Rituximab to Treat Hepatitis C-Associated Cryoglobulinemic Vasculitis

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00029107
• Collaborator: (none)
• Enrollment: 47
• Location: 1
• Arms: 2
• Duration (Months): 113
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy of Rituximab (anti-CD20) in the treatment of patients with hepatitis C associated cryoglobulinemic vasculitis (HCV-CV) who have failed or are intolerant to interferon-alpha/ribavirin therapy. Up to 75 patients may be screened to enroll 34 adult patients with active HCV-CV in this randomized, non-blinded phase I/II trial. Patients will be randomized to receive either Rituximab 375 mg/M(2) on days 1, 8, 15 and 22 beginning at the time of enrollment or standard therapy. Patients in both groups will be maintained on stable doses of any immunosuppressive therapies that they were receiving at the time of enrollment. Response to Rituximab will be assessed by clinical and laboratory parameters.

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 requ...

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C; Vasculitis	Drug: Rituximab	Phase 2

Detailed Description

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 or standard therapy for 6 months after entering the study. All patients will be followed once a month at NIH for disease evaluation and blood tests during that time.

Patients will be given Rituximab 375 mg/m2intravenously once a week for 4 weeks. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Rituximab (Anti-CD20) for the Treatment of Hepatitis C Associated Cryoglobulinemic Vasculitis
• Study Start Date: Dec 1, 2001
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Other: Immediate treatment Patients receive treatment with four weekly infusions of rituximab 375mg/m2 immediately following randomization.	Drug: Rituximab; anti-CD20 monoclonal antibody
Other: Delayed treatment Patients treated with standard therapy (corticosteroids, plasma exchange, etc.). After 6 months, they are eligibile to cross over and receive four weekly infusions of rituximab.	Drug: Rituximab; anti-CD20 monoclonal antibody

Outcome Measures

Primary Outcome Measures

1. Percent of Patients in Remission [month 6]

   The primary endpoint was the difference in rate of remission between the 2 arms at 6 months from study entry.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Michael C Sneller, MD, National Institute of Allergy and Infectious Diseases (NIAID)

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.
• 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.

• Responsible Party: Michael C Sneller, MD, Medical Officer, National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT00029107
• Other Study ID Numbers: 020096; 02-I-0096
• First Posted: Jan 7, 2002
• Last Update Posted: Apr 16, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by Michael C Sneller, MD, Medical Officer, National Institutes of Health Clinical Center (CC): Hepatitis; Vasculitis; Rituximab; Cryoglobulinemia; Hepatitis C; HcV-cV; Cryoglobulinemic Vasculitis
• Additional relevant MeSH terms: Hepatitis A; Hepatitis C; Hepatitis; Vasculitis; Rituximab

Study Results

Participant Flow

Recruitment Details	Between June 2002 and April 2010, a total of 24 patients were enrolled in the study. Twelve patients randomized to the rituximab group and 12 patients to the control group.
Pre-assignment Detail	A total of 47 patients were screened for randomization into this study. Eighteen patients did not meet one or more of the above eligibility criteria. Five eligible patients elected not to enroll in the study because of concerns about potential rituximab toxicity. The remaining 24 patients were enrolled in the study and underwent randomization

Arm/Group Title	Immediate Treatment	Standard Therapy
Arm/Group Description	Patients receive treatment with four weekly infusions of rituximab immediately following randomization.	Receives standard therapy. After 6 months, they are eligibile to cross over and receive four weekly infusions of rituximab.
Period Title: Overall Study
STARTED	12	12
COMPLETED	12	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Immediate Treatment	Standard Therapy	Total
Arm/Group Description	Patients receive treatment with four weekly infusions of rituximab immediately following randomization.	Receives standard therapy. After 6 months, they are eligibile to cross over and receive four weekly infusions of rituximab.	Total of all reporting groups
Overall Participants	12	12	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	12 100%	12 100%	24 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52 (5.6)	51 (4)	51 (4.8)
Sex: Female, Male (Count of Participants)
Female	2 16.7%	4 33.3%	6 25%
Male	10 83.3%	8 66.7%	18 75%
Region of Enrollment (participants) [Number]
United States	12 100%	12 100%	24 100%

Outcome Measures

1. Primary Outcome

Title	Percent of Patients in Remission
Description	The primary endpoint was the difference in rate of remission between the 2 arms at 6 months from study entry.
Time Frame	month 6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Immediate Treatment	Standard Therapy
Arm/Group Description	Patients receive treatment with four weekly infusions of rituximab immediately following randomization.	Receives standard therapy. After 6 months, they are eligibile to cross over and receive four weekly infusions of rituximab.
Measure Participants	12	12
Number (95% Confidence Interval) [percent of participants]	83 691.7%	8 66.7%

Adverse Events

Time Frame	6 months
Adverse Event Reporting Description	Only adverse events that were grade 3 or greater and were possibly or probably related to the study drug were collected and analyzed for the purposes of this study
Arm/Group Title	Immediate Treatment		Standard Therapy
Arm/Group Description	Patients receive treatment with four weekly infusions of rituximab immediately following randomization.		Receives standard therapy. After 6 months, they are eligibile to cross over and receive four weekly infusions of rituximab.
All Cause Mortality
	Immediate Treatment		Standard Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Immediate Treatment		Standard Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/12 (50%)		8/12 (66.7%)
Blood and lymphatic system disorders
Leukopenia	1/12 (8.3%)	1	2/12 (16.7%)	2
thrombocytopenia	1/12 (8.3%)	1	1/12 (8.3%)	1
Hepatobiliary disorders
AST elevation > grade 3	3/12 (25%)	4	3/12 (25%)	3
Infections and infestations
Infection	1/12 (8.3%)	1	2/12 (16.7%)	2
Other (Not Including Serious) Adverse Events
	Immediate Treatment		Standard Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

The study was not blinded. In addition, the study was limited to patients who had failed antiviral therapy.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.