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

Sponsor

University of Southern California (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05623501

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Alcohol-Related Disorders	Drug: Dihydromyricetin	Phase 1

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

12 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This is a single-center dose-escalation study. A total of 12 participants are planned and will be divided into 4 cohorts with 3 participants per cohort. Cohort 1 will consist of three healthy volunteers who will receive DHM in two doses of 300 mg. Cohort 2 will consist of three healthy volunteers who will receive DHM in two doses of 900 mg. Cohort 3 will consist of three healthy volunteers who will receive DHM in two 50mL PO solution doses of 300 mg plus 140mg L-lysine. Cohort 4 will consist of three healthy volunteers who will receive DHM in two 50mL PO solution doses of 900 mg plus 420mg L-lysine. Each participant will be administered the study drug during a 24-hour period. Evaluations will be taken at uniform intervals.This is a single-center dose-escalation study. A total of 12 participants are planned and will be divided into 4 cohorts with 3 participants per cohort. Cohort 1 will consist of three healthy volunteers who will receive DHM in two doses of 300 mg. Cohort 2 will consist of three healthy volunteers who will receive DHM in two doses of 900 mg. Cohort 3 will consist of three healthy volunteers who will receive DHM in two 50mL PO solution doses of 300 mg plus 140mg L-lysine. Cohort 4 will consist of three healthy volunteers who will receive DHM in two 50mL PO solution doses of 900 mg plus 420mg L-lysine. Each participant will be administered the study drug during a 24-hour period. Evaluations will be taken at uniform intervals.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Dec 1, 2022

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Dec 31, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Pharmacokinetics [-0.5 (pre-dose), 0 (1st dose), 0.5, 1, 2, 4, 6, 8 (2nd dose), 12, and 24 hours post-dose.]
serum DHM metabolites will be performed using MRM mass
Adverse Events [24 hours post-dose]
The National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 will be used to assess and grade AE severity

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Southern California	Los Angeles	California	United States	90089

Sponsors and Collaborators

University of Southern California

Investigators

Principal Investigator: Brian Lee, MD, University of Southern California

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Brian P. Lee, Assistant Professor of Medicine, University of Southern California

ClinicalTrials.gov Identifier:

NCT05623501

Other Study ID Numbers:

22-00428

First Posted:

Nov 21, 2022

Last Update Posted:

Nov 21, 2022

Last Verified:

Nov 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Undecided

Plan to Share IPD:

Undecided

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Liver Diseases

Alcohol-Related Disorders

Study Results

No Results Posted as of Nov 21, 2022