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Rituximab in Eosinophilic Granulomatosis With Polyangiitis (REOVAS)

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ClinicalTrials.gov Identifier: NCT02807103
Recruitment Status : Recruiting
First Posted : June 21, 2016
Last Update Posted : March 28, 2019
Sponsor:
Collaborator:
French Vasculitis Study Group
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE May 20, 2016
First Posted Date  ICMJE June 21, 2016
Last Update Posted Date March 28, 2019
Actual Study Start Date  ICMJE December 5, 2016
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 18, 2019)
The percentage of patients who obtained a BVAS=0 and prednisone dose ≤7.5 mg/day at day 180. [ Time Frame: 180 days ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 16, 2016)
Number of patients in complete remission (defined by a Birmingham Vasculitis Activity Score (BVAS) of 0 and a prednisone dose ≤7.5 mg/day ) [ Time Frame: 180 days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 18, 2019)
  • Number of adverse events [ Time Frame: 180 days ]
    expressed as adverse events according to the CTCAE toxicity grading system per patient-year for the following adverse events combined: death (all causes), grade 2 or higher leukopenia or thrombocytopenia, grade 3 or higher infections, hemorrhagic cystitis, malignancies, venous thromboembolic events, hospitalization resulting either from the disease or from a complication due to the study treatment, infusion reactions (within 24 hours of infusion) that result in the cessation of further infusions
  • Number of adverse events [ Time Frame: 360 days ]
    expressed as adverse events according to the CTCAE toxicity grading system per patient-year for the following adverse events combined: death (all causes), grade 2 or higher leukopenia or thrombocytopenia, grade 3 or higher infections, hemorrhagic cystitis, malignancies, venous thromboembolic events, hospitalization resulting either from the disease or from a complication due to the study treatment, infusion reactions (within 24 hours of infusion) that result in the cessation of further infusions
  • Area under the curve for corticosteroids [ Time Frame: 180 days ]
    To measure the corticosteroid dose and to compare the corticosteroid sparing effect of rituximab versus conventional therapy
  • Area under the curve for corticosteroids [ Time Frame: 360 days ]
    To measure the corticosteroid dose and to compare the corticosteroid sparing effect of rituximab versus conventional therapy
  • Number of sequelae assessed by the Vasculitis Damage Index [ Time Frame: 180 days ]
  • Number of sequelae assessed by the Vasculitis Damage Index [ Time Frame: day 180 and day 360 ]
  • ANCA titers and CD19+cells [ Time Frame: day 180 and day 360 ]
  • Health Assessment Questionnaire (HAQ) score [ Time Frame: 180 days ]
    to evaluate functional disability
  • Health Assessment Questionnaire (HAQ) score [ Time Frame: 360 days ]
    to evaluate functional disability
  • Short Form-36 score [ Time Frame: 180 days ]
    to evaluate quality of life
  • Short Form-36 score [ Time Frame: 360 days ]
    to evaluate quality of life
Original Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2016)
  • Number of adverse events [ Time Frame: 180 days ]
    expressed as adverse events according to the CTCAE toxicity grading system per patient-year for the following adverse events combined: death (all causes), grade 2 or higher leukopenia or thrombocytopenia, grade 3 or higher infections, hemorrhagic cystitis, malignancies, venous thromboembolic events, hospitalization resulting either from the disease or from a complication due to the study treatment, infusion reactions (within 24 hours of infusion) that result in the cessation of further infusions
  • Number of adverse events [ Time Frame: 360 days ]
    expressed as adverse events according to the CTCAE toxicity grading system per patient-year for the following adverse events combined: death (all causes), grade 2 or higher leukopenia or thrombocytopenia, grade 3 or higher infections, hemorrhagic cystitis, malignancies, venous thromboembolic events, hospitalization resulting either from the disease or from a complication due to the study treatment, infusion reactions (within 24 hours of infusion) that result in the cessation of further infusions
  • Area under the curve for corticosteroids [ Time Frame: 180 days ]
    To measure the corticosteroid dose and to compare the corticosteroid sparing effect of rituximab versus conventional therapy
  • Area under the curve for corticosteroids [ Time Frame: 360 days ]
    To measure the corticosteroid dose and to compare the corticosteroid sparing effect of rituximab versus conventional therapy
  • Number of sequelae assessed by the Vasculitis Damage Index [ Time Frame: 180 days ]
  • Number of sequelae assessed by the Vasculitis Damage Index [ Time Frame: 360 days ]
  • ANCA titers and CD19+cells [ Time Frame: 180 days ]
  • ANCA titers and CD19+cells [ Time Frame: 360 days ]
  • Health Assessment Questionnaire (HAQ) score [ Time Frame: 180 days ]
    to evaluate functional disability
  • Health Assessment Questionnaire (HAQ) score [ Time Frame: 360 days ]
    to evaluate functional disability
  • Short Form-36 score [ Time Frame: 180 days ]
    to evaluate quality of life
  • Short Form-36 score [ Time Frame: 360 days ]
    to evaluate quality of life
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rituximab in Eosinophilic Granulomatosis With Polyangiitis
Official Title  ICMJE Evaluation of Rituximab-based Regimen Compared to Conventional Therapeutic Strategy For Remission Induction In Patients With Newly-Diagnosed or Relapsing Eosinophilic Granulomatosis With Polyangiitis. Prospective, Randomized, Controlled, Double-blind Study
Brief Summary

Phase III, comparative, multicenter, randomized, controlled, double-blind and superiority research, comparing rituximab-based regimen with conventional therapeutic strategy for the induction of remission in patients with eosinophilic granulomatosis with polyangiitis (EGPA).

Patients with newly diagnosed or relapsing EGPA will be randomized in a 1:1 ratio to receive:

  • Experimental therapeutic strategy based on the use of rituximab (experimental group)
  • Conventional therapeutic strategy based on Five-Factor Score (FFS)-assessed disease severity (comparative group)
Detailed Description

Systemic vasculitides are inflammatory diseases of blood vessels, among which anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are often severe with life-threatening manifestations or complications. AAV include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome).

Cytotoxic drugs and glucocorticoids have been the standard of care for remission induction for nearly five decades. This regimen improved the outcome of severe AAV from death to a strong likelihood of disease control and temporary remission. However, a remission is not obtained in all patients with this combination of drugs, and most patients experience disease flares requiring repeated treatment with associated significant morbidity and mortality.

In 2 prospective controlled trials, rituximab, an anti-CD20 monoclonal antibody, was shown to be non inferior to cyclophosphamide to induce remission with an acceptable safety profile in patients with systemic GPA and MPA. However, patients with EGPA were not included in these trials and rituximab has not been evaluated prospectively to induce remission in this disease which pathogenesis is complex and not only restricted to ANCA responsibility.

In patients with EGPA, overall survival is good when treatment is stratified according to prognostic factors (Five Factor Score) but long-term outcome is not so good since relapses occur in more than 40% of patients, leading to high cumulative morbidity and damage. In small retrospective studies, rituximab seems promising as a remission-induction agent in patients with EGPA, independently from the ANCA status.

The trial detailed here is the first prospective trial evaluating rituximab as induction-remission treatment for EGPA.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
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 (EGPA)
Intervention  ICMJE
  • Drug: Rituximab
    1 g intravenous pulse at day1 and day15
    Other Name: Mabthera
  • Drug: Placebo-rituximab
    intravenous pulses at day1 and day15
    Other Name: nacl
  • Drug: Cyclophosphamide
    intravenous 9 pulses : 600 mg/m2 at days 1, 15 and 29, and then 500 mg-fixed dose at days 50, 71, 92, 113, 134 and 155.
    Other Name: endoxan
  • Drug: Placebo-cyclophosphamide
    intravenous 7 pulses : at days 29, 50, 71, 92, 113, 134 and 155.
    Other Name: Nacl
Study Arms  ICMJE
  • Experimental: Rituximab with FFS=0

    All patients in the rituximab group will receive corticosteroids with a predefined tapering schedule similar to the conventional therapy group.

    Patients with FFS=0 will receive 1 gram of rituximab at day 1 and day 15 as induction treatment

    Intervention: Drug: Rituximab
  • Placebo Comparator: Conventional therapy with FFS=0

    All patients will receive corticosteroids with a predefined tapering schedule similar to the experimental group.

    Patients with FFS=0 will receive placebo-rituximab at day 1 and day 15.

    Intervention: Drug: Placebo-rituximab
  • Experimental: Rituximab with FFS≥1

    All patients in the rituximab group will receive corticosteroids with a predefined tapering schedule similar to the conventional therapy group.

    Patients with FFS≥1 will receive a total of 9 pulses :

    • 1 gram of rituximab at day 1 and day 15 as induction treatment
    • placebo-cyclophosphamide at days 1, 15, 29, 50, 71, 92, 113, 134 and 155.

    Maintenance therapy by azathioprine will be started at day 180 according to the standard of care of these patients, as recommended by the French Vasculitis Study Group.

    Interventions:
    • Drug: Rituximab
    • Drug: Placebo-cyclophosphamide
  • Active Comparator: Conventional therapy with FFS≥1

    All patients will receive corticosteroids with a predefined tapering schedule similar to the experimental group.

    Patients with FFS≥1 will receive intravenous pulses of cyclophosphamide for a total of 9 pulses: 600 mg/m2 at days 1, 15 and 29, and then 500 mg-fixed dose at days 50, 71, 92, 113, 134 and 155.

    Maintenance therapy by azathioprine will be started at day 180 according to the standard of care of these patients, as recommended by the French Vasculitis Study Group.

    Intervention: Drug: Cyclophosphamide
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: June 16, 2016)
108
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2020
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with a diagnosis of EGPA independently of ANCA status,
  • Patient aged of 18 years or older,
  • Patients with newly-diagnosed disease or relapsing disease at the time of screening, with an active disease defined as a Birmingham Vasculitis Activity Score (BVAS) ≥3,
  • Patients within the first 21 days following initiation/increase of corticosteroids at a dose ≤ 1 mg/kg/day (pulses of methylprednisolone before oral corticosteroid therapy are authorized) ,
  • Patient able to give written informed consent prior to participation in the study.

Exclusion Criteria:

  • Patients with GPA, MPA, or other vasculitides, defined by the ACR criteria and/or the Chapel Hill Consensus Conference,
  • Patients with vasculitis in remission of the disease defined as a BVAS <3,
  • Patients with severe cardiac failure defined as class IV in New York Heart Assocation
  • Patients with acute infections or chronic active infections (including HIV, HBV or HCV),
  • Patients with active cancer or recent cancer (<5 years), except basocellular carcinoma and prostatic cancer of low activity controlled by hormonal treatment,
  • Pregnant women and lactation. Patients with childbearing potential should have reliable contraception for the 12 months duration of the study,
  • Patients with EGPA who have already been treated with rituximab within the previous 12 months,
  • Patients with hypersensitivity to a monoclonal antibody or biologic agent,
  • Patients with contraindication to use rituximab, cyclophosphamide, mesna or azathioprine,
  • Patients with other uncontrolled diseases, including drug or alcohol abuse, severe psychiatric diseases, that could interfere with participation in the trial according to the protocol,
  • Patients included in other investigational therapeutic study within the previous 3 months,
  • Patients suspected not to be observant to the proposed treatments,
  • Patients who have white blood cell count ≤4,000/mm3,
  • Patients who have platelet count ≤100,000/mm3,
  • Patients who have ALT or AST level greater that 3 times the upper limit of normal that cannot be attributed to underlying EGPA disease,
  • 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: Benjamin TERRIER, MD, PhD +33 1 58 41 14 61 benjamin.terrier@aphp.fr
Contact: Severine POIGNANT +33 1 58 41 12 11 severine.poignant@aphp.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02807103
Other Study ID Numbers  ICMJE P140915
2016-000275-25 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
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: Xavier PUECHAL, MD, PhD Centre de référence " Maladies systémiques et autoimmunes rares, en particulier Vascularites nécrosantes et Sclérodermies systémiques "
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date February 2019

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