A Novel Pharmacotherapy for Alcoholism and Alcohol Liver Disease
Primary Purpose
Alcoholism,, Alcoholic Liver Disease
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Metadoxine
Sponsored by
About this trial
This is an interventional treatment trial for Alcoholism,
Eligibility 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.
Sites / Locations
- Brown University Center for Alcohol and Addiction Studies
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Metadoxine
Sugar pill
Arm Description
Metadoxine 500mg tablet t.i.d.for 12 weeks
Placebo group
Outcomes
Primary Outcome Measures
Percent Days Abstinent (PDA)
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).
Secondary Outcome Measures
Follow-up PDA
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
We hypothesize that MTDX, compared to placebo has no greater frequency and intensity of Adverse Events (AE).
Full Information
NCT ID
NCT01504295
First Posted
January 4, 2012
Last Updated
July 20, 2015
Sponsor
Brown University
Collaborators
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
1. Study Identification
Unique Protocol Identification Number
NCT01504295
Brief Title
A Novel Pharmacotherapy for Alcoholism and Alcohol Liver Disease
Official Title
A Novel Pharmacotherapy for Alcoholism and Alcohol Liver Disease
Study Type
Interventional
2. Study Status
Record Verification Date
July 2015
Overall Recruitment Status
Completed
Study Start Date
April 2012 (undefined)
Primary Completion Date
January 2015 (Actual)
Study Completion Date
February 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Brown University
Collaborators
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
It is proposed to test metadoxine (MTDX) that it is hypothesized to be 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.
Detailed Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alcoholism,, Alcoholic Liver Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
38 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Metadoxine
Arm Type
Experimental
Arm Description
Metadoxine 500mg tablet t.i.d.for 12 weeks
Arm Title
Sugar pill
Arm Type
Placebo Comparator
Arm Description
Placebo group
Intervention Type
Drug
Intervention Name(s)
Metadoxine
Intervention Description
Improve Liver Function and Reduce ALcohol Use
Primary Outcome Measure Information:
Title
Percent Days Abstinent (PDA)
Description
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).
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Follow-up PDA
Description
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.
Time Frame
12 weeks
Title
Adverse Events
Description
We hypothesize that MTDX, compared to placebo has no greater frequency and intensity of Adverse Events (AE).
Time Frame
12 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
George A Kenna, PhD RPh
Organizational Affiliation
Brown University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Brown University Center for Alcohol and Addiction Studies
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02912
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
11923586
Citation
Shpilenya LS, Muzychenko AP, Gasbarrini G, Addolorato G. Metadoxine in acute alcohol intoxication: a double-blind, randomized, placebo-controlled study. Alcohol Clin Exp Res. 2002 Mar;26(3):340-6.
Results Reference
background
PubMed Identifier
14611722
Citation
Addolorato G, Ancona C, Capristo E, Gasbarrini G. Metadoxine in the treatment of acute and chronic alcoholism: a review. Int J Immunopathol Pharmacol. 2003 Sep-Dec;16(3):207-14. doi: 10.1177/039463200301600304.
Results Reference
background
PubMed Identifier
22095793
Citation
Leggio L, Kenna GA, Ferrulli A, Zywiak WH, Caputo F, Swift RM, Addolorato G. Preliminary findings on the use of metadoxine for the treatment of alcohol dependence and alcoholic liver disease. Hum Psychopharmacol. 2011 Dec;26(8):554-9. doi: 10.1002/hup.1244. Epub 2011 Nov 16.
Results Reference
background
PubMed Identifier
17176456
Citation
Guerrini I, Gentili C, Nelli G, Guazzelli M. A follow up study on the efficacy of metadoxine in the treatment of alcohol dependence. Subst Abuse Treat Prev Policy. 2006 Dec 18;1:35. doi: 10.1186/1747-597X-1-35.
Results Reference
background
PubMed Identifier
9537864
Citation
Caballeria J, Pares A, Bru C, Mercader J, Garcia Plaza A, Caballeria L, Clemente G, Rodrigo L, Rodes J. Metadoxine accelerates fatty liver recovery in alcoholic patients: results of a randomized double-blind, placebo-control trial. Spanish Group for the Study of Alcoholic Fatty Liver. J Hepatol. 1998 Jan;28(1):54-60. doi: 10.1016/s0168-8278(98)80202-x.
Results Reference
background
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A Novel Pharmacotherapy for Alcoholism and Alcohol Liver Disease
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