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

Phase 2

Completed

• Conditions: NAFLD; Nonalcoholic Fatty Liver Disease; Nonalcoholic Steatohepatitis; Digestive System Diseases; Fatty Liver, Nonalcoholic; Type 2 Diabetes Mellitus (T2DM)
• Interventions: Drug: Placebo; Drug: HTD1801

• Registration Number: NCT03656744
• Lead Sponsor: HighTide Biopharma Pty Ltd

Brief Summary

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

Detailed Description

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.

Study Timeline

• Study First Submitted: 2018-08-30
• Study First Submitted QC: 2018-08-30
• Study First Posted: 2018-09-04
• Study Start: 2018-11-26
• Primary Completion: 2020-02-07
• Study Completion: 2020-03-09
• Results First Submitted: 2021-05-12
• Status Verified: 2021-11
• Results First Submitted QC: 2021-11-30
• Last Update Submitted: 2021-11-30
• Results First Posted: 2021-12-29
• Last Update Posted: 2021-12-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 101

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
placebo, bid	Placebo	-
1000mg HTD1801, bid	HTD1801	-
500mg HTD1801, bid	HTD1801	-

Primary Outcome Measures

Name	Time	Method
Absolute Change in Liver Fat Content (LFC) as Measured by MRI-PDFF	Baseline through study Week 18	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.

Secondary Outcome Measures

Name	Time	Method
Number of Subjects Who Achieved ≥5% Absolute Reduction in Liver Fat Content (LFC) as Measured by MRI-PDFF	Baseline through study Week 18	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.
Change in LDL-c	Baseline visit through study week 18	Change in low-density lipoprotein cholesterol (LDL-c) from Baseline to Week 18.
Change in AST	Baseline through study week 18	Absolute change in aspartate aminotransferase (AST) from Baseline to Week 18.
Changes in Hemoglobin A1c	Baseline through study week 18	Changes in HbA1c from Baseline to Week 18.
Number of Subjects Who Normalized LFC to <5% as Measured by MRI-PDFF	Baseline through study Week 18	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.
Change in Serum Triglycerides	Baseline through study week 18	Change in serum triglycerides from Baseline to Week 18.
Change in ALT	Baseline through study week 18	Absolute change in alanine aminotransferase (ALT) from Baseline to Week 18.
Change in TIMP-1	Baseline through study week 18	Change in tissue inhibitor of metalloproteinases 1 (TIMP-1) from Baseline to Week 18.
Change in HA	Baseline through study week 18	Change in hyaluronic acid (HA) from Baseline to Week 18.
Number of Participants Reporting an Adverse Events From Baseline Through Week 18	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.	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.
Change in Fasting Glucose	Baseline through study Week 18	Change in fasting glucose from Baseline to Week 18 .
Proportion of Subjects Who Achieved ≥ 30% Relative Reduction in LFC as Measured by MRI-PDFF	Baseline through study week 18	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.
Change in HDL-c	Baseline through study week 18	Change in high-density lipoprotein cholesterol (HDL-c) from Baseline to Week 18.
Relative Change in LFC as Measured by MRI-PDFF	Baseline through study week 18	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.
Change in HOMA-IR	Baseline through study week 18	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.
Change in ELF Score	Baseline through study week 18	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.
Change in PIIINP	Baseline through study week 18	Change in N-terminal pro-peptide of type III collagen (PIIINP) from Baseline to Week 18.
Change in Total Bile Acids	Baseline through study week 18	Changes in total bile acids from Baseline to Week 18.
Change in FGF19	Baseline through study week 18	Change in fibroblast growth factor 19 (FGF19) from Baseline to Week 18
Proportion of Subjects With Elevated ALT at Baseline Who Normalized ALT at Week 18	Baseline through study week 18	Proportion of subjects with elevated alanine aminotransferase (ALT) at Baseline who normalized ALT at Week 18.
Change in Pro-Peptide of Type III Collagen (Pro-C3)	Baseline through study week 18	Change in Pro-C3 from Baseline to Week 18 for subjects with elevated Pro-C3 at Baseline.

Trial Locations

Locations (15)

Excel Medical Clinical Trials; 🇺🇸 Boca Raton, Florida, United States

Harborview Medical Center; 🇺🇸 Seattle, Washington, United States

Gastro One; 🇺🇸 Germantown, Tennessee, United States

Texas Digestive Disease Consultants; 🇺🇸 Southlake, Texas, United States

Doctors Hospital at Renaissance; 🇺🇸 Edinburg, Texas, United States

National Research Institute; 🇺🇸 Panorama City, California, United States

Cumberland Research Associates; 🇺🇸 Fayetteville, North Carolina, United States

University of Washington Medical Center; 🇺🇸 Seattle, Washington, United States

Florida Research Institute; 🇺🇸 Lakewood Ranch, Florida, United States

Compass Research; 🇺🇸 Orlando, Florida, United States

Pinnacle Clinical Research; 🇺🇸 San Antonio, Texas, United States

Digestive Health Research; 🇺🇸 Hermitage, Tennessee, United States

Institute for Liver Health; 🇺🇸 Tucson, Arizona, United States

Kansas City Research Institute; 🇺🇸 Kansas City, Missouri, United States

Adobe Clinical Research; 🇺🇸 Tucson, Arizona, United States