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

Tracking Information

• First Submitted Date: August 30, 2018
• First Posted Date: September 4, 2018
• Results First Submitted Date: May 12, 2021
• Results First Posted Date: December 29, 2021
• Last Update Posted Date: December 29, 2021
• Actual Study Start Date: November 26, 2018
• Actual Primary Completion Date: February 7, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 20, 2021)

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.

• Original Primary Outcome Measures (submitted: August 30, 2018): Change in liver fat content (LFC) as measured by Magnetic Resonance Imaging (MRI) [ Time Frame: 18 weeks ]

Current Secondary Outcome Measures (submitted: November 30, 2021)

• Change in Fasting Glucose [ Time Frame: Baseline through study Week 18 ]
  Change in fasting glucose from Baseline to Week 18 .
• Changes in Hemoglobin A1c [ Time Frame: Baseline through study week 18 ]
  Changes in HbA1c from Baseline to Week 18.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Change in Serum Triglycerides [ Time Frame: Baseline through study week 18 ]
  Change in serum triglycerides from Baseline to Week 18.
• Change in HDL-c [ Time Frame: Baseline through study week 18 ]
  Change in high-density lipoprotein cholesterol (HDL-c) from Baseline to Week 18.
• Change in AST [ Time Frame: Baseline through study week 18 ]
  Absolute change in aspartate aminotransferase (AST) from Baseline to Week 18.
• Change in ALT [ Time Frame: Baseline through study week 18 ]
  Absolute change in alanine aminotransferase (ALT) from Baseline to Week 18.
• 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.
• 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.
• 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.
• 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.
• 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.
• Change in HA [ Time Frame: Baseline through study week 18 ]
  Change in hyaluronic acid (HA) from Baseline to Week 18.
• Change in Total Bile Acids [ Time Frame: Baseline through study week 18 ]
  Changes in total bile acids from Baseline to Week 18.
• Change in FGF19 [ Time Frame: Baseline through study week 18 ]
  Change in fibroblast growth factor 19 (FGF19) from Baseline to Week 18
• 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.

Original Secondary Outcome Measures (submitted: August 30, 2018)

• Proportion of subjects who achieve a reduction in LFC as measured by MRI [ Time Frame: 18 weeks ]
• Changes in glucose [ Time Frame: 18 weeks ]
• Changes in hemoglobin A1c [ Time Frame: 18 weeks ]
• Changes in low-density lipoprotein cholesterol (LDL-c) [ Time Frame: 18 weeks ]
• Changes in ALT [ Time Frame: 18 weeks ]
• Changes in AST [ Time Frame: 18 weeks ]
• Frequency and severity of adverse events [ Time Frame: 18 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of HTD1801 in Adults With Nonalcoholic Steatohepatitis (NASH) and Type 2 Diabetes Mellitus (T2DM)
• Official Title: A Proof-of-Concept and Dose-Ranging Study Investigating the Efficacy and Safety of HTD1801 in Adults With NASH and T2DM
• 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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: HTD1801
  HTD1801 tablets, 250mg
• Drug: Placebo
  tablets manufactured to mimic HTD1801 tablets

Study Arms

• Experimental: 500mg HTD1801, bid
  Intervention: Drug: HTD1801
• Experimental: 1000mg HTD1801, bid
  Intervention: Drug: HTD1801
• Placebo Comparator: placebo, bid
  Intervention: Drug: Placebo

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 12, 2021): 101
• Original Estimated Enrollment (submitted: August 30, 2018): 117
• Actual Study Completion Date: March 9, 2020
• Actual Primary Completion Date: February 7, 2020 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03656744
• Other Study ID Numbers: HTD1801.PCT012
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: HighTide Biopharma Pty Ltd
• Original Responsible Party: Same as current
• Current Study Sponsor: HighTide Biopharma Pty Ltd
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: HighTide Biopharma Pty Ltd
• Verification Date: November 2021