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

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ClinicalTrials.gov Identifier: NCT03164473
Recruitment Status : Recruiting
First Posted : May 23, 2017
Last Update Posted : February 5, 2019
Sponsor:
Collaborator:
French Vasculitis Study Group
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE May 22, 2017
First Posted Date  ICMJE May 23, 2017
Last Update Posted Date February 5, 2019
Actual Study Start Date  ICMJE March 7, 2018
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 22, 2017)
Duration of remission in weeks [ Time Frame: 28 months ]
accrued number of weeks where a patient remains in remission with BVAS=0 and prednisone dose ≤7.5 mg/day
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03164473 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2017)
  • proportion of patients remaining in remission with a BVAS=0 and prednisone dose ≤7.5 mg/day [ Time Frame: 28 months ]
  • proportion of patients remaining in remission with a BVAS=0 [ Time Frame: 28 months ]
  • proportion of patients with at least one vasculitis relapse (major, minor, either) [ Time Frame: 28 months ]
  • proportion of patients with at least one clinically significant asthma/rhino-sinusal exacerbation [ Time Frame: 28 months ]
    defined as a worsening of asthma/rhino-sinusal disease leading to the doubling (or more) of the existing maintenance dose of corticosteroids for 3 or more days or hospital admission or an emergency department visit.
  • time to first vasculitis relapse [ Time Frame: 28 months ]
  • time to first clinically significant asthma/rhino-sinusal exacerbation [ Time Frame: 28 months ]
    defined as a worsening of asthma/rhino-sinusal disease leading to the doubling (or more) of the existing maintenance dose of corticosteroids for 3 or more days or hospital admission or an emergency department visit.
  • variation of the obstructive pulmonary disease [ Time Frame: 28 months ]
    assessed by change of FEV1 at pulmonary function tests after use of a bronchodilator
  • prednisone dose at months 6, 12, 18, 24 and 28, and area under the curve over the 28 month study period [ Time Frame: 28 months ]
  • proportion of patients with adverse events [ Time Frame: 28 months ]
  • proportion of patients with serious adverse events [ Time Frame: 28 months ]
  • proportion of patients with selected severe adverse events including grade 3 or 4 adverse effects (Common Terminology Criteria for Adverse Events) [ Time Frame: 28 months ]
    necessitating hospitalization, all cause deaths, cancers or infusion reactions (within 24 hours of infusion) that contraindicated further infusions
  • number and causes of deaths over the 28 month study period [ Time Frame: 28 months ]
  • damage assessed by the mean variation of the Vasculitis Damage Index (VDI) [ Time Frame: 28 months ]
  • quality of life assessed by the mean variation of the SF-36 [ Time Frame: 28 months ]
  • disability assessed by the mean variation of the Health Assessment Questionnaire (HAQ) [ Time Frame: 28 months ]
  • number of days of hospitalization [ Time Frame: 28 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Maintenance of Remission With Rituximab Versus Azathioprine for Newly-diagnosed or Relapsing Eosinophilic Granulomatosis With Polyangiitis.
Official Title  ICMJE 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Eosinophilic Granulomatosis With Polyangiitis
Intervention  ICMJE
  • Drug: Rituximab
    pre-emptive 500-mg fixed-dose of IV rituximab every 6 months (total duration of 18 months = 4 infusions)
  • Drug: Azathioprine
    oral tablets : 2 mg/kg/day for 24 months
  • Drug: Placebo-rituximab
    4 infusions for 18 months
  • Drug: Placebo-azathioprine
    oral tablets for 24 months
Study Arms  ICMJE
  • Experimental: Rituximab
    • 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
    Interventions:
    • Drug: Rituximab
    • Drug: Placebo-azathioprine
  • Active Comparator: Azathioprine
    • standard maintenance oral azathioprine therapy (2 mg/kg/day) for 24 months
    • plus 4 placebo−rituximab infusions given every 6 months for 18 months
    Interventions:
    • Drug: Azathioprine
    • Drug: Placebo-rituximab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 22, 2017)
98
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2022
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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 5-10 g) 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Xavier Puechal, MD, PhD + 33 1 58 41 32 41 xavier.puechal@aphp.fr
Contact: Severine Ait el Gaz-Poignant +33 1 58 41 12 11 severine.poignant@aphp.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03164473
Other Study ID Numbers  ICMJE P150922
2016-000627-53 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE French Vasculitis Study Group
Investigators  ICMJE
Study Chair: Benjamin Terrier National Referral Center for Rare Systemic Autoimmune Diseases - Hôpital Cochin
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP