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

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

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

Study Overview

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

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 Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Institute for Liver Health
    • Tucson, Arizona, United States, 85712
      • Adobe Clinical Research
    • Tucson, Arizona, United States, 85711
      • Institute for Liver Health
  • California
    • Panorama City, California, United States, 91402
      • National Research Institute
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Excel Medical Clinical Trials
    • Lakewood Ranch, Florida, United States, 34211
      • Florida Research Institute
    • Orlando, Florida, United States, 32806
      • Compass Research
  • Missouri
    • Kansas City, Missouri, United States, 64131
      • Kansas City Research Institute
  • North Carolina
    • Fayetteville, North Carolina, United States, 28304
      • Cumberland Research Associates
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Gastro One
    • Hermitage, Tennessee, United States, 37076
      • Digestive Health Research
  • Texas
    • Austin, Texas, United States, 78746
      • Pinnacle Clinical Research
    • Edinburg, Texas, United States, 78539
      • Doctors Hospital at Renaissance
    • San Antonio, Texas, United States, 78229
      • Pinnacle Clinical Research
    • Southlake, Texas, United States, 76092
      • Texas Digestive Disease Consultants
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
    • Seattle, Washington, United States, 98195
      • Harborview Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 500mg HTD1801, bid	Drug: HTD1801; HTD1801 tablets, 250mg
EXPERIMENTAL: 1000mg HTD1801, bid	Drug: HTD1801; HTD1801 tablets, 250mg
PLACEBO_COMPARATOR: placebo, bid	Drug: Placebo; tablets manufactured to mimic HTD1801 tablets

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: HighTide Biopharma Pty Ltd

Publications and helpful links

General Publications

• Harrison SA, Gunn N, Neff GW, Kohli A, Liu L, Flyer A, Goldkind L, Di Bisceglie AM. A phase 2, proof of concept, randomised controlled trial of berberine ursodeoxycholate in patients with presumed non-alcoholic steatohepatitis and type 2 diabetes. Nat Commun. 2021 Sep 17;12(1):5503. doi: 10.1038/s41467-021-25701-5.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 26, 2018
• Primary Completion (ACTUAL): February 7, 2020
• Study Completion (ACTUAL): March 9, 2020

Study Registration Dates

• First Submitted: August 30, 2018
• First Submitted That Met QC Criteria: August 30, 2018
• First Posted (ACTUAL): September 4, 2018

Study Record Updates

• Last Update Posted (ACTUAL): December 29, 2021
• Last Update Submitted That Met QC Criteria: November 30, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Liver Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fatty Liver; Non-alcoholic Fatty Liver Disease; Gastrointestinal Diseases; Digestive System Diseases
• Other Study ID Numbers: HTD1801.PCT012

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No