Low-Dose Peginterferon and Ribavirin to Treat Chronic Hepatitis C in Patients Infected With HCV Genotype 2 or 3
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Purpose
This study will examine the effectiveness of low-dose peginterferon and ribavirin therapy for certain patients with chronic hepatitis C-a liver disease that, in some patients, can progress to cirrhosis of the liver, liver cancer, and liver failure. This disease is caused by the hepatitis C virus (HCV). There are six major strains, or genotypes, of HCV. Patients infected with genotypes 2 and 3 respond better and more quickly to the standard treatment for this disease-high-dose peginterferon and ribavirin for 24 to 48 weeks-than do patients with other genotypes. Although the side effects of these medications are more severe at higher doses, patients with all genotypes, including genotypes 2 and 3, currently receive the same standard treatment. This study will examine whether patients infected with HCV genotypes 2 and 3 will respond equally well, and with fewer side effects, to lower doses of peginterferon and ribavirin given for a shorter period of time.
Patients 18 years of age and older with chronic hepatitis C genotype 2 or 3 may be eligible for this study. Each candidate will be screened with a medical history, physical examination, blood tests, and liver ultrasound. Patients who have not had a chest x-ray or electrocardiogram within a year of entering the study will have those tests as well. Additional tests, such as eye examination, hearing test, stress test, or others, will be done if deemed necessary because of the individual's particular medical condition or risk factors for side effects of therapy.
Participants will be admitted to the National Institutes of Health (NIH) Clinical Center for 1 day for supervised administration of the first doses of peginterferon and ribavirin and 24-hour observation. The treatment regimen consists of two capsules of ribavirin twice a day every day and an injection of peginterferon under the skin once a week. Patients will return to the clinic at 2, 4, 8, 12, 16, 20 and 24 weeks after the first dose of therapy for a brief medical history and physical examination, blood test, and check on hepatitis symptoms and treatment side effects. Women capable of becoming pregnant will also have a pregnancy test at each visit.
Patients will be tested for HCV levels after 12 weeks of therapy. Those who are negative for the virus at that time will continue therapy for another 12 weeks to insure that the response lasts. They will be monitored during that time and re-tested for the virus at the end of that period. Patients who do not respond to treatment after 12 weeks will stop low-dose therapy and be offered the higher-dose standard treatment for 48 weeks. Patients who responded after 12 weeks and completed 24 weeks of therapy but subsequently became positive after stopping treatment will also be offered standard high-dose treatment for the full 48-week regimen. Patients on high-dose therapy will return to the clinic every 4 weeks during the 48-week course for evaluation and blood tests. Patients who remain positive for HCV after 24 weeks of high-dose therapy will stop treatment, as a response is unlikely to occur beyond that time.
After treatment, patients will return to the clinic at 4- to 8-week intervals for evaluations until 6 months. At 6 months, they will have a series of blood and urine tests and ultrasound of the liver.
| Condition | Intervention | Phase |
|---|---|---|
|
Hepatitis C |
Drug: Peginterferon alfa-2a Drug: Ribavirin |
Phase 4 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Low Dose Peginterferon and Ribavirin Therapy for Patients With Chronic Hepatitis C Infected With Genotype 2 or 3 |
- Virological Response (Intention to Treat) [ Time Frame: 6 months after stopping therapy ] [ Designated as safety issue: No ]Virological response category. Sustained virological response (SVR) is defined as negative serum HCV RNA at least 6 months after the end of treatment. Non-response is defined as serum HCV RNA positivity on week 12 of treatment. Breakthrough/relapse is defined as HCV RNA becoming negative and subsequently positive on treatment or after treatment is stopped.
- Virological Response Category (Per Protocol) [ Time Frame: 6 months after therapy ] [ Designated as safety issue: No ]Virological response category. Sustained virological response (SVR) is defined as negative serum HCV RNA at least 6 months after the end of treatment. Non-response is defined as serum HCV RNA positivity on week 12 of treatment. Breakthrough/relapse is defined as HCV RNA becoming negative and subsequently positive on treatment or after treatment is stopped.
- First Phase Decline in Logarithm of HCV RNA Level [ Time Frame: 2 days ] [ Designated as safety issue: No ]The 1st phase decline is defined as the log difference between baseline HCV RNA level and the level on day 2 of treatment (see Neumann et al, Science, 1998).
- Slope of Second Phase Decline in HCV Levels [ Time Frame: day 7 to day 28 ] [ Designated as safety issue: No ]The 2nd phase slope is defined as the slope of the logarithmic viral levels from week 1 to week 4 of treatment (see Neumann et al, Science, 1998).
- Time to Negativity [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]Time from treatment initiation to the first negative HCV RNA test during treatment
| Enrollment: | 58 |
| Study Start Date: | March 2003 |
| Study Completion Date: | June 2010 |
| Primary Completion Date: | January 2010 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Low-dose peginterferon and standard dose ribavirin
Patients receive a lower dose of peginterferon (90 mcg per week) and standard dose of ribavirin (800 mg/d) for chronic hepatitis C, genotype 2/3, for 24 weeks.
|
Drug: Peginterferon alfa-2a
90 mcg/week
Other Name: Pegasys
Drug: Ribavirin
800 mg/day
Other Name: Copegus
|
|
Active Comparator: Standard-dose peginterferon and ribavirin
Patients receive the standard, recommended doses of peginterferon (180 mcg per week) and ribavirin (800 mg/d) for chronic hepatitis c, genotype 2/3, for 24 weeks.
|
Drug: Peginterferon alfa-2a
180 mcg/week
Other Name: Pegasys
Drug: Ribavirin
800 mg/day
Other Name: Copegus
|
Detailed Description:
Sixty patients with chronic hepatitis C infected with HCV genotype 2 or 3 will be treated using the combination of either low- or standard dose peginterferon and ribavirin for 24 weeks, with re-treatment using the standard doses and a longer duration (48 weeks) for those who do not respond to or relapse after initial low dose therapy.
Adult patients with chronic hepatitis C who have HCV genotype 2 or 3 and previously have not received anti-viral treatment will be given peginterferon alfa-2a (90 or 180 micrograms weekly by injection) and ribavirin (800 mg daily by mouth). Patients will be monitored at 2- to 4-week intervals for side effects, compliance, complete blood counts, liver biochemical tests and HCV RNA. Patients becoming HCV RNA negative by week 12 will be considered on-treatment responders, continue therapy to week 24, and be monitored thereafter for another 24 weeks. Patients who do not become HCV RNA negative by week 12 as well as patients who relapse after therapy will be retreated with 180 micrograms of peginterferon weekly and 800 mg of ribavirin for another 48 weeks.
The primary outcome will be sustained loss of HCV RNA at 24 weeks after low- or standard-dose combination therapy. Secondary outcomes include viral kinetics and side effects. Because of preliminary results in the initial 31 patients enrolled in this study, the dose of peginterferon was changed from 90 to 180 micrograms weekly for the remaining 29 patients to be enrolled, allowing for a direct comparison of efficacy, viral kinetics and side effects of standard- vs low-dose peginterferon therapy.
This study will evaluate the relative efficacy and safety of the standard versus lower doses of peginterferon with ribavirin in patients with chronic hepatitis C and HCV genotype 2 or 3.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
- INCLUSION CRITERIA:
Age above 18 years, male or female.
Presence of anti-HCV in serum.
Positive HCV RNA determination in serum.
HCV genotype 2 or 3 as determined by Inno LiPa assay or by direct sequencing. Patients with mixed genotypes will not be eligible if they have genotypes other than 2 or 3.
Written informed consent.
EXCLUSION CRITERIA:
Previous treatment with interferon alpha or peginterferon.
Decompensated liver disease, as marked by bilirubin greater than 4 mg/dL, albumin less than 3.0 g/dL, prothrombin time greater than 2 sec prolonged, or history of bleeding esophageal varices, ascites or hepatic encephalopathy.
Patients with ALT levels greater than 1000 U/L (greater than 25 times ULN) will not be enrolled but may be followed until three determinations are below this level.
Pregnancy 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 spermicidal, or birth control pills, or an intrauterine device.
Significant systemic or major illnesses other than liver disease, including congestive heart failure, renal failure (creatinine clearance less than 50 ml/min), organ transplantation, serious psychiatric disease not controlled by psychotropic agents, and angina pectoris.
Evidence of coronary artery disease or cerebral vascular disease, including abnormalities on exercise stress testing in patients with defined risk factors who will be screened for evidence of underlying coronary artery disease.
Pre-existing, severe bone marrow compromise; anemia (hematocrit less than 30%), neutropenia (less than 1000 neutrophils/microliter) or thrombocytopenia (less than 70,000 cells/microliter).
History of hemolytic anemia.
Evidence of another form of liver disease in addition to hepatitis C (for example hepatitis B, autoimmune liver disease, Wilson's disease, alcoholic liver disease).
Active substance abuse, such as alcohol, inhaled or injection drugs within the previous six months.
Evidence of hepatocellular carcinoma: either alfa-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.
Clinical gout.
HIV infection.
Quiescent or active, serious autoimmune disease such as lupus erythematosus, ulcerative colitis, Crohn's disease or rheumatoid arthritis that in the opinion of the investigators might be exacerbated by therapy with alfa interferon.
The use of immunosuppressive medications, including corticosteroids in doses of 10 mg of prednisone or its equivalent and higher.
Contacts and Locations More Information
Publications:
| Responsible Party: | Jay H. Hoofnagle, M.D./National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health |
| ClinicalTrials.gov Identifier: | NCT00056862 History of Changes |
| Other Study ID Numbers: | 030136, 03-DK-0136 |
| Study First Received: | March 25, 2003 |
| Results First Received: | November 12, 2010 |
| Last Updated: | May 26, 2011 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by National Institutes of Health Clinical Center (CC):
|
Hepatitis C Virus Antiviral Agents Hemolysis Neutropenia Cirrhosis Hemolytic Anemia |
Viral Hepatitis Ribavirin Alfa Interferon Pegylated Interferon Hepatitis C HCV |
Additional relevant MeSH terms:
|
Hepatitis Hepatitis A Hepatitis, Chronic Hepatitis C Hepatitis C, Chronic Liver Diseases Digestive System Diseases Hepatitis, Viral, Human Virus Diseases Enterovirus Infections Picornaviridae Infections RNA Virus Infections |
Flaviviridae Infections Ribavirin Peginterferon alfa-2a Interferon-alpha Antiviral Agents Anti-Infective Agents Therapeutic Uses Pharmacologic Actions Antimetabolites Molecular Mechanisms of Pharmacological Action Immunologic Factors Physiological Effects of Drugs |
ClinicalTrials.gov processed this record on October 15, 2012
