A Study of HTD1801 in Adults With Nonalcoholic Steatohepatitis (NASH) and Type 2 Diabetes Mellitus (T2DM)

Study Overview
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Brief Summary
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Randomized, double-blind, placebo-controlled, parallel-group study comparing multiple doses of HTD1801 to placebo.

Detailed Description
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This 18-week randomized, double-blind, parallel-group, proof of concept (POC), dose-ranging study compared multiple doses of HTD1801 to placebo in a 1:1:1 ratio. Since accumulation of hepatic fat is considered the first hit in the pathogenesis of NASH (Adams and Angulo 2006), change in liver fat content (LFC) by magnetic resonance imaging estimated proton density fat fraction (MRI-PDFF) is an appropriate primary endpoint and is consistent with that used in other recent Phase 2 POC studies in NASH (Harrison et al., 2018, Madrigal Pharmaceuticals 2018). The Harrison et al., 2018, Madrigal Pharmaceuticals 2018 study showed clinically meaningful absolute and relative reductions in LFC assessed by MRI-PDFF over 12-week treatment periods thus, it was considered that an 18 week HTD1801 treatment period would therefore be adequate to assess the study's primary endpoint and to maximize collection of exposure and safety related data.

Official Title
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A Proof-of-Concept and Dose-Ranging Study Investigating the Efficacy and Safety of HTD1801 in Adults With NASH and T2DM

Conditions
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Fatty Liver, Nonalcoholic, NAFLD, Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, Digestive System Diseases, Type 2 Diabetes Mellitus (T2DM)

Intervention / Treatment
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* Drug: HTD1801
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of NASH as assessed by MRI Clinically documented diagnosis of T2DM Body mass index (BMI) >25 kg/m2 Exclusion Criteria: Liver disease unrelated to NASH Poorly controlled T2DM or Type 1 Diabetes Mellitus History of alcohol or substance abuse or dependence Inability to undergo MRI for any reason History of significant cardiovascular disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 500mg HTD1801, bid<br> | Drug: HTD1801<br>* HTD1801 tablets, 250mg<br>|
| Experimental: 1000mg HTD1801, bid<br> | Drug: HTD1801<br>* HTD1801 tablets, 250mg<br>|
| Placebo Comparator: placebo, bid<br> | Drug: Placebo<br>* tablets manufactured to mimic HTD1801 tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Liver Fat Content (LFC) as Measured by MRI-PDFF | The primary endpoint was the absolute change in liver fat content (LFC) as measured by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) from Baseline to Week 18. | Baseline through study Week 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Glucose | Change in fasting glucose from Baseline to Week 18 . | Baseline through study Week 18 | 
| Changes in Hemoglobin A1c | Changes in HbA1c from Baseline to Week 18. | Baseline through study week 18 | 
| Proportion of Subjects Who Achieved ≥ 30% Relative Reduction in LFC as Measured by MRI-PDFF | Proportion of subjects who achieved ≥ 30% relative reduction in liver fat content (LFC) as measured by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) from Baseline to Week 18. | Baseline through study week 18 | 
| Relative Change in LFC as Measured by MRI-PDFF | Relative change in liver fat content (LFC) as measured by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) from Baseline to Week 18. | Baseline through study week 18 | 
| Number of Subjects Who Normalized LFC to <5% as Measured by MRI-PDFF | Number of subjects who normalized liver fat content (LFC) to <5% as measured by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) at Week 18. | Baseline through study Week 18 | 
| Number of Subjects Who Achieved ≥5% Absolute Reduction in Liver Fat Content (LFC) as Measured by MRI-PDFF | Number of subjects who achieved ≥5% absolute reduction in liver fat content (LFC) as measured by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) from Baseline to Week 18. | Baseline through study Week 18 | 
| Change in HOMA-IR | Change in homeostasis model assessment-estimated insulin resistance (HOMA-IR) from Baseline to Week 18. The higher the HOMA-IR score, the more insulin resistant a person is. Values of <1 are considered optimal while values >2.9 indicate significant insulin resistance. | Baseline through study week 18 | 
| Change in LDL-c | Change in low-density lipoprotein cholesterol (LDL-c) from Baseline to Week 18. | Baseline visit through study week 18 | 
| Change in Serum Triglycerides | Change in serum triglycerides from Baseline to Week 18. | Baseline through study week 18 | 
| Change in HDL-c | Change in high-density lipoprotein cholesterol (HDL-c) from Baseline to Week 18. | Baseline through study week 18 | 
| Change in AST | Absolute change in aspartate aminotransferase (AST) from Baseline to Week 18. | Baseline through study week 18 | 
| Change in ALT | Absolute change in alanine aminotransferase (ALT) from Baseline to Week 18. | Baseline through study week 18 | 
| Proportion of Subjects With Elevated ALT at Baseline Who Normalized ALT at Week 18 | Proportion of subjects with elevated alanine aminotransferase (ALT) at Baseline who normalized ALT at Week 18. | Baseline through study week 18 | 
| Change in Pro-Peptide of Type III Collagen (Pro-C3) | Change in Pro-C3 from Baseline to Week 18 for subjects with elevated Pro-C3 at Baseline. | Baseline through study week 18 | 
| Change in ELF Score | Change in the enhanced liver fibrosis (ELF) score. The ELF score is calculated using a published algorithm combining the values of a set of extracellular matrix markers, including TIMP-1, PIIINP, and HA. The ELF score has been reported to show good correlations with fibrosis stages in chronic liver disease, with higher ELF scores associated with higher fibrosis stages. The ELF score is hence used as a prognostic marker for disease progression: ELF score < 9.8 : Low risk of progression, ELF score 9.8 to < 11.3 : Moderate risk of progression and ELF score > = 11.3 : High risk of progression. | Baseline through study week 18 | 
| Change in TIMP-1 | Change in tissue inhibitor of metalloproteinases 1 (TIMP-1) from Baseline to Week 18. | Baseline through study week 18 | 
| Change in PIIINP | Change in N-terminal pro-peptide of type III collagen (PIIINP) from Baseline to Week 18. | Baseline through study week 18 | 
| Change in HA | Change in hyaluronic acid (HA) from Baseline to Week 18. | Baseline through study week 18 | 
| Change in Total Bile Acids | Changes in total bile acids from Baseline to Week 18. | Baseline through study week 18 | 
| Change in FGF19 | Change in fibroblast growth factor 19 (FGF19) from Baseline to Week 18 | Baseline through study week 18 | 
| Number of Participants Reporting an Adverse Events From Baseline Through Week 18 | AEs were mapped to MedDRA version 20.1 preferred term (PT) and system organ class (SOC). If the subject experienced multiple events that mapped to a single preferred term, the greatest severity grade according to CTCAE Version 4.0, and strongest investigator assessment of relation to study medication was assigned to the preferred term. If an event had a missing severity or relationship, it was classified as having the highest severity and/or strongest relationship to study medication. The occurrence of TEAEs was summarized by treatment group by SOC, PT, and severity. Separate summaries of treatment-emergent serious adverse events (SAEs), TEAEs related to study drug, severe or life threatening TEAEs, and TEAEs leading to the discontinuation of study treatment were generated. Additionally, the occurrence of liver-specific AEs was summarized by treatment group. All reported adverse events were listed for individual subjects showing verbatim term, PT and SOC. | Adverse events were collected from the time the subject signed the informed consent form through the date of the last visit for a specific subject, that is, approximately 24 weeks in total for a completed subject. |