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Effects of S-Adenosyl Methionine (SAMe) on Viral and Cell Signaling Response to Combination Therapy for Chronic Hepatitis C

Phase 2
18 Years
Not Enrolling
Chronic Hepatitis C

Thank you

Trial Information

Effects of S-Adenosyl Methionine (SAMe) on Viral and Cell Signaling Response to Combination Therapy for Chronic Hepatitis C

S-adenosyl methionine (SAMe) is a nutritional supplement which is available as an
over-the-counter formula. It is a naturally occurring, modified amino acid that is produced
in virtually all cells and participates in many biochemical pathways as a major methyl donor
and may play a role in intracellular interferon signaling.

This study will assess the effects of SAMe on antiviral responses to peginterferon and
ribavirin in patients with chronic hepatitis C, genotype 1, who have failed to respond to a
previous course of therapy. After screening evaluation, patients will receive a first course
of 2 weeks of peginterferon alfa-2a (180 micrograms weekly) and ribavirin (1000-1200 mg
daily) during which symptoms, routine laboratory tests, HCV RNA levels, natural killer (NK)
cell activity, and lymphocyte interferon-signaling responses will be monitored. After a
4-week washout period, patients will start SAMe (800 mg twice daily) for 2 weeks and then
begin a second course of peginterferon and ribavirin in the same doses with similar
monitoring. Therapy will be continued for at least 12 weeks, and patients with an early
viral response will continue for a full 48 weeks. The primary criterion for efficacy of
SAMe will be improved HCV kinetic responses comparing the first and second courses of
peginterferon and ribavirin. Secondary endpoints will be improvement in NK cell activity and
intracellular interferon signaling.

This is a pilot study to determine whether SAMe improves responses to peginterferon therapy
in terms of intracellular interferon signaling, innate immune responses, and decline in
viral levels.

Inclusion Criteria


- Age 18 years or above, male or female

- Serum alanine or aspartate aminotransferase (ALT & AST) activities that are above
the upper limit of normal (ALT greater than 41 or AST greater than 31 IU/L).

- Presence of anti-HCV in serum.

- Presence of HCV RNA genotype 1 in serum at levels above 10,000 copies/ml.

- Previous adequate therapy with interferon and ribavirin or peginterferon and
ribavirin without a sustained virological response. An adequate course of therapy is
defined as at least 12 weeks of interferon in doses of 3 million units three times
weekly or peginterferon in doses of 180 micrograms for peginterferon alfa-2a or 1.5
micrograms/kg for peginterferon alfa 2b once weekly and ribavirin in starting doses
of at least 1000 mg daily. Patients who initiated therapy at these doses, but
required dose modification due to side effects will also be eligible.

- Written informed consent: Patients will be informed of the risk/benefits and
side-effects of the medications used in this protocol and will be advised of the
research blood drawn at each clinic visit. They will be given ample time to read the
consent form and to ask any protocol related questions. Once this is done, the
patient's signature will be obtained on the consent form to enroll them into the


- Evidence of other forms of liver disease.

- Hepatitis B as defined as presence of hepatitis B surface antigen (HBsAg) in serum.

- Primary sclerosing cholangitis as defined by liver histology.

- Wilson disease as defined by ceruloplasmin below the limits of normal and liver
histology consistent with Wilson disease.

- Autoimmune hepatitis as defined by antinuclear antibody (ANA) of 3 EU or greater
(ELISA) and liver histology consistent with autoimmune hepatitis or previous response
to immunosuppressive therapy for autoimmune hepatitis.

- Alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than
normal and liver histology consistent with alpha-1-antitrypsin deficiency.

- Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and
homozygosity for C282Y or compound heterozygosity for C282Y/H63D. Patients with iron
saturation indices of greater than 45% and serum ferritin levels of greater than 300
ng/ml for men and greater than 250 ng/ml for women will undergo genetic testing for
C282Y and H63D.

- Drug induced liver disease as defined on the basis of typical exposure and history.

- Bile duct obstruction as suggested by imaging studies done within the previous six

- Decompensated liver disease, as marked by bilirubin greater than 4 mg/dl, albumin
less than 3.0 gm/l, prothrombin time greater than 2 sec prolonged, Child-Pugh score
of 7 or greater or history of bleeding esophageal varices, ascites or hepatic
encephalopathy. Patients with ALT levels greater than 1000 U/L (greater than 25 times
the upper limit of the normal range) will not be enrolled but may be followed until
three determinations are below this level.

- Significant systemic or major illnesses other than liver disease, including
congestive heart failure, coronary artery disease, cerebrovascular disease, pulmonary
disease with hypoxia, renal failure, organ transplantation, serious psychiatric
disease including depression, malignancy and any other conditions that in the opinion
of the investigator would preclude treatment.

- Pre existing, severe bone marrow compromise; anemia (hematocrit less than 34%),
neutropenia (less than 1000 polymorphonuclear cells/mm(3)) or thrombocytopenia (less
than 70,000 cells/mm(3)).

- Serious autoimmune disease that, in the opinion of the investigators, might be
worsened by interferon therapy, such as lupus erythematous, rheumatoid arthritis or
Crohn's disease

- Known HIV infection.

- Active substance abuse, such as alcohol, inhaled or injection drugs within the
previous one year.

- Pregnancy, lactation or in women of child bearing potential or in spouses of such
women, inability to practice adequate contraception, defined as vasectomy in men,
tubal ligation in women, or use of condoms and spermicide, birth control pills/depot
injection, or an intrauterine device.

- Evidence of hepatocellular carcinoma; either alpha-fetoprotein (AFP) levels greater
than 50 ng/ml (normal less than 9 ng/ml) and/or ultrasound (or other imaging study)
demonstrating a mass suggestive of liver cancer.

- Immunosuppressive therapy with either corticosteroids (more than 5 mg of prednisone
daily) or major immunosuppressive agents (such as azathioprine or 6-mercaptopurine).

- Clinical gout at presentation.

- History of hypersensitivity reactions to S-adenosyl methionine.

- Serum creatinine greater than 1.5mg/dl in men and greater than 1.4 mg/dl for women.

- Any other condition, which in the opinion of the investigators would impede the
patient's participation or compliance in the study.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Improvement in viral kinetics during the first 2 weeks of therapy

Outcome Time Frame:

2 weeks

Safety Issue:



United States: Federal Government

Study ID:




Start Date:

May 2007

Completion Date:

May 2011

Related Keywords:

  • Chronic Hepatitis C
  • Hepatitis C Virus Genotype 1
  • Non-Responders
  • SAMe
  • Natural Killer Cells
  • Interferon Signaling
  • Ribavirin
  • Peginterferon
  • Hemolysis
  • STAT
  • Hepatitis C
  • Hepatitis
  • Hepatitis A
  • Hepatitis, Chronic
  • Hepatitis C
  • Hepatitis C, Chronic



National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892