A Novel Pharmacotherapy for Alcoholism and Alcohol Liver Disease

The recruitment status of this study is unknown because the information has not been verified recently.
Verified January 2012 by Brown University.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Information provided by:
Brown University
ClinicalTrials.gov Identifier:
NCT01504295
First received: January 4, 2012
Last updated: January 2, 2013
Last verified: January 2012
  Purpose

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
Alcoholism,
Alcoholic Liver Disease
Drug: Metadoxine
Drug: Placebo
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) [ 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 [ 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 [ 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.

  • Liver Tests [ Designated as safety issue: No ]
    We hypothesize that MTDX, compared to placebo results in significantly improved liver tests (i.e. AST, ALT, GGT, bilirubin, albumin), during the 12 weeks of drug administration, as well as from discontinuation of the medication to the 3-month follow-up.

  • Quality of Life [ Designated as safety issue: No ]
    We hypothesize that MTDX, compared to placebo results in significantly improved quality of life, as measured by the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF).

  • Alcohol Craving [ Designated as safety issue: No ]
    We hypothesize that MTDX, compared to placebo results in significantly reduced craving for alcohol, as measured by the Obsessive Compulsive Drinking Scale (OCDS).

  • Adverse Events [ 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: December 2012
Arms Assigned Interventions
Experimental: Metadoxine
Metadoxine 500mg t.i.d.
Drug: Metadoxine
Placebo Comparator: Placebo Drug: Placebo

  Eligibility

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

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

Contacts
Contact: Lorenzo Leggio, MD 401-863-6638

Locations
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: Lorenzo Leggio, MD, PhD, Msc         
Principal Investigator: George A Kenna, PhD, RPh         
Sub-Investigator: Robert M Swift, MD, PhD         
Sub-Investigator: William H Zywiak, PhD         
Sub-Investigator: Kittichai Promrat, MD         
Sub-Investigator: Jack R Wands, MD         
Sponsors and Collaborators
Brown University
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT01504295     History of Changes
Other Study ID Numbers: AA021128, R21AA021128
Study First Received: January 4, 2012
Last Updated: January 2, 2013
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on April 16, 2014