Cyclophosphamide and Prednisone Followed by Methotrexate To Treat Vasculitides

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Brief Title

Cyclophosphamide and Prednisone Followed by Methotrexate To Treat Vasculitides

Official Title

A Staged Therapeutic Approach Using Cyclophosphamide and Methotrexate in the Treatment of Wegener's Granulomatosis and Related Vasculitides

Brief Summary

      This study will evaluate the safety and effectiveness of a staged approach to therapy for
      Wegener's granulomatosis and other systemic vasculitides using prednisone plus
      cyclophosphamide followed by methotrexate. Vasculitides involve inflammation of blood vessels
      (vasculitis) that may affect the brain, nerves, eyes, sinuses, lungs, kidneys, intestinal
      tract, skin, joints, heart and other sites. Standard treatment with prednisone and
      cyclophosphamide is very effective, but has significant toxicity (adverse side effects).
      Methotrexate is also an effective treatment and is less toxic, but it is associated with a
      higher rate of disease recurrence and has not been used in patients with severe lung or
      kidney disease. Staged therapy using cyclophosphamide first and then methotrexate may provide
      better results for overall safety and effectiveness.

      Patients 10 to 80 years of age with active Wegener's granulomatosis, polyarteritis nodosa or
      a related systemic vasculitis may be eligible for this study. Candidates will be screened
      with a medical history and physical examination, blood and urine tests, chest X-ray,
      electrocardiogram (EKG) and pulmonary function tests. Other procedures, such as biopsies,
      will be done only as medically indicated.

      Participants will be treated initially with 1 milligram/kilogram body weight of prednisone
      once a day and 2 to 4 mg/kg cyclophosphamide once a day. If the disease improves
      significantly, prednisone will be gradually reduced and stopped, and if remission is
      achieved, cyclophosphamide will be stopped. Methotrexate will then be started at 0.3 mg/kg
      body weight once a week and then increased to 0.5 mg/kg after 2 to 4 weeks. Methotrexate
      therapy will continue for at least 2 years. If at the end of 2 years the disease remains in
      remission, the methotrexate will be gradually reduced and stopped. If, on the other hand,
      active disease recurs during methotrexate treatment, the therapy will be changed. The new
      choice of treatment will depend on the severity of recurrence, pre-existing medical
      conditions, and previous adverse reactions to prednisone, cyclophosphamide and methotrexate.

      Patients will be seen periodically for a physical examination and blood tests to evaluate
      disease activity, response to therapy and drug side effects. X-rays will be done as medically
      indicated. Evaluations will be scheduled once a month until the patient has been on
      methotrexate for 3 months and then every 3 months for the next 18 months. Patients whose
      disease remains in remission at that time and are off all medications will be seen every 6
      months for another 4 visits.
    

Detailed Description

      The purpose of this study is to assess the efficacy and safety of a staged treatment regimen
      in Wegener's granulomatosis and related vasculitides in which patients will receive
      glucocorticoid plus cyclophosphamide at disease onset; cyclophosphamide will be switched to
      methotrexate upon disease remission. At the current time, cyclophosphamide plus
      glucocorticoids are the standard of care for the treatment of these disorders. Although this
      regimen has brought about a marked improvement in survival rate, it has been associated with
      significant toxicity. Methotrexate plus glucocorticoids have recently been investigated in
      patients with non life-threatening disease and while this regimen appears to have less
      toxicity than standard therapy it may be associated with a higher rate of disease relapse. By
      inducing patients with cyclophosphamide and glucocorticoids then switching to methotrexate at
      remission, we hope to combine the efficacy of cyclophosphamide with the more favorable
      toxicity profile of methotrexate. If successful, this regimen could provide a safer, yet
      effective therapeutic option which would be applicable to all patients regardless of disease
      severity. In this study, patients will be initially treated with cyclophosphamide and
      glucocorticoids and then switched from cyclophosphamide to methotrexate upon quiescence of
      disease activity. If at the end of two full years of methotrexate therapy there is continued
      evidence of disease remission, the drug will be tapered and ultimately discontinued. Patients
      will be prospectively monitored for evidence of disease activity 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 effects. This study will be open
      to patients with systemically active Wegener's granulomatosis or related vasculitis
      regardless of their degree of disease severity.
    


Study Type

Observational




Condition

Vasculitis



Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

100

Start Date

March 1995

Completion Date

March 2004


Eligibility Criteria

        INCLUSION CRITERIA:

        Documentation of WG based on clinical characteristics and histopathological evidence of
        vasculitis. Patients with a positive C- or P-ANCA and glomerulonephritis as evidence 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 will also be eligible.

        Age 10-80 years.

        Evidence of active disease as defined by a Vasculitis Disease Activity Index of greater
        than or equal to 3 or if begun on CTX and glucocorticoid at an outside institution, a
        history of a Vasculitis Disease Activity Index greater than or equal to 3 at the time of
        therapy initiation.

        EXCLUSION CRITERIA:

        Evidence of active systemic infection which, in the judgement of the investigator, is of
        greater danger to the patient than the underlying vasculitis. 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.

        Patients who are pregnant or who are nursing infants will not be eligible. Fertile women
        must have a negative pregnancy test within one week prior to study entry and must be using
        an effective means of birth control.

        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.

        Inability to comply with study guidelines.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00001473

Organization ID

950091

Secondary IDs

95-I-0091


Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)


Study Sponsor

, , 


Verification Date

March 2004