An Open Label Pilot Study Examining the Use of Rituximab in Patients With Wegener’s Granulomatosis Who Have Experienced Disease Relapse on Standard Therapies

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Brief Title

An Open Label Pilot Study Examining the Use of Rituximab in Patients With Wegener's Granulomatosis Who Have Experienced Disease Relapse on Standard Therapies

Official Title

An Open Label Pilot Study Examining the Use of Rituximab in Patients With Wegener's Granulomatosis Who Have Experienced Disease Relapse on Standard Therapies

Brief Summary

      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.
    

Detailed Description

      This pilot study will seek to investigate the use of rituximab in patients with Wegener's
      granulomatosis who have experienced disease relapse through standard therapies. Rituximab is
      a chimeric monoclonal antibody directed against CD20, which induces B cell death and results
      in rapid and sustained depletion of circulating and tissue-based B cells. The objectives of
      this protocol will be to establish the safety of rituximab in Wegener's granulomatosis, to
      examine the ability of rituximab to reduce the level of circulating antineutrophil
      cytoplasmic antibodies (ANCA), and to preliminarily explore whether rituximab is able to
      prevent disease relapse. This prospective standardized open label trial will enroll 10
      patients who have a well-documented history of disease relapse while receiving
      immunosuppressive therapy given according to published regimens and who are ANCA positive
      after remission induction. Patients will be enrolled once they have achieved remission from a
      recent relapse and are receiving either methotrexate or azathioprine for remission
      maintenance. All patients will receive rituximab 375 mg/M(2) once a week for 4 weeks. During
      and following the rituximab treatment period, patients will remain on their remission
      maintenance agent of methotrexate or azathioprine. Patients who are enrolled while on
      prednisone will continue to taper the dosage to discontinuation as medically permitted.
      Following the 4 weekly infusions of rituximab, patients will be followed prospectively for
      evidence of effective B cell depletion, features of drug toxicity, level of circulating ANCA,
      and clinical disease status. Patients whose ANCA levels become undetectable following the
      infusion of rituximab may be retreated with a second 4 week course of rituximab should their
      ANCA titer become positive (greater than or equal to 1:40) and there has been a return of B
      cells in the peripheral blood. Methotrexate or azathioprine will be continued for two years
      past remission, after which time, this will be tapered and discontinued. Patients will
      continue to be monitored for two years off all immunosuppressive therapy or if a disease
      relapse should occur, for a minimum of 12 months after the last rituximab infusion.
    

Study Phase

Phase 1

Study Type

Interventional




Condition

Wegener's Granulomatosis

Intervention

Rituximab


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

10

Start Date

October 2003

Completion Date

August 2005


Eligibility Criteria

        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.)
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00072592

Organization ID

040022

Secondary IDs

04-I-0022


Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)


Study Sponsor

, , 


Verification Date

August 2005