Liver Cancer Prevention Trial in Patients With Chronic Hep C Infection

Phase 2

Completed

Conditions: Adult Primary Liver Cancer
Hepatitis C Infection

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

Registration Number: NCT00513461

Lead Sponsor: Chao Family Comprehensive Cancer Center

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 110

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (SAMe)	S-adenosyl-L-methionine disulfate p-toluene-sulfonate	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.
Arm I (SAMe)	laboratory biomarker analysis	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.
Arm I (SAMe)	immunoenzyme technique	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.
Arm I (SAMe)	high performance liquid chromatography	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.
Arm II (placebo)	placebo	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.
Arm II (placebo)	laboratory biomarker analysis	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.
Arm II (placebo)	immunoenzyme technique	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.
Arm II (placebo)	high performance liquid chromatography	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.

Primary Outcome Measures

Name	Time	Method
Change in Serum AFP Levels	Baseline to week 24	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.

Secondary Outcome Measures

Name	Time	Method
SAMe	Baseline to week 24	Change in SAMe levels
Change in SAMe Metabolites - S-adenosylhomocysteine (SAH)	Baseline to week 24	S-adenosylhomocysteine (SAH)
Change in SAMe Metabolites - Methionine	Baseline to week 24	Methionine will be measured using HPLC with fluorescence detection.
Change in SAMe Metabolites - Total Homocysteine (tHcy)	Baseline to week 24	Total homocysteine (tHcy)
Treatment-related Changes in Serum DCP for Hepatocellular Carcinoma	Baseline to week 24	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).
Treatment-related Changes in Serum AFP-L3 (Expressed as the Percentage of Total AFTP) for Hepatocellular Carcinoma	Baseline to week 24	AFP-L3 assay will be performed by Wako Laboratories using their LiBASys platform.
Change in SAMe Metabolites - Plasma GSH	Baseline to week 24	Plasma GSH will be measured using HPLC with fluorescence detection.
Change in SAMe Metabolites - Malondialdehyde (MDA)	Baseline to week 24	malondialdehyde
Change in SAMe Metabolites - 4-hydroxynonenal (4-HNE)	Baseline to week 24	Serum marker of oxidative stress. One mechanism by which SAMe is hypothesized to be beneficial is by reducing oxidative stress.
Change in Markers of Liver Disease - AST	Baseline to week 24	AST measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays.
Change in Markers of Liver Disease - ALT	Baseline to week 24	ALT measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays.
HCV RNA	Baseline to week 24	Change in HCV RNA levels. Serum level of HVC RNA was measured using COBAS TaqMan HCV test (Roche Molecular Systems).
Changes in Quality of Life - Physical Score	Baseline to week 24	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).
Changes in Quality of Life - Mental Score	Baseline to week 24	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).

Trial Locations

Locations (5): University of California At San Diego
🇺🇸
San Diego, California, United States
Veterans Administration Los Angeles Healthcare System
🇺🇸
Los Angeles, California, United States
University of Arizona Health Sciences Center
🇺🇸
Tucson, Arizona, United States
Chao Family Comprehensive Cancer Center
🇺🇸
Orange, California, United States
Veterans Administration Long Beach Medical Center
🇺🇸
Long Beach, California, United States