Liver Cancer Prevention Trial in Patients With Chronic Hep C Infection

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

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

Study Overview

• Status: Completed
• Conditions: Adult Primary Liver Cancer; Hepatitis C Infection
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: placebo; Drug: S-adenosyl-L-methionine disulfate p-toluene-sulfonate; Other: immunoenzyme technique; Other: high performance liquid chromatography

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.

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona Health Sciences Center
  • California
    • Long Beach, California, United States, 90822
      • Veterans Administration Long Beach Medical Center
    • Los Angeles, California, United States, 90073
      • Veterans Administration Los Angeles Healthcare System
    • Orange, California, United States, 92868
      • Chao Family Comprehensive Cancer Center
    • San Diego, California, United States, 92103
      • University of California at San Diego

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (SAMe); 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.	Other: laboratory biomarker analysis; Correlative studies; Drug: S-adenosyl-L-methionine disulfate p-toluene-sulfonate; Given PO; Other Names: SAMe disulfate p-toluene-sulfonate; Other: immunoenzyme technique; Correlative studies; Other Names: immunoenzyme techniques; Other: high performance liquid chromatography; Correlative studies; Other Names: HPLC
Placebo Comparator: Arm II (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.	Other: laboratory biomarker analysis; Correlative studies; Other: placebo; Given PO; Other Names: PLCB; Other: immunoenzyme technique; Correlative studies; Other Names: immunoenzyme techniques; Other: high performance liquid chromatography; Correlative studies; Other Names: HPLC

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Chao Family Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: John Hoefs, Chao Family Comprehensive Cancer Center

Publications and helpful links

General Publications

• Morgan TR, Osann K, Bottiglieri T, Pimstone N, Hoefs JC, Hu KQ, Hassanein T, Boyer TD, Kong L, Chen WP, Richmond E, Gonzalez R, Rodriguez LM, Meyskens FL. A Phase II Randomized, Controlled Trial of S-Adenosylmethionine in Reducing Serum alpha-Fetoprotein in Patients with Hepatitis C Cirrhosis and Elevated AFP. Cancer Prev Res (Phila). 2015 Sep;8(9):864-72. doi: 10.1158/1940-6207.CAPR-15-0029. Epub 2015 Jun 30.

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: August 6, 2007
• First Submitted That Met QC Criteria: August 6, 2007
• First Posted (Estimate): August 8, 2007

Study Record Updates

• Last Update Posted (Actual): August 10, 2018
• Last Update Submitted That Met QC Criteria: August 9, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Communicable Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Infections; Hepatitis; Hepatitis C; Liver Neoplasms
• Other Study ID Numbers: UCI 06-07 / NCI-2009-00897; N01CN35160 (U.S. NIH Grant/Contract); CDR0000558657 (Registry Identifier: PDQ (Physician Data Query)); UCI04-3-01 (Other Grant/Funding Number: NCI)