 2-point improvement in non-alcoholic fatty liver disease (NAFLD) activity score (NAS) and no worsening of liver fibrosis | Up to 60 Weeks | 
| Endpoint 3 | Percentage of subjects with a ≥1-stage improvement in liver fibrosis. | Up to 60 Weeks | 
| Endpoint 4 | Percentage of subjects with a ≥1-stage improvement in liver fibrosis and no worsening of non-alcoholic steatohepatitis (NASH). | Up to 60 Weeks | 
| Endpoint 5 | Percentage of subjects with a ≥2-stage improvement in liver fibrosis. | Up to 60 Weeks | 
| Endpoint 6 | Percentage of subjects with a ≥2-point improvement in non-alcoholic fatty liver disease activity score (NAS) and no worsening of liver fibrosis. | Up to 60 Weeks | 
| Endpoint 7 | Percentage of subjects with an improvement in each of the individual non-alcoholic fatty liver disease activity score (NAS) components (ballooning, inflammation, or steatosis). | Up to 60 Weeks | 
| Endpoint 8 | Percentage of subjects with improvement of non-alcoholic steatohepatitis (NASH) based on overall histopathologic interpretation. | Up to 60 Weeks | 
| Endpoint 9 | Absolute and percent change in alanine aminotransferase (ALT) from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 10 | Absolute and percent change in aspartate aminotransferase (AST) from baseline to end of treatment. | Up to 60 Weeks. | 
| Endpoint 11 | Absolute and percent change in gamma-glutamyl transferase (GGT) from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 12 | Absolute and percent change in total bilirubin from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 13 | Absolute and percent change in direct bilirubin from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 14 | Absolute and percent change in hemoglobin A1c (HbA1c) from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 15 | Absolute and percent change in fasting plasma glucose from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 16 | Absolute and percent change in body weight from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 17 | Absolute and percent change in body mass index (BMI) from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 18 | Absolute and percent change in hip circumference from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 19 | Absolute and percent change in waist circumference from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 20 | Absolute and percent change in total cholesterol from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 21 | Absolute and percent change in low-density lipoprotein cholesterol (LDL-c) from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 22 | Absolute and percent change in lipoprotein A (Lpa) from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 23 | Absolute and percent change in high-density lipoprotein cholesterol (HDL-c) from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 24 | Absolute and percent change in triglycerides from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 25 | Absolute and percent change in apolipoprotein B (ApoB) from baseline to end of treatment. | Up to 60 Weeks | 
| Endpoint 26 | Absolute and percent change in liver stiffness as measured by vibration-controlled transient elastography (VCTE) using FibroScan® device from baseline to end of treatment. The VCTE score is measured in Kilopascal Pressure Unit (kPa) and ranges from 2 to 75 kPa. The higher the kPa score the more severe the liver stiffness. | Up to 60 Weeks | 
| Endpoint 27 | Absolute and percent change in liver fat content as measured by controlled attenuation parameter (CAP) using FibroScan® device from baseline to end of treatment. The controlled attenuation parameter (CAP) score is measured in decibels per meter (dB/m) it ranges from 100 to 400 dB/m. The higher the controlled attenuation parameter (CAP) score the more severe the steatosis. | Up to 60 Weeks | 
| Endpoint 28 | Absolute and percent change in the FibroScan-AST (FAST) score from baseline to end of treatment. Fast score will be calculated based on LSM, CAP and AST values using FAST equation. An equal to or more than 0.35 value thru equal or less than 0.81 value is positive predictive value for nonalcoholic steatohepatitis and a negative predictive value from 0.73 to 1.0. | Up to 60 Weeks |