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Rituximab in Eosinophilic Granulomatosis With Polyangiitis (REOVAS)

Primary Purpose

Eosinophilic Granulomatosis With Polyangiitis (EGPA)

Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Rituximab
Placebo-rituximab
Cyclophosphamide
Placebo-cyclophosphamide
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Eosinophilic Granulomatosis With Polyangiitis (EGPA) focused on measuring Rituximab, remission induction, eosinophilic granulomatosis with polyangiitis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Hôpital Cochin

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Active Comparator

Arm Label

Rituximab with FFS=0

Conventional therapy with FFS=0

Rituximab with FFS≥1

Conventional therapy with FFS≥1

Arm Description

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

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.

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.

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.

Outcomes

Primary Outcome Measures

The percentage of patients who obtained a BVAS=0 and prednisone dose ≤7.5 mg/day at day 180.

Secondary Outcome Measures

Number of adverse events
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
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
To measure the corticosteroid dose and to compare the corticosteroid sparing effect of rituximab versus conventional therapy
Area under the curve for corticosteroids
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
Number of sequelae assessed by the Vasculitis Damage Index
ANCA titers and CD19+cells
Health Assessment Questionnaire (HAQ) score
to evaluate functional disability
Health Assessment Questionnaire (HAQ) score
to evaluate functional disability
Short Form-36 score
to evaluate quality of life
Short Form-36 score
to evaluate quality of life

Full Information

First Posted
May 20, 2016
Last Updated
April 13, 2021
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
French Vasculitis Study Group
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1. Study Identification

Unique Protocol Identification Number
NCT02807103
Brief Title
Rituximab in Eosinophilic Granulomatosis With Polyangiitis
Acronym
REOVAS
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
April 2021
Overall Recruitment Status
Completed
Study Start Date
December 5, 2016 (Actual)
Primary Completion Date
October 21, 2020 (Actual)
Study Completion Date
October 21, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
French Vasculitis Study Group

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Eosinophilic Granulomatosis With Polyangiitis (EGPA)
Keywords
Rituximab, remission induction, eosinophilic granulomatosis with polyangiitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
107 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Rituximab with FFS=0
Arm Type
Experimental
Arm Description
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
Arm Title
Conventional therapy with FFS=0
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Rituximab with FFS≥1
Arm Type
Experimental
Arm Description
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.
Arm Title
Conventional therapy with FFS≥1
Arm Type
Active Comparator
Arm Description
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 Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Mabthera
Intervention Description
1 g intravenous pulse at day1 and day15
Intervention Type
Drug
Intervention Name(s)
Placebo-rituximab
Other Intervention Name(s)
nacl
Intervention Description
intravenous pulses at day1 and day15
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
endoxan
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo-cyclophosphamide
Other Intervention Name(s)
Nacl
Intervention Description
intravenous 7 pulses : at days 29, 50, 71, 92, 113, 134 and 155.
Primary Outcome Measure Information:
Title
The percentage of patients who obtained a BVAS=0 and prednisone dose ≤7.5 mg/day at day 180.
Time Frame
180 days
Secondary Outcome Measure Information:
Title
Number of adverse events
Description
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
Time Frame
180 days
Title
Number of adverse events
Description
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
Time Frame
360 days
Title
Area under the curve for corticosteroids
Description
To measure the corticosteroid dose and to compare the corticosteroid sparing effect of rituximab versus conventional therapy
Time Frame
180 days
Title
Area under the curve for corticosteroids
Description
To measure the corticosteroid dose and to compare the corticosteroid sparing effect of rituximab versus conventional therapy
Time Frame
360 days
Title
Number of sequelae assessed by the Vasculitis Damage Index
Time Frame
180 days
Title
Number of sequelae assessed by the Vasculitis Damage Index
Time Frame
day 180 and day 360
Title
ANCA titers and CD19+cells
Time Frame
day 180 and day 360
Title
Health Assessment Questionnaire (HAQ) score
Description
to evaluate functional disability
Time Frame
180 days
Title
Health Assessment Questionnaire (HAQ) score
Description
to evaluate functional disability
Time Frame
360 days
Title
Short Form-36 score
Description
to evaluate quality of life
Time Frame
180 days
Title
Short Form-36 score
Description
to evaluate quality of life
Time Frame
360 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Xavier PUECHAL, MD, PhD
Organizational Affiliation
Centre de référence " Maladies systémiques et autoimmunes rares, en particulier Vascularites nécrosantes et Sclérodermies systémiques "
Official's Role
Study Chair
Facility Information:
Facility Name
Hôpital Cochin
City
Paris
ZIP/Postal Code
75014
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://www.vascularites.org/
Description
Related Info

Learn more about this trial

Rituximab in Eosinophilic Granulomatosis With Polyangiitis

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