Liver Cancer Prevention Trial in Patients With Chronic Hep C Infection

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.

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