IMPROVE: Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy in ANCA Associated Systemic Vasculitis
IMPROVE: Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy in ANCA Associated Systemic Vasculitis
The aim of IMPROVE is to define the optimal maintenance therapy for ANCA-associated
 vasculitides (AASV) by comparing the AZA (standard regimen) with MMF in terms of efficacy,
 i.e. in preventing relapses.

 HYPOTHESIS :

 MMF might be more effective than azathioprine as maintenance drug in AASV patients, reducing
 by 50% relapse rate, with a same frequency of adverse effects
AASV, including Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) and renal
 limited vasculitis (RLV), are progressive, multisystem, autoimmune diseases which require the
 prescription of immunosuppressive therapy. Treatment using corticosteroids and cytotoxic
 drugs has been standardised (ECSYSVASTRIAL project), but relapse rate remains high and
 treatment-related toxicity is non negligible. The IMPROVE trial aims to reduce this relapse
 rate by using mycophenolate mofetil (MMF) for maintenance therapy. The potential benefit of
 MMF has been suggested in a published open and uncontrolled study. Patients with newly
 diagnosed systemic AASV will be randomly assigned to receive either MMF or reference
 treatment with azathioprine (AZA), once remission has been obtained with cyclophosphamide and
 prednisone. MMF and AZA will be continued for a total of 42 months of therapy with
 concomitant prednisone dose tapering. The study will last 48 months. Hence, within the last 6
 months of the study duration, the patients will not receive any immunosuppressive drugs.

 The primary end-point will the disease-free period, taken as the period of time from
 remission until relapse or study end; secondary end-points will be adverse events, cumulative
 damage (assessed using damage score VDI) and immunosuppressive drug cumulative dose.
Inclusion Criteria:

 -  Newly diagnosed patients with WG, MPA or renal-limited vasculitis.

 -  ANCA positivity. ANCA positivity requires PR3-ANCA or a typical cANCA pattern by
 indirect immunofluorescence (IIF), preferably confirmed by anti-PR3 ELISA. MPO-ANCA
 determined by ELISA requires demonstration of pANCA, and pANCA by IIF requires
 confirmation by anti-MPO ELISA. Optionally, central review of ANCA serology can be
 performed.

 -  Age 18 to 75 years

 Exclusion Criteria:

 -  Any cytotoxic drug within previous year, unless started within one months of entry and
 according to the protocol design

 -  Co-existence of another systemic autoimmune disease, e.g. SLE

 -  Hepatitis B or Hepatitis C infection

 -  HIV positivity

 -  Failure to achieve remission after 6 months of CYC therapy

 -  Failure to control progressive disease with induction protocol

 -  Malignancy (usually exclude unless agreed with trial co-ordinator)

 -  Pregnancy or inadequate contraception

 -  Age below 18 and above 75 years*

 -  Endstage renal failure unless active extrarenal disease requires treatment (temporal
 dependency of hemodialysis is not an exclusion criterion)

 -  Inability for informed consent

 -  After discussion with the trial administrator, patients less than 18 years may be
 incorporated on separate application according to the appropriate local ethic
 committee.