IMPROVE: Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy in ANCA Associated Systemic Vasculitis

Renal Limited Vasculitis Clinical Trial

Official title:

Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy in ANCA Associated Systemic Vasculitis

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00307645
• Other study ID #: P991003
• Status: Terminated
• Phase: Phase 3
• First received: March 27, 2006
• Last updated: April 7, 2006
• Start date: May 2003
• Est. completion date: August 2009

Study information

• Verified date: March 2003
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 160
• Est. completion date: August 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• ANCA Associated Systemic Vasculitis Including Wegener’s
• Granulomatosis and Microscopic Polyangiitis and
• Microscopic Polyangiitis
• Renal Limited Vasculitis
• Systemic Vasculitis
• Vasculitis

Intervention

Drug:
• Cyclophosphamide

• Mycophenolate mofetil

• Azathioprine

• Prednisone (and methylprednisolone)

Locations

Country	Name	City	State
France	Hopital Cochin	Paris
United Kingdom	Addenbrooke's Hospital - Departement of Medecine	Cambridge

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Countries where clinical trial is conducted

France,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	the disease-free period, defined as the time between the beginning
Primary	of the maintenance therapy (AZA or MMF) and the first relapse (minor or major)
Primary	or the end of the protocol (at 48 months)
Secondary	relapse rate
Secondary	rate of side-effects and intolerance
Secondary	cumulative doses (AZA, CS, MMF)
Secondary	AUC for BVAS, SF-36 or VDI
Secondary	Evolution of titers of ANCA and CRP