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This study will examine the safety and effectiveness of daclizumab (also called Zenapax or anti-CD25) in patients with Wegener's granulomatosis, a type of vasculitis (blood vessel inflammation). Wegener's granulomatosis can affect many parts of the body, including the brain, nerves, eyes, sinuses, lungs, kidneys, intestinal tract, skin, joints, heart, and other sites. Standard treatment is a combination of prednisone and a cytotoxic agent (a drug that interferes with cell growth), 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 focus on the effectiveness of daclizumab in preventing disease relapse.
The Food and Drug Administration approved daclizumab in 1997 for preventing kidney transplant rejection, and the drug has also been studied in people with an eye infection called uveitis. The drug works by binding to a protein on T lymphocytes (white blood cells of the immune system) called CD25. This prevents another protein, called interleukin-2, from binding to this site, thereby preventing a series of events that normally results in inflammation.
Patients between 10 and 75 years of age with Wegener's granulomatosis 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 conducted. All patients will begin treatment with prednisone and cyclophosphamide daily. Those who improve on this regimen will reduce the prednisone gradually and continue with cyclophosphamide until their disease is in remission. While taking cyclophosphamide, patients must have blood and urine tests done every 1 to 2 weeks. Those who achieve disease remission will stop cyclophosphamide and start taking methotrexate once a week, usually by mouth but possibly by injection into the muscle or skin. Blood and urine tests will be conducted once a week for 4 weeks while the dosage is being adjusted and then once a month for the duration of treatment. Patients on methotrexate whose prednisone dose is reduced to 10 to 30 mg every other day will be randomly assigned either to receive or not receive daclizumab in addition to the methotrexate. Daclizumab is given intravenously (through a plastic tube inserted into a vein) the day after the randomization, then again in 2 weeks, 4 weeks, and once a month for 18 months.
All patients will continue to taper their prednisone dose until it is stopped. Methotrexate will continue for 2 years. Patients whose disease remains in remission at this time will decrease the methotrexate dose. If there is no active disease when both prednisone and methotrexate have been stopped, no further treatment will be given. If disease recurs at a later time, treatment will be reinstituted. The treatment will be determined by the severity of disease, other medical conditions, and history of side effects. Patients not randomized to daclizumab who relapse while still taking methotrexate may be offered re-treatment with daclizumab.
Patients will be evaluated in the outpatient clinic every 4 to 8 weeks until randomization. Patients not taking daclizumab will be followed every 4 to 12 weeks; those taking the drug will be seen every 2 weeks for the first month, every month after that during the 18-month treatment period, and every 4 to 12 weeks until all medications stop. Follow-up evaluations include a physical examination, blood draws and, if medically indicated, X-rays. The total study duration is 60 to 70 months.
The purpose of this study is to assess the safety and efficacy of daclizumab as an adjunctive treatment to methotrexate in maintaining remission that has been induced by cyclophosphamide and glucocorticoids in patients with Wegener's granulomatosis. In this study, all patients will initially receive daily cyclophosphamide and glucocorticoids and then at disease remission, cyclophosphamide will be discontinued and patients will receive methotrexate for remission maintenance. Following the switch to methotrexate and when the prednisone dose has been tapered to 20mg QOD (plus or minus 10mg QOD), patients in remission will be randomized to receive daclizumab or not receive daclizumab. Those randomized to receive daclizumab will be treated with 1 mg/kg intravenously on day 0, week 2, week 4 and every month thereafter for a total of 18 months (20 doses). Regardless to which arm the patient is randomized, they will continue to receive methotrexate. Two years after the methotrexate was started, if the patient remains in remission, this will be tapered and discontinued. Patients will be prospectively monitored for evidence of disease relapse and drug toxicity. Specific parameters that will be obtained include the time to disease remission, the rate and time of disease relapse, and the incidence of drug-related adverse events.
Endpoint Classification: Safety/Efficacy Study, Primary Purpose: Treatment
National Institute of Allergy and Infectious Diseases (NIAID)
National Institutes of Health Clinical Center (CC)
Published on BioPortfolio: 2014-08-27T03:55:59-0400
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