A Novel Pharmacotherapy for Alcoholism and Alcohol Liver Disease

Treatments for ALD have limited success when drinking continues. Cessation of alcohol
consumption or a significant reduction in alcohol intake improves histology and survival of
patients with any stage of ALD. While alcohol abstinence may not be sufficient to provide a
total recovery of ALD, patients with uncomplicated ALD have a 5-year survival of almost 90%
if they stop drinking. Consequently, abstinence is the most important therapeutic
intervention for patients with ALD. When combined with psychosocial treatments, currently
approved medications can improve outcomes for some AD individuals; however, these treatments
are unsuccessful for many others. One of the limiting factors that must be taken into
consideration when using currently approved medications such as disulfiram or naltrexone is
liver function. Given their hepatic metabolism, disulfiram or naltrexone both increase the
risk of hepatotoxicity in AD individuals. Therefore, a pharmacotherapy that is effective for
AD, that is safe for the liver and able to recover alcohol-related liver damage thereby
improving liver function, would be an ideal medication. However as of now, no drug has been
found to provide all of these benefits to AD individuals. It is proposed therefore to test
metadoxine (MTDX) that it is hypothesized is significantly beneficial for the treatment of
alcoholism and ALD. Metadoxine is currently approved in Europe for acute and chronic alcohol
intoxication but has never been tested in the US. Furthermore, MTDX is used in Europe to
treat ALD. Preliminary evidence shows that MTDX reduces alcohol consumption in AD
individuals. If the role of MTDX in reducing alcohol consumption and improve liver function
is confirmed by a rigorous study design, then MTDX might represent a truly innovative
pharmacotherapy for AD, given the potential to be used for AD individuals with ALD. However
until this proposal, MTDX has never been investigated as a treatment for AD able to reduce
both alcohol consumption and improve alcohol-related liver damage via a double-blind
placebo-controlled study. This project therefore proposes to conduct a 12-week (followed by
a 3-month follow-up), double-blind, placebo-controlled, between-subject randomized clinical
trial with MTDX (500mg t.i.d.) in AD individuals.

Inclusion Criteria:

- age ≥18;

- females must be post-menopausal for ≥1 year, surgically sterile, or practicing a
birth control before entry and throughout the study; have a negative urine pregnancy
test at screening and before randomization;

- current DSM-IV diagnosis of alcohol use disorder (or if relevant at study
start-DSM-V) with current (i.e. past 90 days prior to screening) "at-risk" drinking
defined as an average overall consumption of ≥28 drinks/week for men and ≥21
drinks/week for women;

- desire abstinence;

- evidence of alcoholic liver disease (ALD) based on a thorough history, physical
examination, and laboratory tests (i.e. the De Ritis ratio of AST:ALT ratio ~2:1),
which is characteristic of ALD.

Exclusion Criteria:

- lifetime DSM diagnosis of schizophrenia, bipolar disorder, or other psychosis;

- in the investigators' opinion, risk of suicide (e.g. active plan, or recent attempt
in last year);

- current DSM-IV diagnosis of dependence on any psychoactive substance other than
alcohol and nicotine;

- repeated positive urine screen for any substance other than marijuana;

- history of hospitalization for alcohol intoxication delirium or alcohol withdrawal
delirium;

- Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) score >10, at any
assessment;

- having received a psychological and/or pharmacological treatment for alcohol or
having participated in a treatment research study within the past 90 days;

- having participated in any clinical trial with an investigational agent within the
past 30 days;

- treatment with levodopa/carbidopa or reported diagnosis of Parkinson's disease;

- AST and/or ALT >10 x upper normal limit; Child-Pugh-Turcotte (CPT) score stage C,
model for end-stage liver disease (MELD) score >21 (CPT and MELD scores are assessed
by blood tests - e.g. bilirubin, albumin, INR, Cr - and medical history); and/or
medical history positive for decompensated liver disease (ascites, encephalopathy,
variceal bleeding or hepatorenal syndrome) and/or medical history positive for
hepatocellular carcinoma; 11) history of allergy to MTDX or PCA and pyridoxol;

- other serious illnesses, e.g. kidney failure.