Clinical trial NCT05623501: Phase I, Dose-Escalation Study of Dihydromyricetin (DHM) to Treat Alcohol-Associated Liver Disease
Official title: Phase I, Dose-Escalation Study of Dihydromyricetin (DHM) to Treat Alcohol-Associated Liver Disease
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Alcohol-Related Disorders
Lead sponsor: University of Southern California
Sponsor class: OTHER
First posted: 2022-11-21
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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 as liquid suspension. Cohort 2 will consist of three healthy volunteers who will receive DHM in two doses of 900 mg as liquid suspension. 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, requiring two consecutive days of visits to research clinic. Evaluations will be taken at uniform intervals.
Primary purpose: TREATMENT

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).

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).

Eligibility criteria: 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

Primary outcomes:
measure: Pharmacokinetic of DHM
timeFrame: -0.5 (pre-dose), 0 (1st dose), 0.5, 1, 2, 4, 6, 8 (2nd dose), 10, and 24 hours post-dose.
measure: Adverse Events
timeFrame: 24 hours post-dose
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
Study officials:
affiliation: University of Southern California
name: Brian Lee, MD
role: PRINCIPAL_INVESTIGATOR
References: