Maintenance of Remission With Rituximab Versus Azathioprine for Newly-diagnosed or Relapsing Eosinophilic Granulomatosis With Polyangiitis.

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Brief Title

Maintenance of Remission With Rituximab Versus Azathioprine for Newly-diagnosed or Relapsing Eosinophilic Granulomatosis With Polyangiitis.

Official Title

MAINtenance of Remission With RITuximab Versus Azathioprine for Patients With Newly-diagnosed or Relapsing Eosinophilic Granulomatosis With Polyangiitis. A Prospective, Randomized, Controlled, Double-blind Study: the MAINRITSEG Trial

Brief Summary

      The purpose of this study is to investigate, after achievement of remission, the efficacy of
      rituximab compared with azathioprine maintenance therapy on duration of remission, in
      patients with relapsing or newly-diagnosed Eosinophilic granulomatosis with polyangiitis EPGA
      receiving standard of care therapy including glucocorticoid therapy reduction/withdrawal.
    

Detailed Description

      Rituximab, an anti-CD20 monoclonal antibody, has been shown to be as effective as
      cyclophosphamide to induce GPA and MPA remission, with an acceptable safety profile, leading
      to its registration by the FDA and EMA as remission-induction therapy in these patients.

      In addition, the MAINRITSAN trial has demonstrated that 500 mg rituximab given every 6 months
      for 18 months was significantly more effective than azathioprine standard of care to maintain
      remission in patients with GPA or MPA, with a similar profile of tolerance.

      EGPA patients were excluded from these trials. Long-term studies have shown that only 29% of
      EGPA patients achieved long-term remission and that relapses occurred in more than 40% of
      them, leading to high cumulative morbidity and damage. Moreover, most patients cannot be
      weaned off corticosteroids due to asthma and rhino-sinusal manifestations, even after
      vasculitis remission.

      However, recent retrospective series indicated that rituximab may also be an effective
      remission induction and maintenance agent in refractory or relapsing EGPA. REOVAS, the first
      randomized controlled trial with rituximab as induction therapy in EGPA, has started within
      the French Vasculitis Study Group network.

      The MAINRITSEG trial is a phase III, comparative, multicenter, randomized, double-blind,
      double-dummy and superiority trial, comparing pre-emptive low-dose rituximab-based regimen
      with azathioprine standard therapy, for the remission maintenance in newly-diagnosed or
      relapsing EGPA.

      Patients, with newly diagnosed or relapsing EGPA, after achievement of remission, will be
      randomized in a 1:1 ratio to receive:

        -  Standard regimen: maintenance oral azathioprine (2 mg/kg/day) for 24 months. This
           control group will receive conventional therapy plus 4 infusions of placebo-rituximab
           (every 6 months for 18 months)

        -  Experimental regimen: pre-emptive 500-mg fixed-dose of rituximab every 6 months for 18
           months (4 infusions). This group will receive intravenous rituximab plus orally
           placebo-azathioprine for 24 months.

      All patients will receive standard of care therapy including glucocorticoid therapy
      reduction/withdrawal.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Duration of remission in weeks

Secondary Outcome

 proportion of patients remaining in remission with a BVAS=0 and prednisone dose ≤7.5 mg/day

Condition

Eosinophilic Granulomatosis With Polyangiitis

Intervention

Rituximab

Study Arms / Comparison Groups

 Rituximab
Description:  pre-emptive 500-mg fixed-dose of IV rituximab every 6 months (total duration of 18 months = 4 infusions)
plus orally placebo-azathioprine for 24 months

Publications

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

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

98

Start Date

March 7, 2018

Completion Date

July 2024

Primary Completion Date

July 2024

Eligibility Criteria

        Inclusion Criteria:

          -  patients with a diagnosis of EGPA according to Lanham and/or ACR 1990 criteria and/or
             Revised Chapel Hill Nomenclature and/or MIRRA study inclusion criteria

          -  18 years of age or more

          -  with newly-diagnosed EGPA or after a vasculitis flare and remission achieved within
             the past year

          -  independently of ANCA status

          -  within 30-360 days following achievement of vasculitis remission (corresponding to a
             Birmingham Vasculitis Activity Score (BVAS)=0) achieved with an induction regimen
             including the one used in the REOVAS trial: either CS alone or in association with CYC
             (total dose ranging from 4.5-10 g for patients <65 years old and from 3-10g for
             patients ≥65 years old) or RTX (2 x 1g (D1, D15) or 4 weekly 375 mg/m2).

          -  with a stable prednisone dose for 30 days or no more prednisone

          -  after oral immunosuppressive drug cessation if started at remission.

          -  Patients included in the REOVAS trial and achieving remission can be included at month
             12 visit if they fulfil the other criteria

          -  Patients able to give written informed consent prior to participation in the study.

          -  Affiliation with a mode of social security (profit or being entitled).

        Exclusion Criteria:

          -  patients with GPA, MPA or other vasculitides

          -  patients with vasculitis not in remission defined as a BVAS >0

          -  acute or chronic active infections (including HIV, HBV or HCV)

          -  active or recent cancer ( <5 years), except basocellular carcinoma and low activity
             prostatic cancer controlled by hormonal treatment

          -  severe heart failure (New York Heart Association Class IV) or severe, uncontrolled
             cardiac disease

          -  pregnant women and lactation

          -  patients with childbearing potential will have reliable contraception for all the
             duration of the study and another 12 months after

          -  patients who had already been treated with rituximab before the last relapse/flare

          -  patients who have been treated with rituximab with a different induction regimen than
             2 x 1g (D1, D14) or 4 weekly 375 mg/m2 infusions

          -  hypersensitivity to a monoclonal antibody or biologics

          -  contraindication to rituximab or azathioprine

          -  other uncontrolled diseases, including drug or alcohol abuse, severe psychiatric
             diseases, that could interfere with participation

          -  patients included in other investigational therapeutic study within the previous 3
             months except in the REOVAS trial, after which patients achieving remission can be
             included if they fulfil the other criteria

          -  patients suspected not to be observant to the proposed treatments

          -  white blood cell count ≤4,000/mm3

          -  platelet count ≤100,000/mm3

          -  ALT or AST level >3 times the upper limit of normal

          -  patients not able to stop allopurinol and febuxostat which may enhance azathioprine
             toxicity

          -  patients unable to give written informed consent prior to participation in the study.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Benjamin Terrier, + 33 1 58 41 32 41, [email protected]

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT03164473

Organization ID

P150922

Secondary IDs

2016-000627-53

Responsible Party

Sponsor

Study Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

 French Vasculitis Study Group

Study Sponsor

Benjamin Terrier, Study Chair, National Referral Center for Rare Systemic Autoimmune Diseases - Hôpital Cochin


Verification Date

May 2021