WEGENT - Comparison of Methotrexate or Azathioprine as Maintenance Therapy for ANCA-Associated Vasculitides

Study Overview
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Brief Summary
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Remission of ANCA-associated vasculitis can be obtained in approximately 80% of the patients with a combination of corticosteroids and cyclophosphamide. However, relapses are frequent. This point warrants the prescription of a maintenance treatment with a less toxic immunosuppressant for several months to years. The optimal drug in this indication is not determine. We decided therefore to compare the 2 most used drugs in this indication. Induction therapy consists in the combination of corticosteroids and intravenous cyclophosphamide pulses. Corticotherapy consisted first in one daily methylprednisolone pulse, for 1 to 3 days, followed by oral prednisolone at the dose of 1 mg/kg/d for 3 weeks, then progressively tapered and stopped at the 18th month from the diagnosis. Cyclophosphamide is administered every 2 weeks for the first 3 bolus (0.6 g/m2 - D1, 15 and 30), then every 3 weeks (0.7 g/m2). Once remission is achieved, patients receive 3 additional bolus (0.7 g/m2). At that time, patients are randomized for a maintenance treatment with azathioprine (2 mg/kg/d, orally) or oral methotrexate (starting at the dose of 0.3 mg/kg/wk, then progressively increased every weeks by 2.5mg, if necessary, to a maximum and optimal dose of 25 mg/wk) for 12 months.

Official Title
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Treatment of ANCA-Associated Vasculitides : Corticosteroids and Pulse Cyclophosphamide Followed by Maintenance Therapy With Methotrexate or Azathioprine: a Prospective Multicenter Randomized Trial

Conditions
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Systemic Wegener's Granulomatosis

Intervention / Treatment
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* Drug: Azathioprine: 2 mg/kg/day
* Drug: methotrexate 0.3 mg/kg/week, to a maximum and optimal dose of 25 mg/week


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged over 18 years-old with newly diagnosed systemic Wegener's granulomatosis, microscopic polyangitis with at least one factor of poor prognosis according to the five factors score (proteinuria > 1 g/day, renal insufficiency defined as a serum creatininemia > 140 µmol/L, specific cardiomyopathy, gastrointestinal tract and/or CNS involvement). Exclusion Criteria: MPA patients with no poor prognosis factor; localized WG; relapse of previously known WG or MPA; treatment with corticosteroids for more than 1 month prior to diagnosis and start of immunosuppressant; co-existence of another multi-system autoimmune disease; malignancy (unless considered in complete remission and with no therapy for at least 3 years); contra-indication to corticosteroids or study immunosuppressants; pregnancy or no use of contraception in non-menopaused women; infection with human immunodeficiency virus; mental or physical disturbances not permitting to give consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Azathioprine: 2 mg/kg/day|nan|
|Drug: methotrexate 0.3 mg/kg/week, to a maximum and optimal dose of 25 mg/week|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety/Efficacy |  |  | 
| Frequency of severe adverse events in each arm. Hypothesis based upon NIH data was a rate of 6% severe adverse event with methotrexate compared to 30% with azathioprine (24% in one study on RA and 46% in one study on Sjögren syndrome). |  |  | 
| Evaluation was planned after the last included patient has completed the assigned trial regimen (after 12 months of maintenance regimen or because of drug withdrawal). |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse-free survival rate. |  |  | 
| Cumulative event-free survival rate (adverse event- and relapse-free survival rate). |  |  | 
| Health quality assessment using HAQ and SF36. |  |  | 
| Efficacy of induction therapy with pulsed cyclophosphamide. |  |  | 
| Second evaluation of the same outcome parameters is planned 5 years after the last included patient has completed the assigned trial regimen. |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Wegener's granulomatosis,, microscopic polyangiitis,, ANCA-associated vasculitis,, methotrexate,, azathioprine