Liver Cancer Prevention Trial in Patients With Chronic Hep C Infection

Study Overview
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Brief Summary
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This randomized phase II trial studies how well S-Adenosyl-L-Methionine Disulphate P-Toluene-Sulfonate (SAMe) works compared to a placebo in preventing liver cancer in patients with chronic hepatitis C infection. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of SAMe may keep cancer from forming in patients with advanced liver disease

Detailed Description
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PRIMARY OBJECTIVE: I. To determine whether treatment with SAMe for 24 weeks reduces serum level of alpha-fetoprotein (AFP) in patients with advanced liver disease due to chronic hepatitis C. SECONDARY OBJECTIVE: I. To determine whether treatment with SAMe for 24 weeks reduces serum levels of des-gamma carboxyprothrombin (DCP) and alpha-fetoprotein-L3 (AFP-L3) in patients with advanced liver disease due to chronic hepatitis C (hepatocellular carcinoma tumor markers). II. To determine whether treatment with SAMe for 24 weeks alters biochemical markers of liver disease (e.g., serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], albumin, or bilirubin, etc.) and hepatitis C viral load in patients with advanced liver disease due to chronic hepatitis C (hepatitis C liver disease). III. To determine whether treatment with SAMe for 24 weeks reduces serum levels of tumor necrosis factor-alpha (TNF-alpha), plasma levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) and urine levels of F2-isoprostane in patients with advanced liver disease due to chronic hepatitis C (oxidative stress). IV. To determine whether treatment with SAMe for 24 weeks reduces plasma levels of methionine and homocysteine and increases plasma glutathione (GSH) and SAMe in patients with advanced liver disease due to chronic hepatitis C (SAMe metabolites). V. To determine the safety, tolerability and quality of life of SAMe treatment (up to 2,400 mg/day) for 24 weeks in patients with advanced liver disease due to chronic hepatitis C. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive SAMe orally (PO) twice daily (BID) for 24 weeks in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive placebo PO once daily (QD) for weeks 1-4, PO BID for weeks 5-8, and PO three times daily (TID) for weeks 9-24 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 6 weeks.

Official Title
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A Phase II, Randomized, Controlled Trial of The Safety and Efficacy of S-Adenosyl-L-Methionine Disulphate P-Toluene-Sulfonate (SAMe) in Reducing Serum Alpha-Fetoprotein (AFP) in Patients With Hepatitis C and Moderately Elevated AFP

Conditions
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Adult Primary Liver Cancer, Hepatitis C Infection

Intervention / Treatment
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* Drug: S-adenosyl-L-methionine disulfate p-toluene-sulfonate
* Other: placebo
* Other: laboratory biomarker analysis
* Other: immunoenzyme technique
* Other: high performance liquid chromatography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic hepatitis C infection diagnosed by presence of hepatitis C ribonucleic acid (RNA) in serum by test of hepatitis C virus (HCV) RNA No significant alcohol use (7 or fewer drinks per week) for the past 12 months Serum AFP (at screening) between 15 and 100 ng/mL (15 ng/mL =< AFP =< 100 ng/mL) as measured by the Bayer Advai Centaur chemiluminescence system OR Serum AFP between 10 and 100 ng/mL (10 ng/mL =< AFP =<100 ng/mL) as measured by Diagnostic Products Corporation Immulite assay system OR AFP between 12 and 100 ng/mL (12 ng/mL =< AFP =< 100 ng/mL) as measured by Ortho ECiQ assay system Evidence of advanced liver disease based on one or more of the following: Platelet count less than 150,000/mm^3 Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio > 0.75 Liver biopsy demonstrating bridging fibrosis or cirrhosis No treatment with interferon (recombinant interferon alfa), peginterferon (PEG-interferon alfa-2b), or ribavirin for at least 4 months, and not anticipated to start specific treatment for hepatitis C during the study (30 weeks) Ultrasound (or adequate computed tomography [CT] or magnetic resonance imaging [MRI]) examination of the liver within 6 months prior to randomization revealing no masses in the liver suggestive of hepatocellular carcinoma Willing to refrain from consuming over-the-counter SAMe and vitamin pills containing B-vitamins while participating in this study (30 weeks) Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Leukocytes > 1,000/ mm^3 Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Liver disease other than from hepatitis C (e.g., hepatitis B, hemochromatosis, fat in more than 33% of hepatocytes, if liver biopsy has been performed., etc.); subjects with a past history of alcohol use can be enrolled into the study provided they have consumed less than 7 drinks/week for the past 12 months Evidence of mass in liver by radiologic examination that is suggestive of hepatocellular carcinoma within 6 months prior to randomization Model for End-Stage Liver Disease (MELD) score greater than 15 within 60 days prior to enrollment Ascites which is clinically detectable Use of SAMe during 4 months prior to randomization Hospitalization within the past 5 years for mania or for bipolar disease Concurrent use of monoamine oxidase inhibitors (MAO) or other drugs that increase the concentration of serotonin Participants may not be receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to SAMe Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Children are excluded from this study but will be eligible for future pediatric trials, if applicable Pregnant women are excluded from this study; serum pregnancy must be performed and be negative in all women of child bearing potential within 2 weeks prior to enrollment; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with SAMe, breastfeeding should be discontinued if the mother is treated with SAMe Subjects with any medical psychosocial condition that, in the opinion of the investigator, could jeopardize the subject's participation in and compliance with the study criteria

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (SAMe)<br>Patients receive SAMe PO QD for weeks 1-4, PO BID for weeks 5-8, and PO TID for weeks 9-24 in the absence of disease progression or unacceptable toxicity. | Drug: S-adenosyl-L-methionine disulfate p-toluene-sulfonate<br>* Given PO<br>* Other names: SAMe disulfate p-toluene-sulfonate;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: immunoenzyme technique<br>* Correlative studies<br>* Other names: immunoenzyme techniques;Other: high performance liquid chromatography<br>* Correlative studies<br>* Other names: HPLC;|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO QD for weeks 1-4, PO BID for weeks 5-8, and PO TID for weeks 9-24 in the absence of disease progression or unacceptable toxicity. | Other: placebo<br>* Given PO<br>* Other names: PLCB;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: immunoenzyme technique<br>* Correlative studies<br>* Other names: immunoenzyme techniques;Other: high performance liquid chromatography<br>* Correlative studies<br>* Other names: HPLC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum AFP Levels | Measured using an Food and Drug Administration (FDA)-approved assay. Mean change over time for the SAMe and placebo groups will be estimated. Differences in the change over time between the treated and control groups will be tested using a two-group repeated measures analysis of variance model. | Baseline to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related Changes in Serum DCP for Hepatocellular Carcinoma | To determine whether treatment with SAMe for 24 weeks reduces serum levels of des-gamma carboxyprothrombin (DCP) in patients with advanced liver disease due to chronic hepatitis C (hepatocellular carcinoma tumor markers). | Baseline to week 24 | 
| Treatment-related Changes in Serum AFP-L3 (Expressed as the Percentage of Total AFTP) for Hepatocellular Carcinoma | AFP-L3 assay will be performed by Wako Laboratories using their LiBASys platform. | Baseline to week 24 | 
| SAMe | Change in SAMe levels | Baseline to week 24 | 
| Change in SAMe Metabolites - S-adenosylhomocysteine (SAH) | S-adenosylhomocysteine (SAH) | Baseline to week 24 | 
| Change in SAMe Metabolites - Methionine | Methionine will be measured using HPLC with fluorescence detection. | Baseline to week 24 | 
| Change in SAMe Metabolites - Total Homocysteine (tHcy) | Total homocysteine (tHcy) | Baseline to week 24 | 
| Change in SAMe Metabolites - Plasma GSH | Plasma GSH will be measured using HPLC with fluorescence detection. | Baseline to week 24 | 
| Change in SAMe Metabolites - Malondialdehyde (MDA) | malondialdehyde | Baseline to week 24 | 
| Change in SAMe Metabolites - 4-hydroxynonenal (4-HNE) | Serum marker of oxidative stress. One mechanism by which SAMe is hypothesized to be beneficial is by reducing oxidative stress. | Baseline to week 24 | 
| Change in Markers of Liver Disease - AST | AST measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays. | Baseline to week 24 | 
| Change in Markers of Liver Disease - ALT | ALT measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays. | Baseline to week 24 | 
| HCV RNA | Change in HCV RNA levels. Serum level of HVC RNA was measured using COBAS TaqMan HCV test (Roche Molecular Systems). | Baseline to week 24 | 
| Changes in Quality of Life - Physical Score | Change from Baseline to Week 24 in Quality of life as as assessed with Short Form (SF)-36 Physical Component Scores. Measured quality of life using the SF-36, a widely used and general questionnaire of quality of life. Possible scores range from 0 and 100. High scores reflect good QOL and low scores reflect bad QOL. Change in QOL = (Week 24 score - Baseline score). | Baseline to week 24 | 
| Changes in Quality of Life - Mental Score | Change from Baseline to Week 24 in Quality of life as as assessed with Short Form (SF)-36 Mental Component Scores. Measured quality of life using the SF-36, a widely used and general questionnaire of quality of life. Possible scores range from 0 and 100. High scores reflect good QOL and low scores reflect bad QOL. Change = (Week 24 score - Baseline score). | Baseline to week 24 |