Etanercept to Treat Wegener’s Granulomatosis

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Brief Title

Etanercept to Treat Wegener's Granulomatosis

Official Title

Phase I/II Trial of TNFR:Fc (Etanercept) in Patients With Wegener's Granulomatosis

Brief Summary

      This study will examine the use of etanercept (also called Enbrel or TNFR:Fc) in patients
      with Wegener's granulomatosis, a type of vasculitis (blood vessel inflammation). Wegener's
      granulomatosis may affect many parts of the body, including the brain, nerves, eyes, sinuses,
      lungs, kidneys, intestinal tract, skin, joints, heart, and other sites. Generally, the
      greater the disease involvement, the more life-threatening it is. Standard treatment is a
      combination of prednisone and a cytotoxic agent-usually cyclophosphamide or methotrexate.
      However, many patients treated with this regimen have a disease relapse, and others cannot
      take these drugs because of severe side effects. This study will evaluate etanercept's safety
      and effectiveness, and particularly its value in reducing the need for prednisone and
      preventing disease relapse.

      The Food and Drug Administration has approved etanercept for treating rheumatoid arthritis,
      another inflammatory disease. The drug works by blocking the activity of TNF-a protein made
      by white blood cells that is involved in the inflammatory process. Since prednisone also
      affects inflammatory proteins and lowers TNF production, the use of etanercept may reduce the
      need for prednisone in patients with Wegener's granulomatosis, and thus the risk of its side
      effects.

      Patients between 10 and 70 years of age with Wegener's granulomatosis who have never taken
      prednisone, methotrexate or cyclophosphamide, or have taken these drugs for less than 3 weeks
      may be eligible for this study.

      Participants will have a medical history review and physical examination, including
      laboratory studies. If medically indicated, X-rays, consultations and biopsies (surgical
      removal of a small tissue sample) of affected organs will also be done. All patients will
      begin treatment with prednisone, methotrexate and etanercept. Those who improve on this
      regimen will stop prednisone gradually over 3 months. Those who achieve disease remission at
      the end of another 3 months will be randomly assigned to either continue taking etanercept
      and methotrexate for another 12 months or to stop etanercept and continue only methotrexate
      for the next 12 months (after which methotrexate will gradually be stopped). Patients who are
      not in remission by the 6-month point will continue taking etanercept until they go into
      remission, when they will be assigned to stop or not stop etanercept, as described above.
      Patients who do not achieve remission within 12 months of beginning treatment will be taken
      off the study. Patients who have a disease relapse while on the study will likely be switched
      to treatment with prednisone and either methotrexate or cyclophosphamide. Patients randomized
      to stop etanercept and who have a relapse within a year of stopping the drug may be offered
      re-treatment on this protocol, but with continuing etanercept for a full year after
      remission.

      Patients will be evaluated in the outpatient clinic every 2 to 4 weeks for the first 4 months
      and every 1 to 3 months after that. Patients whose disease is in remission and who stop all
      medications will be followed every 3 to 6 months for 2 years. Follow-up evaluations include a
      physical examination, blood draws and, if medically indicated, X-rays. The total study
      duration is 60 to 70 months.
    

Detailed Description

      The purpose of the study is to assess the safety, pharmacokinetics, and immunologic effects
      of a recombinant fusion protein that consists of the soluble tumor necrosis factor receptor
      linked to the Fc portion of human IgG1 (TNFR:Fc) in patients with Wegener's granulomatosis. A
      secondary objective is to determine if TNFR:Fc demonstrates anti-inflammatory activity in the
      treatment of Wegener's granulomatosis. Specifically, we will seek to examine whether TNFR:Fc
      is able to reduce the need for glucocorticoid treatment and lower relapse rates. Patients
      will be eligible to participate in this protocol when there is evidence that the disease is
      active but is not immediately life-threatening. In this study, patients will receive TNFR:Fc
      (25mg subcutaneously twice weekly) together with methotrexate and prednisone. In all patients
      the prednisone will be tapered over a 3 month schedule. At the end of 6 months, patients in
      remission will be randomized to either continue TNFR:Fc for another 12 months or stop. All
      patients will continue methotrexate for 1 year after they enter remission after which time it
      will be tapered and discontinued.
    

Study Phase

Phase 2

Study Type

Interventional




Condition

Vasculitis

Intervention

Etanercept


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

60

Start Date

February 1999

Completion Date

March 2005


Eligibility Criteria

        INCLUSION CRITERIA:

        Documentation of Wegener's granulomatosis 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 Wegener's
        granulomatosis or a related systemic vasculitides have been excluded will also be eligible:
        a) a positive assay for anti-neutrophil cytoplasmic autoantibodies (C- or P-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; b) a
        positive assay for anti-neutrophil cytoplasmic autoantibodies (C- or P-ANCA) and the
        presence of granulomatous inflammation on biopsy plus abnormal chest radiograph (defined as
        the presence of nodules, fixed infiltrates, or cavities) plus nasal/oral inflammation on
        clinical examination.

        Subjects must be between the ages of 10 - 70 years.

        Subject must have evidence of active major organ disease.

        Patients who have never been previously seen at the NIH will be eligible if the above
        conditions are met and they either: are not receiving treatment; have been receiving
        prednisone at induction doses and MTX for less than 3 weeks; have been receiving prednisone
        at induction doses and CYC for less than 3 weeks but did not have severe disease.

        EXCLUSION CRITERIA:

        Patients with evidence of bacterial sepsis.

        Patients with evidence of other active systemic infection which in the judgment of the
        investigator, is of greater danger to the patient than the underlying vasculitis.

        Pregnant or subjects who are nursing infants.

        Fertile women must have a negative pregnancy test within one week prior to study entry and
        all participants must be using effective means of birth control.

        Patients with one or more of the following: serum creatinine greater than 2.5 mg/dl or
        creatinine clearance less than 35 ml/min; pulmonary disease resulting in a pO(2) less than
        70 mmHg, or FVC, FEV(1) or DLCO less than 70% of predicted; any Wegener's
        granulomatosis-related disease manifestation that, in the judgment of the investigators, is
        immediately life-threatening.

        Hemocytopenia: platelet count less than 80,000/mm(3), leukocyte count less than
        3,000/mm(3), hematocrit less than 20% (in the absence of gastrointestinal bleeding or
        hemolytic anemia).

        Liver function test abnormalities greater than three times upper limits of normal (either
        serum GOT, GPT, alkaline phosphatase, and/or bilirubin).

        Processes associated with an increased risk of MTX toxicity: acute or chronic liver
        disease, past history of alcohol abuse (greater than 14 oz. of 100 proof liquor or
        equivalent per week), ongoing alcohol use of any volume that cannot be discontinued upon
        entry into the study.

        Serological evidence of infection with human immunodeficiency virus, hepatitis C, or a
        positive hepatitis B surface antigen. A serological determination will be performed within
        two weeks of beginning study participation.

        Treatment with any investigational drug within 30 days.

        Known allergy to TNFR:Fc.

        Individuals with a history of psychiatric illness that in the opinion of the principal
        investigator (PI) would preclude entrance into the study.

        History of multiple sclerosis or other demyelinating disease.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

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Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00001901

Organization ID

990040

Secondary IDs

99-I-0040


Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)


Study Sponsor

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Verification Date

March 2005