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

• ClinicalTrials.gov Identifier: NCT03656744
• Recruitment Status: Completed
• First Posted: September 4, 2018
• Results First Posted: December 29, 2021
• Last Update Posted: December 29, 2021
• Sponsor: HighTide Biopharma Pty Ltd
• Information provided by (Responsible Party): HighTide Biopharma Pty Ltd

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Fatty Liver, Nonalcoholic; NAFLD; Nonalcoholic Fatty Liver Disease; Nonalcoholic Steatohepatitis; Digestive System Diseases; Type 2 Diabetes Mellitus (T2DM)	Drug: HTD1801; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 101 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Proof-of-Concept and Dose-Ranging Study Investigating the Efficacy and Safety of HTD1801 in Adults With NASH and T2DM
• Actual Study Start Date: November 26, 2018
• Actual Primary Completion Date: February 7, 2020
• Actual Study Completion Date: March 9, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Absolute Change in Liver Fat Content (LFC) as Measured by MRI-PDFF [ Time Frame: 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 :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Institute for Liver Health

Chandler, Arizona, United States, 85224

Institute for Liver Health

Tucson, Arizona, United States, 85711

Adobe Clinical Research

Tucson, Arizona, United States, 85712

United States, California

National Research Institute

Panorama City, California, United States, 91402

United States, Florida

Excel Medical Clinical Trials

Boca Raton, Florida, United States, 33434

Florida Research Institute

Lakewood Ranch, Florida, United States, 34211

Compass Research

Orlando, Florida, United States, 32806

United States, Missouri

Kansas City Research Institute

Kansas City, Missouri, United States, 64131

United States, North Carolina

Cumberland Research Associates

Fayetteville, North Carolina, United States, 28304

United States, Tennessee

Gastro One

Germantown, Tennessee, United States, 38138

Digestive Health Research

Hermitage, Tennessee, United States, 37076

United States, Texas

Pinnacle Clinical Research

Austin, Texas, United States, 78746

Doctors Hospital at Renaissance

Edinburg, Texas, United States, 78539

Pinnacle Clinical Research

San Antonio, Texas, United States, 78229

Texas Digestive Disease Consultants

Southlake, Texas, United States, 76092

United States, Washington

Harborview Medical Center

Seattle, Washington, United States, 98195

University of Washington Medical Center

Seattle, Washington, United States, 98195

Sponsors and Collaborators

HighTide Biopharma Pty Ltd

Investigators

• Study Director: Adrian Di Bisceglie, MD,FACP,FAASLD; HighTide Therapeutics USA, LLC

  Study Documents (Full-Text)

Documents provided by HighTide Biopharma Pty Ltd:

Study Protocol  [PDF] March 27, 2019

Statistical Analysis Plan  [PDF] March 25, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: HighTide Biopharma Pty Ltd
• ClinicalTrials.gov Identifier: NCT03656744
• Other Study ID Numbers: HTD1801.PCT012
• First Posted: September 4, 2018
• Results First Posted: December 29, 2021
• Last Update Posted: December 29, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Digestive System Diseases; Gastrointestinal Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases