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Liver Cancer Prevention Trial in Patients With Chronic Hep C Infection

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ClinicalTrials.gov Identifier: NCT00513461
Recruitment Status : Completed
First Posted : August 8, 2007
Results First Posted : August 10, 2018
Last Update Posted : August 10, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Chao Family Comprehensive Cancer Center, University of California, Irvine

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

Condition or disease Intervention/treatment Phase
Adult Primary Liver Cancer Hepatitis C Infection Drug: S-adenosyl-L-methionine disulfate p-toluene-sulfonate Other: placebo Other: laboratory biomarker analysis Other: immunoenzyme technique Other: high performance liquid chromatography Phase 2

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  (Clinical Trial)
Actual Enrollment : 110 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
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 Start Date : October 2007
Actual Primary Completion Date : August 2012
Actual Study Completion Date : December 2013

Resource links provided by the National Library of Medicine


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.
Drug: S-adenosyl-L-methionine disulfate p-toluene-sulfonate
Given PO
Other Name: SAMe disulfate p-toluene-sulfonate

Other: laboratory biomarker analysis
Correlative studies

Other: immunoenzyme technique
Correlative studies
Other Name: immunoenzyme techniques

Other: high performance liquid chromatography
Correlative studies
Other Name: 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: placebo
Given PO
Other Name: PLCB

Other: laboratory biomarker analysis
Correlative studies

Other: immunoenzyme technique
Correlative studies
Other Name: immunoenzyme techniques

Other: high performance liquid chromatography
Correlative studies
Other Name: HPLC




Primary Outcome Measures :
  1. Change in Serum AFP Levels [ Time Frame: 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 :
  1. Treatment-related Changes in Serum DCP for Hepatocellular Carcinoma [ Time Frame: 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).

  2. Treatment-related Changes in Serum AFP-L3 (Expressed as the Percentage of Total AFTP) for Hepatocellular Carcinoma [ Time Frame: Baseline to week 24 ]
    AFP-L3 assay will be performed by Wako Laboratories using their LiBASys platform.

  3. SAMe [ Time Frame: Baseline to week 24 ]
    Change in SAMe levels

  4. Change in SAMe Metabolites - S-adenosylhomocysteine (SAH) [ Time Frame: Baseline to week 24 ]
    S-adenosylhomocysteine (SAH)

  5. Change in SAMe Metabolites - Methionine [ Time Frame: Baseline to week 24 ]
    Methionine will be measured using HPLC with fluorescence detection.

  6. Change in SAMe Metabolites - Total Homocysteine (tHcy) [ Time Frame: Baseline to week 24 ]
    Total homocysteine (tHcy)

  7. Change in SAMe Metabolites - Plasma GSH [ Time Frame: Baseline to week 24 ]
    Plasma GSH will be measured using HPLC with fluorescence detection.

  8. Change in SAMe Metabolites - Malondialdehyde (MDA) [ Time Frame: Baseline to week 24 ]
    malondialdehyde

  9. Change in SAMe Metabolites - 4-hydroxynonenal (4-HNE) [ Time Frame: Baseline to week 24 ]
    Serum marker of oxidative stress. One mechanism by which SAMe is hypothesized to be beneficial is by reducing oxidative stress.

  10. Change in Markers of Liver Disease - AST [ Time Frame: Baseline to week 24 ]
    AST measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays.

  11. Change in Markers of Liver Disease - ALT [ Time Frame: Baseline to week 24 ]
    ALT measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays.

  12. HCV RNA [ Time Frame: Baseline to week 24 ]
    Change in HCV RNA levels. Serum level of HVC RNA was measured using COBAS TaqMan HCV test (Roche Molecular Systems).

  13. Changes in Quality of Life - Physical Score [ Time Frame: 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).

  14. Changes in Quality of Life - Mental Score [ Time Frame: 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).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00513461


Locations
United States, Arizona
University of Arizona Health Sciences Center
Tucson, Arizona, United States, 85724
United States, California
Veterans Administration Long Beach Medical Center
Long Beach, California, United States, 90822
Veterans Administration Los Angeles Healthcare System
Los Angeles, California, United States, 90073
Chao Family Comprehensive Cancer Center
Orange, California, United States, 92868
University of California At San Diego
San Diego, California, United States, 92103
Sponsors and Collaborators
Chao Family Comprehensive Cancer Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: John Hoefs Chao Family Comprehensive Cancer Center

Publications of Results:
Responsible Party: Chao Family Comprehensive Cancer Center, Cancer Center, University of California, Irvine
ClinicalTrials.gov Identifier: NCT00513461     History of Changes
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 )
First Posted: August 8, 2007    Key Record Dates
Results First Posted: August 10, 2018
Last Update Posted: August 10, 2018
Last Verified: August 2018

Additional relevant MeSH terms:
Infection
Hepatitis
Hepatitis C
Liver Neoplasms
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Flaviviridae Infections
RNA Virus Infections
Digestive System Neoplasms
Neoplasms by Site
Neoplasms