Daclizumab to Treat Wegener's Granulomatosis
Daclizumab to Treat Wegener's Granulomatosis
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.
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-proteinase 3 or anti-myeloperoxidase 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-proteinase 3 or anti-myeloperoxidase 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.

 Evidence of active disease or if begun on cyclophosphamide (CYC) and glucocorticoids at an
 outside institution, a history of a active disease at the time of therapy initiation.

 Willingness to travel to the NIH every 2-4 weeks if they are randomized to receive
 daclizumab.

 Willingness of both women and men to use an effective means of birth control while
 receiving treatment through this study.

 EXCLUSION CRITERIA:

 Evidence of active infection which, in the judgement 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.

 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.

 History of CYC- or methotrexate-induced pneumonitis or other hypersensitivity reactions to
 these drugs with past treatment.

 History of transitional cell carcinoma (TCC) of the bladder.

 History of any malignant neoplasm except in situ anogenital carcinoma, adequately treated
 basal or squamous cell carcinoma of the skin, or solid tumors (other than TCC of the
 bladder cancer) treated with curative therapy and disease free for at least 5 years.

 Inability to comply with study guidelines.

 Hemocytopenia: platelet count less 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.