- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00072592
An Open Label Pilot Study Examining the Use of Rituximab in Patients With Wegener's Granulomatosis Who Have Experienced Disease Relapse on Standard Therapies
This study will examine the use of rituximab in patients with Wegener's granulomatosis (WG) who have experienced a relapse of the disease through standard therapies. Rituximab is an antibody directed against the human protein called CD20, found on the surface of normal and abnormal B lymphocytes. Rituximab decreases the number of B lymphocytes. This study will examine the safety of rituximab in WG and rituximab's ability to reduce the level of circulating antineutrophil cytoplasmic antibodies (ANCA), which are antibodies that react to substances found in white blood cells. ANCA have been found to be strongly associated with WG. The study will also explore whether rituximab can reduce the occurrence of disease relapse. WG is a disease marked by inflammation of blood vessels. It can involve many different parts of the body, including the sinuses, lungs, kidneys, brain, nerves, eyes, intestinal tract, skin, joint, heart, and others. Before the use of cytotoxic drug therapy, WG was almost always fatal if untreated, with a mortality rate of 93% within 2 years.
Patients 18 to 75 years of age who have a history of at least one relapse of the disease despite standard treatments, who have had active WG within the previous 12 months and are in remission, who are receiving either methotrexate or azathioprine for remission maintenance, and who have circulating ANCA, may be eligible for this study.
A minimum of 22 visits to the clinic will be required to complete the entire study. Patients will undergo a comprehensive medical evaluation, with laboratory studies and x-rays. There may also be consultations and possible biopsies of affected organs only if medically indicated for diagnosis and treatment of the disease. In the 4-week period that patients will receive rituximab infusions, the methotrexate or azathioprine will be continued at the same dosage unless there are side effects that requite the medication to be temporarily stopped or the dosage reduced. Patients will receive four doses of rituximab, at 375 mg per meter squared of body surface area, once a week. It will be infused into a vein, through an intravenous catheter. For the first dose, patients will be admitted as inpatients for at least 24 hours, for monitoring during the infusion and for any reactions associated with it. The second, third, and fourth rituximab infusions may be given either on an inpatient or outpatient basis to be decided on how the patient tolerates the first infusion.
Following the four infusions, there will be blood tests to monitor the safety of the medication and the status of the disease, to be done at home every week for 4 weeks. Results will be sent to the researchers by fax. Patients will be asked to return to the clinic 1 month after the fourth infusion and every 1 to 3 months afterward. If there are no side effects or a relapse of the disease, the methotrexate or azathioprine will be continued for 2 years past remission. If by then the disease then remains in remission, the dose of either medication will be gradually decreased and eventually stopped. The usual schedule is to reduce methotrexate by 2.5 mg per month and to reduce azathioprine by 25 mg per month. If at that point there are no signs of active disease, the patients' illness will be considered to be in continued remission and no further treatment will be necessary. If relapse does occur, treatment would be different than previously. In most cases, treatment would involve prednisone and cyclophosphamide or methotrexate If the ANCA finding is negative after rituximab treatment and again becomes positive, and there is evidence of a return of B lymphocytes, patients may receive a second course of four rituximab infusions.
Study Overview
Detailed Description
Study Type
Enrollment
Phase
- Phase 1
Contacts and Locations
Study Locations
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Maryland
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Bethesda, Maryland, United States, 20892
- National Institute of Allergy and Infectious Diseases (NIAID)
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- ADULT
- OLDER_ADULT
- CHILD
Accepts Healthy Volunteers
Genders Eligible for Study
Description
INCLUSION CRITERIA:
Documentation of WG based on clinical characteristics and histopathologic and/or angiographic evidence of vasculitis. In the absence of histopathologic and/or angiographic evidence of vasculitis, patients who meet one of the following criteria and in whom infectious and autoimmune diseases that may mimic WG have been excluded will also be eligible:
A positive assay for anti-PR-3 or anti-MPO autoantibodies (ANCA) and the presence of glomerulonephritis defined by red blood cell casts and proteinuria or renal biopsy showing necrotizing glomerulonephritis in the absence of immune deposits.
A positive assay for anti-PR-3 or anti-MPO autoantibodies and at least 2 of the following: the presence of granulomatous inflammation on biopsy; abnormal chest radiograph (defined as the presence of nodules, fixed infiltrates, or cavities); nasal/oral inflammation on clinical examination.
Age 18-75 years.
Previous history of greater than or equal to 1 disease relapse as defined in Appendix I in patients fitting one of the below categories:
Disease relapse occurred while receiving MTX or AZA for remission maintenance following remission induction with daily CYC according to standard regimens on which there has been published data
Disease relapse occurred while on MTX following MTX induction according to the standard regimen on which there has been published data (98) in a patient who is unable to receive or is intolerant to daily CYC.
Active WG within the past 12 months for which the patient received induction therapy with glucocorticoids combined with daily CYC or MTX according to standard regimens
Evidence of current disease remission as defined in Appendix I and is currently receiving remission maintenance therapy consisting of MTX or AZA according to standard regimens. Patients may concurrently be receiving prednisone that is being tapered. Patients who completed their prednisone taper and are no longer receiving systemic glucocorticoids will be eligible if they are within 6 months of the time of prednisone discontinuation.
Circulating ANCA as defined by the presence of antibodies detectable by indirect immunofluorescence performed by the NIH Clinical Immunology laboratory at a titer of greater than or equal to 1:40 on two determinations done at least 4 weeks apart. Patients who are historically ANCA positive and become ANCA negative during remission induction will be eligible if they again become positive to a level of greater than or equal to 1:40 on two determinations done at least 4 weeks apart at a prednisone dose of less than or equal to 50mg QOD or within 6 months following the discontinuation of prednisone.
Willingness to travel to the NIH
Willingness of both women and men to use an effective means of birth control while receiving treatment through this study. Effective contraception methods include abstinence, surgical sterilization of either partner, barrier methods such as diaphragm, condom, cap or sponge, or hormonal contraception.
EXCLUSION CRITERIA:
Evidence of active infection, which, in the judgment of the investigator, is of greater danger to the patient than the underlying vasculitis.
Patients who are pregnant or who are nursing infants will not be eligible. Women of childbearing potential must have a negative pregnancy test within one week prior to study entry.
Serological evidence of infection with human immunodeficiency virus (HIV), hepatitis C, or a positive hepatitis B surface antigen. A serological determination will be performed within two weeks of beginning study participation.
Inability to comply with study guidelines.
Hemocytopenia: platelet count greater than 80,000/mm(3), absolute neutrophil count less than 1500/mm(3), hematocrit less than 20% (in the absence of gastrointestinal bleeding or hemolytic anemia).
Known allergy to murine proteins
Use of illegal drugs or alcohol abuse (alcohol use that would prevent a patient from fulfilling the study requirements or that would increase the risk of study procedures.)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
Collaborators and Investigators
Publications and helpful links
General Publications
- Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, Fauci AS. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992 Mar 15;116(6):488-98. doi: 10.7326/0003-4819-116-6-488.
- Reinhold-Keller E, Beuge N, Latza U, de Groot K, Rudert H, Nolle B, Heller M, Gross WL. An interdisciplinary approach to the care of patients with Wegener's granulomatosis: long-term outcome in 155 patients. Arthritis Rheum. 2000 May;43(5):1021-32. doi: 10.1002/1529-0131(200005)43:53.0.CO;2-J. Erratum In: Arthritis Rheum. 2000 Oct;43(10):2379.
- Talar-Williams C, Hijazi YM, Walther MM, Linehan WM, Hallahan CW, Lubensky I, Kerr GS, Hoffman GS, Fauci AS, Sneller MC. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996 Mar 1;124(5):477-84. doi: 10.7326/0003-4819-124-5-199603010-00003.
Study record dates
Study Major Dates
Study Start
Study Completion
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Respiratory Tract Diseases
- Immune System Diseases
- Autoimmune Diseases
- Lung Diseases
- Vasculitis
- Lung Diseases, Interstitial
- Systemic Vasculitis
- Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
- Granulomatosis with Polyangiitis
- Physiological Effects of Drugs
- Antirheumatic Agents
- Antineoplastic Agents
- Immunologic Factors
- Antineoplastic Agents, Immunological
- Rituximab
Other Study ID Numbers
- 040022
- 04-I-0022
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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