Brief Title
Steroids and Methotrexate to Treat Systemic Vasculitis
Official Title
An Open Trial of the Efficacy of Glucocorticoids and Methotrexate (MTX) in the Treatment of Systemic Vasculitis
Brief Summary
This study will evaluate the safety and effectiveness of prednisone and methotrexate in
treating severe Wegener's granulomatosis and other systemic vasculitides. These diseases
involve inflammation of blood vessels (vasculitis) that may affect the brain, nerves, eyes,
sinuses, lungs, kidneys, intestinal tract, skin, joints, heart and other sites. Current
treatment with prednisone and the anti-cancer drug cyclophosphamide is effective, but has
significant side effects and a high rate of disease recurrence. In a small number of patients
with vasculitis, prednisone and methotrexate, another anti-cancer drug, have led to marked
improvement, with fewer side effects than are seen with cyclophosphamide. This study will
evaluate this drug combination in a larger patient population.
Patients 10 to 80 years of age with active Wegener's granulomatosis, polyarteritis nodosa,
Churg-Strauss vasculitis, or microscopic polyangiitis overlap may be eligible for this 2 1/2
to 3-year study. In addition, patients with glomerulonephritis (a type of kidney disease) and
a positive blood test for C-ANCA (antibodies found in certain vasculitic kidney diseases) or
inflammatory sinusitis or lung nodule or infiltrates in the absence of infection may also be
enrolled.
Participants will take prednisone daily, by mouth, and low-dose methotrexate weekly, by mouth
or by injection either under the skin, into a muscle or into a vein. Patients who
significantly improve with treatment will gradually reduce, and eventually stop, the
prednisone. If the remission lasts, methotrexate will also be reduced and stopped after 2 1/2
years. If active disease recurs, the original treatment program may be started again.
Patients who never achieve complete remission with treatment but whose symptoms are well
controlled and experience no serious side effects may choose to either continue low-dose
methotrexate or stop therapy.
Patients will be hospitalized 4 to 6 times a year, about 2 to 8 days each time, depending on
their disease severity and response to illness. In addition, they will have the following
tests and procedures:
- Medical history and physical examination (upon admission to the study and then every 1
to 3 months).
- Blood tests for blood cell counts and for levels of enzymes that indicate liver damage
(upon admission, then weekly, and finally, no less than monthly).
- Additional blood tests to measure blood chemistries and evaluate kidney function (upon
admission and again when clinically indicated).
- Chest X-rays (upon admission and when clinically indicated).
- Computerized tomography (CT) and magnetic resonance imaging (as needed).
- Electrocardiogram (upon admission and then as clinically indicated).
- Lung function studies (upon admission and at least every 6 months or as clinically
indicated).
- Ear, nose and throat evaluations (as clinically indicated).
- Liver biopsy, if blood tests to monitor liver function are persistently abnormal. This
procedure is done in the hospital under sedation to induce relaxation and drowsiness.
The skin over the liver (upper right abdomen) is numbed with a local anesthetic and a
needle is passed rapidly in and out of the liver to collect a small tissue sample for
microscopic examination.
Detailed Description
Previous studies at the NIH have demonstrated that in over 90% of cases of Wegener's
granulomatosis (WG) and other systemic necrotizing vasculitides, glucocorticoid (GC) and
daily low dose cyclophosphamide (CP) therapy has resulted in marked improvement and even
remission. However, such therapy has been associated with about 50% relapses, 10% resistance
to initial treatment and significant toxicity in almost all patients. Consequently, we have
attempted to identify alternative therapies for the systemic vasculitides that would be less
toxic then daily CP. An NIH study of the efficacy of intermittent high dose intravenous CP
and daily GC (Protocol #88-I-56) revealed that 79% of 14 patients with WG either failed to
respond to treatment, did not sustain improvement or could not tolerate continued treatment
during a period of approximately two years. In another study (Protocol #89-I-18), we
evaluated treatment with GC and weekly oral doses of methotrexate (MTX) in 15 patients with
Takayasu's arteritis, in whom disease previously failed to be controlled with GC, GC + CP, or
in whom remission with such treatment was followed by relapse. Fifty-three percent (8/15) of
patients previously dependent on GC were able to achieve remission and discontinue GC
therapy. Five of seven patients who remained on GC were in remission and receiving at least
50% less GC than prior to MTX therapy. Only three patients had progressive disease. The mean
follow-up period was 20 months. We have also recently analyzed our results for MTX + GC
therapy and 29 patients with WG. Seventy-six percent of patients had marked improvement and
69% achieved remission. Seventy-two percent of those in remission have not required GC
therapy for a mean period 10 months. We conclude that weekly low dose MTX therapy is a
feasible alternative to CP in the treatment of systemic vasculitis. Judgement of the ultimate
value of such therapy should be deferred until a greater number of patients have been studied
over a longer period of time.
Study Phase
Phase 2
Study Type
Interventional
Condition
Inflammation
Intervention
prednisone and methotrexate
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
100
Start Date
March 1990
Completion Date
February 2004
Eligibility Criteria
INCLUSION CRITERIA:
Diagnosis: Wegener's granulomatosis.
Age: 10-80 years.
Qualifications to eligibility:
Prior documentation of vasculitis based on clinical characteristics and histopathological
and/or angiographic evidence of vasculitis. Patients will be eligible for this study
regardless of whether they are currently receiving immunosuppressive therapies. Failure to
respond to prior therapy with other cytotoxic agents or toxicity from such agents, in the
setting of persistent disease, will constitute one reason for eligibility for this study.
In the absence of histopathological and/or angiographic evidence of vasculitis, patients
with the following criteria will also be eligible:
A. Positive C-ANCA (done at the NIH), and
B. Glomerulonephritis as evidenced by the presence of red blood cell casts and proteinuria
or renal biopsy showing necrotizing glomerulonephritis in the absence of positive
immunofluorescence for immunoglobulin and complement, and
C. One or more of the following:
Inflammatory sinusitis with histopathological evidence of granulomatous inflammation and
negative special stains for mycobacteria and fungi. Sinusitis must be present for at least
3 months and have failed to respond to at least 2 weeks of antibiotic therapy directed
against likely pathogens (H. influenza, S. pneumonia, and upper respiratory tract anaerobic
bacteria);
Pulmonary nodule or infiltrates in a patient in the absence of infection.
Evidence of active disease as defined by a Vasculitis Disease Activity Index of greater
than or equal to 3 (Appendix I) or if begun on immunosuppressive therapy at an outside
institution, a history of a Vasculitis Disease Activity Index greater than or equal to 3
during the past 6 months.
EXCLUSION CRITERIA:
Evidence of infection by gram stain and/or culture specimens. In those instances in which
infection cannot be ruled out by gram stain and culture of secretions or collections of
fluid in involved organs, it may be necessary to obtain a biopsy of the affected tissue for
microbiological and histopathological studies.
Recent (within four weeks) increase in GC or cytotoxic drug therapy.
Patients who are pregnant or nursing infants will not be eligible. Fertile women should
have a negative pregnancy test within one week prior to study entry and should be using
effective means of birth control.
Processes that would predispose to enhanced risk of MTX toxicity: acute or chronic liver
disease, alcohol abuse (greater than 14 oz of 100 proof liquor or equivalent per week),
active peptic ulcer disease, and inability to comply with study guidelines.
Serological evidence of infection with human immunodeficiency virus (a serological
determination will be performed within two weeks of study entry).
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
NCT00001256
Organization ID
900086
Secondary IDs
90-I-0086
Study Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor
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Verification Date
February 2004