Randomized, Controlled Trial of S-adenosylmethionine in Alcoholic Liver Disease (RCT SAMe)

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
Loma Linda University
ClinicalTrials.gov Identifier:
NCT00851981
First received: February 24, 2009
Last updated: September 9, 2010
Last verified: September 2010
  Purpose

Background: Alcoholic liver disease is one of the most important causes of chronic liver disease in this country. There is currently no treatment for chronic alcoholic liver disease other than abstinence. Hepatic methionine metabolism is abnormal in these patients and one of the consequences is depletion of S-adenosylmethionine (SAMe) levels, which can affect numerous important cellular processes. SAMe has been increasingly utilized for the treatment of liver diseases although the protective mechanisms remain unclear. A recent randomized double-blind trial using SAMe in patients with alcoholic liver disease and found improvement in 2-year survival in those with less advanced liver disease. However, important changes in methionine metabolism and histological changes were not included in the study. Aim: The goal of this study is to determine the effect of SAMe administration on key metabolic abnormalities of the methionine cycle and on the recovery from alcoholic liver disease.


Condition Intervention Phase
Alcoholic Hepatitis
Other: Placebo
Dietary Supplement: SAMe
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Effect of Oral S-Adenosylmethionine Administration on Abnormalities of Hepatic Methionine Metabolism and Disease Progression in Alcoholic Liver Disease. A Randomized, Double Blind, Placebo-controlled Trial

Resource links provided by NLM:


Further study details as provided by Loma Linda University:

Primary Outcome Measures:
  • Change in plasma homocysteine, hepatic GSH and SAMe levels and hepatic expression of TNF,MAT1A,MAT2A,MS,CBS and BHMT. [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Changes in routine liver pathology,c-myc expression and markers of apoptosis, stellate cell activation and hepatocyte proliferation. [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: October 2008
Study Completion Date: May 2010
Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: 1 Other: Placebo
TID
Active Comparator: SAMe Dietary Supplement: SAMe
300 mg TID

Detailed Description:

Methods: This is a randomized, double blind, placebo-controlled trial. Thirty patients with stable alcoholic hepatitis (Maddrey Score < 32) without cirrhosis who meet entry criteria will receive either 400 mg of SAMe (n=15) or placebo (n=15) three times a day for the duration of one year. History, physical assessment, various blood tests and a liver biopsy will be performed prior to treatment. Patients will have repeat blood tests on subsequent follow-up visits every month for the first two months, then every two months thereafter. They will also be encouraged to abstain from alcohol during these visits. A post-treatment liver biopsy will be obtained at the end of the trial. The primary outcome parameters include serum homocysteine, SAMe and TNFalpha levels, and the expression of key hepatic enzymes of the methionine cycle and of hepatic SAMe and glutathione levels. Histological progression of alcoholic liver disease, clinical and biochemical indices of liver disease, and quality of life assessment will also be examined.

  Eligibility

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

Inclusion Criteria:

  • Patients must be chronic alcohol users, defined by a history of ethanol consumption on average > 40g/day for women and 60g/day for men for at least 1 year before inclusion.
  • The presumptive diagnosis for alcoholic hepatitis will be: recent binge drinking; compatible physical findings (one or more: jaundice, enlarged liver, hepatic bruit, abdominal pain, loss of appetite, nausea); and a compatible biochemical profile (moderate elevation of AST over ALT, elevated total serum bilirubin); or a liver-spleen colloid scan suggestive of reticulo-endothelial redistribution and hepatic arterialization.
  • The diagnosis of alcoholic hepatitis must be confirmed on liver biopsy, showing typical features of acute sclerosing hyaline necrosis 70.
  • The degree of portal fibrosis as determined on liver biopsy, graded according to the Knodell score-modified by Ishak 71 must be less than or equal to 5 out of a possible score of 6, 6 indicating cirrhosis.
  • The alcoholic hepatitis must be "stable", i.e. not requiring treatment by either pentoxifylline 72 or prednisone, with a Maddrey Score 73 {(PTpatient - PTcontrol) x 4.6 + TBmg/dL} < 32.
  • Patients must be willing to participate in the trial, remain abstinent to alcohol, and compliant to the treatment regimen, and undergo a post-treatment liver biopsy.

Exclusion Criteria:

  • Patients who have either compensated cirrhosis (biopsy proven) or a clinical picture of severe cirrhosis defined as Child's class C and/or with a recent history (within one month) of decompensated liver disease (history of ascites, encephalopathy or variceal bleeding within one month of trial entry). These patients have reduced life expectancy below one year and are most often severely coagulopathic and cannot be biopsied.
  • Patients who have severe acute alcoholic hepatitis of poor prognosis defined as a Maddrey Score > 32. These patients have a mortality rate of 50% during their hospitalization period when untreated by either prednisone or pentoxifylline.
  • Patients who are receiving hepatotropic treatments such as colchicine, penicillamine, corticosteroids, ursodeoxycholic acid, and pentoxifylline.
  • Patients who are receiving known hepatotoxic long-term treatments such as NSAIDs, statins, neuroleptics, certain anti-convulsive medications, or high-dose acetaminophen.
  • Patients suspected of having hepatocellular carcinoma.
  • Patients who have contra-indications to liver biopsy.
  • Patients who have a liver biopsy that does not yield sufficient specimen for analyses.
  • Patients who have untreated deficiencies of folic acid, vitamin B6 or B12.
  • Patients who have chronic active Hepatitis B or C, hemochromatosis, autoimmune hepatitis, or a cholangiopathy.
  • Patients with psychotic disorders, and in particular manic depression (contra indication to SAMe treatment).
  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: NCT00851981

Locations
United States, California
Loma Linda University
Loma Linda, California, United States, 92354
Sponsors and Collaborators
Loma Linda University
Investigators
Principal Investigator: Michel H Mendler, M.D. Loma Linda Univeristy
  More Information

No publications provided

Responsible Party: Michel H. Mendler, M.D. / PI, Loma Linda Univeristy
ClinicalTrials.gov Identifier: NCT00851981     History of Changes
Other Study ID Numbers: 55302, 1R21AA014269-01A1
Study First Received: February 24, 2009
Last Updated: September 9, 2010
Health Authority: United States: Institutional Review Board

Keywords provided by Loma Linda University:
Alcohol Liver Disease

Additional relevant MeSH terms:
Hepatitis, Alcoholic
Hepatitis
Hepatitis A
Liver Diseases
Liver Diseases, Alcoholic
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Alcohol-Induced Disorders
Alcohol-Related Disorders
Substance-Related Disorders

ClinicalTrials.gov processed this record on July 10, 2014