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Bethesda, Maryland 20892


Purpose:

This study will examine the effectiveness of pegylated interferon, or peginterferon (a long-acting form of alpha interferon) plus ribavirin in treating hepatitis C (genotype 1) infection with and without kidney disease. (Genotype 1 is a strain of hepatitis C virus that has a lower success rate of therapy.) Combination therapy with alpha interferon and ribavirin is the recommended treatment for hepatitis C infection in patients without kidney disease. However, it is not successful in all patients. An early predictor of who is or is not likely to respond to therapy would allow treatment to be stopped in non-responders within 2 to 4 weeks rather than 6 or 12 months. This study will determine whether early changes in viral levels with treatment predict the ultimate outcome. It will also compare responses in patients without and with kidney disease to better evaluate problems of therapy in the latter group. Ribavirin is not given to people with kidney disease because of possible severe drug side effects. However, because patients with kidney disease are poor treatment responders and because ribavirin increases the success of therapy in patients without kidney disease 2- to 3-fold, however, this study will look for a dose of the drug that can safely be given to patients with kidney disease. Patients 18 years of age and older with hepatitis C, genotype 1, with or without kidney disease may be eligible for this study. Candidates will be screened with a medical history and physical evaluation, blood tests, symptom questionnaires, 24-hour urine collection, chest X-ray, electrocardiogram, and liver ultrasound. A liver biopsy (removal of a small piece of liver tissue) will be done in patients who have not had one within the last year. Additional procedures, such as eye examination, treadmill stress test, hearing test, or others may be required depending on the individual's medical condition. Patients without kidney disease will be randomly assigned to one of two treatment groups: Group A will take both peginterferon (by injection under the skin once a week) and ribavirin (capsules by mouth) from the start of therapy; Group B will start treatment with peginterferon alone and add ribavirin after 4 weeks. Patients with kidney disease (Group C) will start with peginterferon alone and add ribavirin 4 weeks later. All patients will be admitted to the NIH Clinical Center for a few days when treatment starts in order to draw blood at precise intervals (6, 12, 24, 48, and 72 hours after the first peginterferon injection) for measurements of viral levels. Blood will then be drawn once a week for 4 weeks (just before each injection) to determine how rapidly viral levels decrease with treatment and to measure blood levels of interferon and ribavirin. After 4 weeks of therapy, patients will have a blood test and check of symptoms and side effects every 4 weeks for 24 weeks (every 2 weeks for Group C patients until the optimum ribavirin dose is found) and then every 8 weeks for the remainder of the study. They will have a physical examination and urine test every 12 weeks. Patients will be tested for hepatitis virus RNA after 24 weeks of therapy to determine if they are a responder or non-responder. Responders will be advised to continue therapy for a full 48 weeks to ensure a continued response when treatment stops. Non-responders-whose chances for a lasting response are estimated at only 2%-will be offered the option to continue treatment, to stop treatment and continue being followed without treatment, or to enroll in other studies of non-responders. At the end of the 72-week treatment and follow-up, patients will have the same blood and urine tests as were done at the beginning of the study and a repeat liver ultrasound.


Study summary:

Up to 105 patients with chronic hepatitis C will be enrolled in a study of the combination of pegylated alpha interferon and ribavirin for 48 weeks with the option of early discontinuation of therapy for patients who do not respond within 24 weeks of starting therapy. Adult patients will be chosen who have chronic hepatitis C, HCV RNA in serum, HCV genotype 1 and liver histology showing chronic hepatitis C. Patients with advanced liver disease and clinical decompensation and patients who have received alpha interferon in the past will not be eligible. The 100 patients will consist of four groups: Groups A, B and D will comprise 25 patients each with typical uncomplicated chronic hepatitis C; Group C will comprise 25 patients with renal insufficiency or renal failure on chronic dialysis awaiting kidney transplantation. Group D will comprise up to 30 patients with typical uncomplicated chronic hepatitis C. After medical evaluation and liver biopsy, patients will begin receiving pegylated alpha interferon (peginterferon) by subcutaneous injection in a dose of 180 mcg per week. After the initial injection, patients will have blood taken and symptoms recorded at 12, 24, 48, 72 hours and weekly thereafter for four weeks. Patients in Groups A, B and C will receive peginterferon weekly, whereas patients in Group D will receive it twice weekly in a reduced dose (90 mcg per injection) for the first 4 weeks of treatment and weekly in a dose of 180 mcg per injection thereafter. Patients in Groups A and D will also begin receiving ribavirin orally in a dose of 1000 mg (if body weight is less than 75 kg) or 1200 mg daily (if body weight greater than or equal to 75 kg) given in capsules of 200 mg twice daily starting with the first dose of peginterferon. Patients in Group B will start ribavirin in the doses given above after the first month of therapy (with the fifth injection: week 4). Patients in Group C (renal disease) will start ribavirin in a dose of 200 mg daily after the first month (week 4) of therapy; in this group the dose of ribavirin will be gradually increased at 4 week intervals on the basis of tolerance (hemolysis and anemia). During the initial 24-week period of combination therapy, patients will be seen in the outpatient clinic for medical interview, physical examinations and blood tests at 2 to 4 week intervals. At 24 weeks, patients will be classified as either responders or non-responders based upon HCV RNA testing. Both groups will be offered therapy for another 24 weeks (total treatment = 48 weeks). Because sustained responses are rare in patients who have not become HCV RNA negative by 24 weeks, non-responders will be offered the option of stopping therapy early and being followed on no therapy. After stopping therapy, patients will be followed at 1 to 2 month intervals and undergo repeat medical evaluation (without liver biopsy) at the 72 week point (18 months after enrollment). The primary criterion for success of therapy overall will be sustained loss of HCV RNA as assessed at 18 months. Secondary criteria will be normalization of ALT levels and improvement of symptoms. This study will allow for therapy of patients with chronic hepatitis C with the combination of peginterferon and ribavirin demonstrating whether early viral kinetics are predictive of outcome of therapy. This study will also allow for comparison of the kinetics of loss of HCV RNA comparing peginterferon alone to peginterferon with ribavirin, peginterferon given once weekly to peginterferon given twice weekly, and comparing kinetics between patients with and without renal disease. The study will also allow for assessment of the safety of addition of ribavirin in patients with renal compromise.


Criteria:

- INCLUSION CRITERIA: All Patients: - Age 18 years or above, male or female. - Presence of HCV RNA (with or without anti-HCV) in serum. - Genotype 1 HCV as determined by probe specific hybridization (Inno-Lipa assay). - Evidence of chronic hepatitis on liver biopsy done within the previous 48 months with a necroinflammatory histology activity index of at least 3 (out of a maximum of 18). - Written informed consent. Additional inclusion criteria for Groups A, B and D: -Serum alanine (ALT) or asparatate aminotransferase (AST) above the upper limit of the normal range (ALT 41 greater than IU/L: AST greater than 31 IU/L) on any serum testing during the previous six months. Additional inclusion criteria for Group C: - Chronic renal disease with creatinine clearance less than 50 cc/min or serum creatinine greater than 2.0 mg%. - If on chronic hemodialysis or peritoneal dialysis, stable clinical condition including stable hematocrit. - If on chronic dialysis, potential candidacy for renal transplantation. EXCLUSION CRITERIA: Previous treatment with alpha interferon. If cirrhosis is present, decompensated liver disease, as marked by bilirubin greater than 4 mg%, albumin less than 3.0 gm%, prothrombin time greater than 2 sec prolonged, or history of bleeding esophageal varices, ascites or hepatic encephalopathy. Serum ALT or AST levels greater than 1000 U/L (greater than 25 times ULN). Such patients 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 spermacide, or birth control pills, or an intrauterine device. Significant systemic or major illnesses other than renal failure (in Group C), including congestive heart failure, organ transplantation, serious psychiatric disease or depression, human immunodeficiency virus (HIV) infection, and angina pectoris. Pre-existing anemia (hematocrit less than 33%) or known history of hemolytic anemia. In patients in Group C, erythropoetin therapy will be modified to achieve an adequate hemocrit if clinically indicated. Other antiviral therapy within the last 6 months. Immunosuppressive therapy with either corticosteroids (more than 5 mg of prednisone daily) or major immunosuppressive agents (such as azathioprine or 6-mercaptopurine). Evidence of another form of liver disease in addition to viral hepatitis (for example autoimmune liver disease, Wilson's disease, alcoholic liver disease, hemochromatosis, alpha-1-antitrypsin deficiency). 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. Active substance abuse, such as alcohol, inhaled or injection drugs within the previous year. Evidence of hepatocellular carcinoma; either alphafetoprotein (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. Active, serious autoimmune disease such as lupus erythematosis, ulcerative colitis, Crohn's disease or rheumatoid arthritis that in the opinion of the investigators might be exacerbated by therapy with alpha interferon.


NCT ID:

NCT00028093


Primary Contact:

N/A


Backup Contact:

N/A


Location Contact:

Bethesda, Maryland 20892
United States



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Site Status: N/A


Data Source: ClinicalTrials.gov

Date Processed: June 25, 2018

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