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Liver Cancer Prevention Trial in Patients With Chronic Hep C Infection

Primary Purpose

Adult Primary Liver Cancer, Hepatitis C Infection

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
S-adenosyl-L-methionine disulfate p-toluene-sulfonate
placebo
laboratory biomarker analysis
immunoenzyme technique
high performance liquid chromatography
Sponsored by
Chao Family Comprehensive Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Adult Primary Liver Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Arizona Health Sciences Center
  • Veterans Administration Long Beach Medical Center
  • Veterans Administration Los Angeles Healthcare System
  • Chao Family Comprehensive Cancer Center
  • University of California At San Diego

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm I (SAMe)

Arm II (placebo)

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).
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.
SAMe
Change in SAMe levels
Change in SAMe Metabolites - S-adenosylhomocysteine (SAH)
S-adenosylhomocysteine (SAH)
Change in SAMe Metabolites - Methionine
Methionine will be measured using HPLC with fluorescence detection.
Change in SAMe Metabolites - Total Homocysteine (tHcy)
Total homocysteine (tHcy)
Change in SAMe Metabolites - Plasma GSH
Plasma GSH will be measured using HPLC with fluorescence detection.
Change in SAMe Metabolites - Malondialdehyde (MDA)
malondialdehyde
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.
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.
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.
HCV RNA
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
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
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).

Full Information

First Posted
August 6, 2007
Last Updated
August 9, 2018
Sponsor
Chao Family Comprehensive Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00513461
Brief Title
Liver Cancer Prevention Trial in Patients With Chronic Hep C Infection
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
October 2007 (undefined)
Primary Completion Date
August 2012 (Actual)
Study Completion Date
December 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Chao Family Comprehensive Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Primary Liver Cancer, Hepatitis C Infection

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
110 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (SAMe)
Arm Type
Experimental
Arm Description
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 Title
Arm II (placebo)
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
S-adenosyl-L-methionine disulfate p-toluene-sulfonate
Other Intervention Name(s)
SAMe disulfate p-toluene-sulfonate
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
placebo
Other Intervention Name(s)
PLCB
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
immunoenzyme technique
Other Intervention Name(s)
immunoenzyme techniques
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
high performance liquid chromatography
Other Intervention Name(s)
HPLC
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Change in Serum AFP Levels
Description
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.
Time Frame
Baseline to week 24
Secondary Outcome Measure Information:
Title
Treatment-related Changes in Serum DCP for Hepatocellular Carcinoma
Description
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).
Time Frame
Baseline to week 24
Title
Treatment-related Changes in Serum AFP-L3 (Expressed as the Percentage of Total AFTP) for Hepatocellular Carcinoma
Description
AFP-L3 assay will be performed by Wako Laboratories using their LiBASys platform.
Time Frame
Baseline to week 24
Title
SAMe
Description
Change in SAMe levels
Time Frame
Baseline to week 24
Title
Change in SAMe Metabolites - S-adenosylhomocysteine (SAH)
Description
S-adenosylhomocysteine (SAH)
Time Frame
Baseline to week 24
Title
Change in SAMe Metabolites - Methionine
Description
Methionine will be measured using HPLC with fluorescence detection.
Time Frame
Baseline to week 24
Title
Change in SAMe Metabolites - Total Homocysteine (tHcy)
Description
Total homocysteine (tHcy)
Time Frame
Baseline to week 24
Title
Change in SAMe Metabolites - Plasma GSH
Description
Plasma GSH will be measured using HPLC with fluorescence detection.
Time Frame
Baseline to week 24
Title
Change in SAMe Metabolites - Malondialdehyde (MDA)
Description
malondialdehyde
Time Frame
Baseline to week 24
Title
Change in SAMe Metabolites - 4-hydroxynonenal (4-HNE)
Description
Serum marker of oxidative stress. One mechanism by which SAMe is hypothesized to be beneficial is by reducing oxidative stress.
Time Frame
Baseline to week 24
Title
Change in Markers of Liver Disease - AST
Description
AST measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays.
Time Frame
Baseline to week 24
Title
Change in Markers of Liver Disease - ALT
Description
ALT measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays.
Time Frame
Baseline to week 24
Title
HCV RNA
Description
Change in HCV RNA levels. Serum level of HVC RNA was measured using COBAS TaqMan HCV test (Roche Molecular Systems).
Time Frame
Baseline to week 24
Title
Changes in Quality of Life - Physical Score
Description
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).
Time Frame
Baseline to week 24
Title
Changes in Quality of Life - Mental Score
Description
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).
Time Frame
Baseline to week 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Hoefs
Organizational Affiliation
Chao Family Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Arizona Health Sciences Center
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85724
Country
United States
Facility Name
Veterans Administration Long Beach Medical Center
City
Long Beach
State/Province
California
ZIP/Postal Code
90822
Country
United States
Facility Name
Veterans Administration Los Angeles Healthcare System
City
Los Angeles
State/Province
California
ZIP/Postal Code
90073
Country
United States
Facility Name
Chao Family Comprehensive Cancer Center
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
University of California At San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92103
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
26130251
Citation
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.
Results Reference
result

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Liver Cancer Prevention Trial in Patients With Chronic Hep C Infection

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