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
Patients between 10 and 75 years of age with Wegener's granulomatosis may be eligible for
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
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
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
- 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
- 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
Willingness of both women and men to use an effective means of birth control while
receiving treatment through this study.
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
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
Known allergy to murine proteins.