Chronic Hepatitis CPhase 2NCT00475176
S-Adenosyl Methionine (SAMe) to Treat Patients With Chronic Hepatitis C
A Phase 2 study testing Peginterferon alfa-2a, Ribavirin and S-adenosyl methionine for Chronic Liver Disease in people with Chronic Hepatitis C, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.
Trial summary
This study will examine the effectiveness of S-adenosyl methionine (SAMe) in combination with peginterferon and ribavirin for treating hepatitis C virus. One out of three patients with hepatitis C develops cirrhosis of the liver, which can lead to liver failure or liver cancer. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Hepatitis C
- What is being tested?
- Peginterferon alfa-2a, Ribavirin and S-adenosyl methionine for Chronic Liver Disease
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteUnited States
- Study dates
- May 2007to May 2011
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 protocol.
Who cannot join
- 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.
Show all 22Show fewer
- 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 months.
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Effects of S-Adenosyl Methionine (SAMe) on Viral and Cell Signaling Response to Combination Therapy for Chronic Hepatitis C
This study will examine the effectiveness of S-adenosyl methionine (SAMe) in combination with peginterferon and ribavirin for treating hepatitis C virus. One out of three patients with hepatitis C develops cirrhosis of the liver, which can lead to liver failure or liver cancer. SAMe is a nutritional supplement that is made naturally in all cells of the body and acts to improve how the body handles stress. In laboratory experiments with liver cells, SAMe decreases the injury caused by liver toxins and improves the ability of interferon to block hepatitis C virus.
Patients 18 years of age and older with hepatitis C infection who did not respond successfully to prior treatment with interferon and ribavirin or peginterferon and ribavirin may be eligible for this study.
Read more
Participants receive the following treatment:
- Peginterferon (given by injection) and ribavirin (taken by mouth) for 2 weeks
- Washout period (no medications) for 4 weeks
- SAMe (taken by mouth) for 2 weeks
- Peginterferon, ribavirin and SAMe for 12-48 weeks, depending on patient response to treatment.
Participants have a thorough physical evaluation before beginning treatment and again at the study's end. After starting treatment, patients return for clinic visits and blood tests weekly for the first several weeks, then less frequently (at 2-week, then 4-week and 8-week intervals until up to 72 weeks) to monitor symptoms, drug side effects, hepatitis C virus levels, liver enzyme levels and immune responses to hepatitis C.
...
Read the detailed description
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.
- Conditions
- Chronic Hepatitis C
- Being tested
- Peginterferon alfa-2a, Ribavirin, S-adenosyl methionine for Chronic Liver Disease
- Keywords
- Hepatitis C Virus Genotype 1, Non-Responders, SAMe, Natural Killer Cells, Interferon Signaling, Ribavirin, Peginterferon, Hemolysis, STAT, Hepatitis C
- Medical subject headings
- Hepatitis C, Chronic, Hemolysis, Hepatitis C
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Peginterferon alfa-2aDrug
RibavirinDrug
S-adenosyl methionine for Chronic Liver DiseaseDrug
| Study group | Role | What they receive |
|---|---|---|
| S-Adenosyl Methionine | Experimental | Not described Receives: Drug: Peginterferon alfa-2a; Drug: Ribavirin; Drug: S-adenosyl methionine for Chronic Liver Disease |
What is being measured
The primary outcome is the main question the study is designed to answer.
Improvement in Viral Kinetics During the First 2 Weeks of Therapy
Improvement of slopes of decline in hepatitis C virus Ribonucleic acid in second course compared with first course in days 7 to 14 of therapy
Measured: Days 7 to 14 of therapy
Secondary outcomes (1)
2-log Decline in HCV RNA by Week 12 (Early Virological Response) and Sustained Eradication of HCV RNA (Sustained Virological Response).
2-log decline in HCV RNA by week 12 (early virological response) and sustained eradication of HCV RNA (sustained virological response).
Measured: 12 weeks from start of therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 May 2007 (estimated)
- Study startMay 2007
- Primary completionMay 2011
- Study completionMay 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Chronic Hepatitis CStudies of the same condition, open and under way.
- More trials run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Jay Hoofnagle, M.D., National Institutes of Health Clinical Center (CC)
- Investigators
- Jay Hoofnagle, MD, Principal investigator, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00475176
- Sponsor's protocol ID
- 070143
- Other IDs
- 07-DK-0143, 07-DK-0143
- Status last verified
- May 2013
- First submitted
- 17 May 2007
- Last updated
- 5 Jul 2013
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001 Jul 5;345(1):41-52. doi: 10.1056/NEJM200107053450107. No abstract available.
PubMed 11439948Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006 May 16;144(10):705-14. doi: 10.7326/0003-4819-144-10-200605160-00004.
PubMed 16702586Thomas DL, Seeff LB. Natural history of hepatitis C. Clin Liver Dis. 2005 Aug;9(3):383-98, vi. doi: 10.1016/j.cld.2005.05.003.
PubMed 16023972Feld JJ, Modi AA, El-Diwany R, Rotman Y, Thomas E, Ahlenstiel G, Titerence R, Koh C, Cherepanov V, Heller T, Ghany MG, Park Y, Hoofnagle JH, Liang TJ. S-adenosyl methionine improves early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders. Gastroenterology. 2011 Mar;140(3):830-9. doi: 10.1053/j.gastro.2010.09.010. Epub 2010 Sep 17.
PubMed 20854821
Study at a glance
From the registry record, last updated by the sponsor on 5 Jul 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of S-Adenosyl Methionine (SAMe) on Viral and Cell Signaling Response to Combination Therapy for Chronic Hepatitis C
- ClinicalTrials.gov ID
- NCT00475176
- Acronym / sponsor ID
- 070143
- Conditions
- Chronic Hepatitis C
- Keywords
- Hepatitis C Virus Genotype 1, Non-Responders, SAMe, Natural Killer Cells, Interferon Signaling, Ribavirin, Peginterferon, Hemolysis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)US National Institutes of Health
- Study start
- May 2007
- Primary completion
- May 2011 (actual)
- Study completion
- May 2011 (actual)
- First posted
- 21 May 2007 (estimated)
- Results
- Posted 5 Jul 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will examine the effectiveness of S-adenosyl methionine (SAMe) in combination with peginterferon and ribavirin for treating hepatitis C virus. One out of three patients with hepatitis C develops cirrhosis of the liver, which can lead to liver failure or liver cancer. SAMe is a nutritional supplement that is made naturally in all cells of the body and acts to improve how the body handles stress. In laboratory experiments with liver cells, SAMe decreases the injury caused by liver toxins and improves the ability of interferon to block hepatitis C virus.
Patients 18 years of age and older with hepatitis C infection who did not respond successfully to prior treatment with interferon and ribavirin or peginterferon and ribavirin may be eligible for this study.
Participants receive the following treatment:
- Peginterferon (given by injection) and ribavirin (taken by mouth) for 2 weeks
- Washout period (no medications) for 4 weeks
- SAMe (taken by mouth) for 2 weeks
- Peginterferon, ribavirin and SAMe for 12-48 weeks, depending on patient response to treatment.
Participants have a thorough physical evaluation before beginning treatment and again at the study's end. After starting treatment, patients return for clinic visits and blood tests weekly for the first several weeks, then less frequently (at 2-week, then 4-week and 8-week intervals until up to 72 weeks) to monitor symptoms, drug side effects, hepatitis C virus levels, liver enzyme levels and immune responses to hepatitis C.
...
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| S-Adenosyl Methionine | Experimental | Drug: Peginterferon alfa-2a, Drug: Ribavirin, Drug: S-adenosyl methionine for Chronic Liver Disease |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (22 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Peginterferon alfa-2a | Drug | S-Adenosyl Methionine |
| Ribavirin | Drug | S-Adenosyl Methionine |
| S-adenosyl methionine for Chronic Liver Disease | Drug | S-Adenosyl Methionine |
Primary outcome
Improvement in Viral Kinetics During the First 2 Weeks of Therapy
Time frame: Days 7 to 14 of therapy
Improvement of slopes of decline in hepatitis C virus Ribonucleic acid in second course compared with first course in days 7 to 14 of therapy
1 secondary outcome
2-log Decline in HCV RNA by Week 12 (Early Virological Response) and Sustained Eradication of HCV RNA (Sustained Virological Response).
Time frame: 12 weeks from start of therapy
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Jul 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 11439948Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001 Jul 5;345(1):41-52. doi: 10.1056/NEJM200107053450107. No abstract available.
- Background: PubMed 16702586Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006 May 16;144(10):705-14. doi: 10.7326/0003-4819-144-10-200605160-00004.
- Background: PubMed 16023972Thomas DL, Seeff LB. Natural history of hepatitis C. Clin Liver Dis. 2005 Aug;9(3):383-98, vi. doi: 10.1016/j.cld.2005.05.003.
- Derived from this study: PubMed 20854821Feld JJ, Modi AA, El-Diwany R, Rotman Y, Thomas E, Ahlenstiel G, Titerence R, Koh C, Cherepanov V, Heller T, Ghany MG, Park Y, Hoofnagle JH, Liang TJ. S-adenosyl methionine improves early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders. Gastroenterology. 2011 Mar;140(3):830-9. doi: 10.1053/j.gastro.2010.09.010. Epub 2010 Sep 17.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jay Hoofnagle, MD principal investigator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Peginterferon alfa-2a, Ribavirin and S-adenosyl methionine for Chronic Liver Disease in people with Chronic Hepatitis C, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Jul 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 5 Jul 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Improvement in Viral Kinetics During the First 2 Weeks of Therapy (time frame: Days 7 to 14 of therapy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00475176, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jul 2013.