A Novel Pharmacotherapy for Alcoholism and Alcohol Liver Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Brown University
Information provided by (Responsible Party):
George Kenna, Brown University
ClinicalTrials.gov Identifier:
First received: January 4, 2012
Last updated: July 15, 2014
Last verified: July 2014

Alcohol use disorders in the United States (US) account for about 1 death every 5 minutes including 32% of all traffic fatalities, an average of one fatality related to alcohol every 39 minutes. Alcohol liver disease (ALD) is often present in alcohol dependent (AD) patients. 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.

Condition Intervention Phase
Alcoholic Liver Disease
Drug: Metadoxine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Novel Pharmacotherapy for Alcoholism and Alcohol Liver Disease

Resource links provided by NLM:

Further study details as provided by Brown University:

Primary Outcome Measures:
  • Percent Days Abstinent (PDA) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    We hypothesize that metadoxine (MTDX), compared to placebo significantly increases percent days abstinent (PDA) during the 12 weeks of drug administration, as measured by the timeline follow-back (TLFB).

  • AST/ALT ratio [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    We hypothesize that MTDX, compared to placebo results in significant reduction in the AST/ALT ratio (a typical biomarker of alcoholic liver disease [ALD]) during the 12 weeks of drug administration.

Secondary Outcome Measures:
  • Follow-up PDA [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    We hypothesize that MTDX, compared to placebo results in significantly higher PDA from discontinuation of the medication to the 3-month follow-up, as measured by the TLFB.

  • Adverse Events [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
    We hypothesize that MTDX, compared to placebo has no greater frequency and intensity of Adverse Events (AE).

Estimated Enrollment: 83
Study Start Date: April 2012
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Metadoxine
Metadoxine 500mg tablet t.i.d.for 12 weeks
Drug: Metadoxine
Placebo Comparator: Sugar pill
Placebo group
Drug: Metadoxine


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01504295

Contact: Lorenzo Leggio, MD 401-863-6638

United States, Rhode Island
Brown University Center for Alcohol and Addiction Studies Recruiting
Providence, Rhode Island, United States, 02912
Contact: Lorenzo Leggio, MD    401-863-6638      
Principal Investigator: George A Kenna, PhD RPh         
Principal Investigator: Lorenzo Leggio, MD,PhD, MS         
Sub-Investigator: Robert M Swift, MD, PhD         
Sub-Investigator: William H Zywiak, PhD         
Sponsors and Collaborators
Brown University
  More Information

Responsible Party: George Kenna, Assistant Professor of Psychiatry, Brown University
ClinicalTrials.gov Identifier: NCT01504295     History of Changes
Other Study ID Numbers: AA021128, R21AA021128
Study First Received: January 4, 2012
Last Updated: July 15, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Liver Diseases
Liver Diseases, Alcoholic
Alcohol-Induced Disorders
Alcohol-Related Disorders
Chemically-Induced Disorders
Digestive System Diseases
Mental Disorders
Substance-Related Disorders
Alcohol Deterrents
Central Nervous System Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on July 05, 2015