Clinical trial NCT00513461: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Adult Primary Liver Cancer
Hepatitis C Infection
Lead sponsor: University of California, Irvine
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-08-08
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Change in Serum AFP Levels
timeFrame: Baseline to week 24
Secondary outcomes:
measure: Treatment-related Changes in Serum DCP for Hepatocellular Carcinoma
timeFrame: Baseline to week 24
measure: Treatment-related Changes in Serum AFP-L3 (Expressed as the Percentage of Total AFTP) for Hepatocellular Carcinoma
timeFrame: Baseline to week 24
measure: SAMe
timeFrame: Baseline to week 24
measure: Change in SAMe Metabolites - S-adenosylhomocysteine (SAH)
timeFrame: Baseline to week 24
measure: Change in SAMe Metabolites - Methionine
timeFrame: Baseline to week 24
measure: Change in SAMe Metabolites - Total Homocysteine (tHcy)
timeFrame: Baseline to week 24
measure: Change in SAMe Metabolites - Plasma GSH
timeFrame: Baseline to week 24
measure: Change in SAMe Metabolites - Malondialdehyde (MDA)
timeFrame: Baseline to week 24
measure: Change in SAMe Metabolites - 4-hydroxynonenal (4-HNE)
timeFrame: Baseline to week 24
measure: Change in Markers of Liver Disease - AST
timeFrame: Baseline to week 24
measure: Change in Markers of Liver Disease - ALT
timeFrame: Baseline to week 24
measure: HCV RNA
timeFrame: Baseline to week 24
measure: Changes in Quality of Life - Physical Score
timeFrame: Baseline to week 24
measure: Changes in Quality of Life - Mental Score
timeFrame: Baseline to week 24
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Health Sciences Center
state: Arizona
city: Long Beach
country: United States
facility: Veterans Administration Long Beach Medical Center
state: California
city: Los Angeles
country: United States
facility: Veterans Administration Los Angeles Healthcare System
state: California
city: Orange
country: United States
facility: Chao Family Comprehensive Cancer Center
state: California
city: San Diego
country: United States
facility: University of California At San Diego
state: California
Study officials:
affiliation: Chao Family Comprehensive Cancer Center
name: John Hoefs
role: PRINCIPAL_INVESTIGATOR
References:
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.