Protocol Number: 02-I-0096

Title:

Rituximab (Anti-CD20) for the Treatment of Hepatitis C Associated Cryoglobulinemic Vasculitis

Number:

02-I-0096

Summary:

This study will examine the safety and effectiveness of the drug Rituximab in treating hepatitis C-associated cryoglobulinemic vasculitis. About 5 percent of patients with hepatitis C develop cryoglobulinemic vasculitis. This syndrome, characterized by inflammation of blood vessels (vasculitis), may involve the skin, joints, kidneys, nerves and other sites, and cause skin rashes, joint pain, weakness, fatigue, and numbness. About 10 to 30 percent of patients develop kidney disease, which, in some cases, can lead to kidney failure.

Although the cause of cryoglobulinemic vasculitis is not known, a critical component is the presence of cryoglobulins-abnormal proteins that white blood cells called B lymphocytes produce in response to the chronic hepatitis C infection. Rituximab decreases the number of B cells. The Food and Drug Administration approved Rituximab in 1997 for the treatment of B-cell non-Hodgkin's lymphoma.

Patients between 18 and 75 years of age with hepatitis C and signs and symptoms of cryoglobulinemic vasculitis may be eligible for this study. They must have failed, or been unable to tolerate, treatment with IFN-a and ribavirin. Candidates will be screened with a history and physical examination, electrocardiogram (ECG), blood and urine tests, 24-hour urine collection and chest X-ray, if clinically indicated.

Participants will be randomly assigned to receive Rituximab upon entering the study or 6 months after entering the study. Those whose treatment is delayed 6 months will be followed once a month at NIH for disease evaluation and blood tests during that time.

Patients will be given Rituximab intravenously (through a vein) once a week for 4 weeks. For the first dose, patients will be admitted to the hospital for at least 24 hours after the infusion for monitoring. Subsequent infusions will be given on an inpatient or outpatient basis, depending on how the infusion is tolerated. The day before each infusion they will have a history and physical examination, blood work, and other tests, such as X-rays, as clinically indicated.

After the four infusions, patients will be followed for drug side effects and response to treatment. They will have blood tests every week for 4 weeks and will then return to NIH for 1 day every month for 12 months for a physical examination, blood tests, and X-rays, if medically indicated. Visits may be more frequent, if necessary, and patients may be asked to stay longer than a day if test findings require further investigation.

Patients whose cryoglobulinemic vasculitis improves and remains inactive for 12 months after completing Rituximab therapy will have completed the study. Those who benefit from treatment but have a later worsening of disease may receive a second course of four infusions, with follow-up for 12 months after the last infusion. Patients who do not respond to treatment and whose disease worsens will be advised of other treatment options, but will be asked to return to NIH monthly for 12 months for follow-up.

Sponsoring Institute:

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA

Diagnosis of HCV-CV: must have all of the following

HCV infection documented by serology and/or plasma HCV RNA.

One or more organ system with objective evidence of active vasculitis such as:

Palpable purpura;

Glomerulonephritis (defined by the presence of glomerular hematuria and/or new or worsening proteinuria);

Acute peripheral neuropathy.

Detectable cryoglobulins and/or RF.

Failure of treatment with IFN-alpha and ribavirin to control manifestations of HCV-CV OR intolerance to IFN-alpha/ribavirin regimen.

Patients must have a personal physician responsible for the care of their HCV.

Ages of 18 and 75 years

Willingness to use effective contraception during and for 12 months following Rituximab treatment. Effective contraception methods include abstinence, surgical sterilization of either partner, barrier methods such as diaphragm, condom, cap or sponge, or hormonal contraception.

EXCLUSION CRITERIA

Recent (within 4 weeks) initiation of or increase in immunosuppressive therapy.

Active systemic infection (other than hepatitis C).

Pregnancy or breast feeding.

Prior treatment with Rituximab.

Known allergy to murine proteins.

Significant renal insufficiency (creatinine clearance less than 30 ml/min).

Presence of life-threatening HCV-CV; defined as rapidly progressive glomerulonephritis (defined as a doubling of the serum creatinine over a 3 month period), CNS vasculitis, cardiac disease due to active vasculitis, or GI vasculitis (defined by ischemic bowel, perforation, or infarction).

Significant hepatic insufficiency as manifested by Child-Pugh classification of B or C.

History of variceal bleeding, encephalopathy.

History of liver transplantation.

Co-infection with either HBV or HIV.

Any underlying medical condition that in the judgment of the investigator would put the patient at increased risk for serious infusion-related adverse events.

Special Instructions: Currently Not Provided

Keywords:

Hepatitis

Vasculitis

Rituximab

Cryoglobulinemia

Recruitment Keywords:

Hepatitis C

Vasculitis

HcV-cV

Cryoglobulinemic Vasculitis

Cryoglobulinemia

Conditions:

Hepatitis C

Vasculitis

Investigational Drug(s):

Rituximab

Investigational Device(s):

None

Contacts:

William Sachau, R.N.
National Institutes of Health
Building 10
Room 8C416
10 Center Drive
Bethesda, Maryland 20892
Phone: (301) 435-7940
Fax: (301) 402-1137

Electronic Address: wsachau@nih.gov

Citations:

Ferri C, Greco F, Longombardo G, Palla P, Moretti A, Marzo E, Fosella PV, Pasero G, Bombardieri S. Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia. Arthritis Rheum. 1991 Dec;34(12):1606-10. PMID: 1660716

Misiani R, Bellavita P, Fenili D, Borelli G, Marchesi D, Massazza M, Vendramin G, Comotti B, Tanzi E, Scudeller G, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med. 1992 Oct 1;117(7):573-7.

PMID: 1326246

Cacoub P, Fabiani FL, Musset L, Perrin M, Frangeul L, Leger JM, Huraux JM, Piette JC, Godeau P. Mixed cryoglobulinemia and hepatitis C virus. Am J Med. 1994 Feb;96(2):124-32. PMID: 7509124

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