Phase I, Dose-Escalation Study of Dihydromyricetin (DHM) to Treat Alcohol-Associated Liver Disease

The current proposal is designed as a first-in-human Phase 1 open-label, dose-escalation study to assess the safety, pharmacokinetics, and the maximum tolerated dose of DHM among healthy volunteers using a purified form of DHM from a local cGMP compliant source (Master Herbs, Inc).

Study Overview

• Status: Not yet recruiting
• Conditions: Alcohol-Related Disorders
• Intervention / Treatment: Drug: Dihydromyricetin

Detailed Description

Dihydromyricetin (DHM), a bioactive flavonoid from an edible plant (ampelopsis grossedentata), is reported to have multiple protective effects against chemical-induced liver injuries. For example, the antioxidant activity and cellular metabolic protective effects of DHM may act via the AMP kinase (AMPK) and nicotinamide adenine dinucleotide (NAD+)-dependent Sirtuin (Sirt)-1 energy regulating pathway. Furthermore, there is accumulating evidence supporting the use of DHM for the treatment of alcohol use disorder and the possible reduction/prevention of alcohol-associated liver disease in animal models. DHM may represent a novel approach to counteract alcohol-induced liver damage and promote alcohol metabolism via changes in hepatocellular bioenergetics and mitochondrial biogenesis driven by the AMPK/Sirt-1/PGC-1α axis.

These preclinical data suggest the potential of DHM as a novel therapeutic agent in alcohol-related diseases. However, further study in humans is warranted. While DHM has been used for herbal tea in traditional Chinese medicine for hundreds of years, and there has been a small clinical trial using DHM in China among individuals with non-alcoholic fatty liver disease, there have been no controlled human studies published that have assessed the safety, pharmacokinetics, or optimal dosing of DHM in humans.

DHM is marketed as a dietary supplement in the United States and is not regulated by the Food and Drug Administration (FDA) as a drug. Because the FDA has little control over the quality of herbal products such as DHM, it is necessary to quantitatively estimate the potentially active ingredients and the pharmacokinetic (PK) profile with oral administration.

The current proposal is designed as a first-in-human Phase 1 open-label, dose-escalation study to assess the safety, pharmacokinetics, and the maximum tolerated dose of DHM among healthy volunteers using a purified form of DHM from a local cGMP compliant source (Master Herbs, Inc).

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Brian Lee, MD; Phone Number: 323-442-5576; Email: brian.lee@med.usc.edu

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90089
      • University of Southern California
      • Contact: Brian Lee, MD; Phone Number: 323-442-5576; Email: brian.lee@med.usc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• No prior medical history of alcohol use disorder or alcohol-associated liver disease
• Between 18-60 years old

Exclusion Criteria:

• Weight below 50kg.
• Advanced liver disease
• Other acute liver diseases
• HIV co-infection
• History of pancreatic or biliary disease
• Acute illness that would interfere with drug absorption
• Pregnancy
• Participants who are currently taking drugs with CYP3A4 effects
• FIB-4 Index > 1.30
• History of Alcohol Use Disorder (AUD) determined by score > 8 on AUDIT questionnaire

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; DHM 300mg x1 dose	Drug: Dihydromyricetin; Dose-escalation and lysine preparation
Experimental: Cohort 2; DHM 900mg x1 dose	Drug: Dihydromyricetin; Dose-escalation and lysine preparation
Experimental: Cohort 3; DHM 300mg x1 dose + Lysine 140mg x1 dose	Drug: Dihydromyricetin; Dose-escalation and lysine preparation
Experimental: Cohort 4; DHM 900mg x1 dose + Lysine 420mg x1 dose	Drug: Dihydromyricetin; Dose-escalation and lysine preparation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	The National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 will be used to assess and grade AE severity	24 hours post-dose
Pharmacokinetic of DHM	serum DHM metabolites will be performed using MRM mass	-0.5 (pre-dose), 0 (1st dose), 0.5, 1, 2, 4, 6, 8 (2nd dose), 10, and 24 hours post-dose.

Collaborators and Investigators

• Sponsor: University of Southern California
• Investigators: Principal Investigator: Brian Lee, MD, University of Southern California

Study record dates

Study Major Dates

• Study Start (Estimated): September 15, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: November 11, 2022
• First Submitted That Met QC Criteria: November 11, 2022
• First Posted (Actual): November 21, 2022

Study Record Updates

• Last Update Posted (Actual): September 3, 2024
• Last Update Submitted That Met QC Criteria: August 28, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Digestive System Diseases; Substance-Related Disorders; Liver Diseases; Alcohol-Related Disorders
• Other Study ID Numbers: 22-00428

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No