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

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

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.

Study Overview

• Status: Unknown
• Conditions: Systemic Wegener's Granulomatosis
• Intervention / Treatment: Drug: Azathioprine: 2 mg/kg/day; Drug: methotrexate 0.3 mg/kg/week, to a maximum and optimal dose of 25 mg/week

• Study Type: Interventional
• Enrollment: 126
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75
    • Christian PAGNOUX

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
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
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.

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Publications and helpful links

General Publications

• Pagnoux C, Mahr A, Hamidou MA, Boffa JJ, Ruivard M, Ducroix JP, Kyndt X, Lifermann F, Papo T, Lambert M, Le Noach J, Khellaf M, Merrien D, Puechal X, Vinzio S, Cohen P, Mouthon L, Cordier JF, Guillevin L; French Vasculitis Study Group. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008 Dec 25;359(26):2790-803. doi: 10.1056/NEJMoa0802311.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: January 1, 1999

Study Registration Dates

• First Submitted: July 6, 2006
• First Submitted That Met QC Criteria: July 6, 2006
• First Posted (Estimate): July 7, 2006

Study Record Updates

• Last Update Posted (Estimate): October 10, 2007
• Last Update Submitted That Met QC Criteria: October 9, 2007
• Last Verified: October 1, 2007

More Information

Terms related to this study

• Keywords: methotrexate,; azathioprine; Wegener's granulomatosis,; microscopic polyangiitis,; ANCA-associated vasculitis,
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Immune System Diseases; Autoimmune Diseases; Lung Diseases; Lung Diseases, Interstitial; Systemic Vasculitis; Vasculitis; Granulomatosis with Polyangiitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate; Azathioprine
• Other Study ID Numbers: 97.129