Title: Combination of Pegylated Interferon and Ribavirin as Therapy
for Patients with Chronic Hepatitis C with and without Renal Disease
Number: 02-DK-0065
Summary: 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.


Sponsoring Institute:
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK)
Recruitment Detail
Type: Active Accrual Of New Subjects
Gender: Male & Female
Referral Letter Required: No
Population Exclusion(s): None

Eligibility 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 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.

Special Instructions: Currently Not Provided
Keywords:
Chronic Hepatitis
Cirrhosis
Hepatitis C Virus
Combination Therapy
Hemolysis
Ribavirin
Alpha Interferon
Peginterferon
Antiviral Agents
Viral Hepatitis
Hemosis
Hemolytic Anemia
Renal Failure
Renal Dialysis
Recruitment Keyword(s):
Hepatitis
Hepatitis C
Condition(s):
Hepatitis C
Investigational Drug(s):
Pegylated Interferon Alpha-2a and Ribavirin
Investigational Device(s):
None
Intervention(s):
None
Supporting Site:
N/A

Contact(s):
Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793