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

Study Overview
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Brief Summary
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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).

Detailed Description
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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).

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

Conditions
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Alcohol-Related Disorders

Intervention / Treatment
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* Drug: Dihydromyricetin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics | 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), 12, and 24 hours post-dose. | 
| 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 |