Rituximab in Eosinophilic Granulomatosis With Polyangiitis (REOVAS)

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

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)

Study Overview

• Status: Completed
• Conditions: Eosinophilic Granulomatosis With Polyangiitis (EGPA)
• Intervention / Treatment: Drug: Rituximab; Drug: Placebo-rituximab; Drug: Placebo-cyclophosphamide; Drug: Cyclophosphamide

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: Interventional
• Enrollment (Actual): 107
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris
    • Paris, Paris, France, 75014
      • Hopital Cochin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Drug: Rituximab; 1 g intravenous pulse at day1 and day15; Other Names: Mabthera
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.	Drug: Placebo-rituximab; intravenous pulses at day1 and day15; Other Names: nacl
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.	Drug: Rituximab; 1 g intravenous pulse at day1 and day15; Other Names: Mabthera; Drug: Placebo-cyclophosphamide; intravenous 7 pulses : at days 29, 50, 71, 92, 113, 134 and 155.; Other Names: Nacl
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.	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 Names: endoxan

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	180 days
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	360 days
Area under the curve for corticosteroids	To measure the corticosteroid dose and to compare the corticosteroid sparing effect of rituximab versus conventional therapy	180 days
Area under the curve for corticosteroids	To measure the corticosteroid dose and to compare the corticosteroid sparing effect of rituximab versus conventional therapy	360 days
Number of sequelae assessed by the Vasculitis Damage Index		180 days
Number of sequelae assessed by the Vasculitis Damage Index		day 180 and day 360
ANCA titers and CD19+cells		day 180 and day 360
Health Assessment Questionnaire (HAQ) score	to evaluate functional disability	180 days
Health Assessment Questionnaire (HAQ) score	to evaluate functional disability	360 days
Short Form-36 score	to evaluate quality of life	180 days
Short Form-36 score	to evaluate quality of life	360 days

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: URC-CIC Paris Descartes Necker Cochin; French Vasculitis Study Group
• Investigators: Study Chair: Xavier PUECHAL, MD, PhD, Centre de référence " Maladies systémiques et autoimmunes rares, en particulier Vascularites nécrosantes et Sclérodermies systémiques "

Publications and helpful links

General Publications

• Terrier B, Pugnet G, de Moreuil C, Bonnotte B, Benhamou Y, Chauveau D, Besse MC, Duffau P, Limal N, Neel A, Urbanski G, Jourde-Chiche N, Martin-Silva N, Campagne J, Mekinian A, Schleinitz N, Ackermann F, Fauchais AL, Froissart A, Le Gallou T, Uzunhan Y, Viallard JF, Berezne A, Chiche L, Taille C, Direz G, Durel CA, Godmer P, Trad S, Lambert M, de Menthon M, Quemeneur T, Cadranel J, Charles P, Dossier A, Jilet L, Guillevin L, Abdoul H, Puechal X; French Vasculitis Study Group. Rituximab Versus Conventional Therapy for Remission Induction in Eosinophilic Granulomatosis With Polyangiitis : A Randomized Controlled Trial. Ann Intern Med. 2025 Sep;178(9):1249-1257. doi: 10.7326/ANNALS-24-03947. Epub 2025 Jul 29.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2016
• Primary Completion (Actual): October 21, 2020
• Study Completion (Actual): October 21, 2020

Study Registration Dates

• First Submitted: May 20, 2016
• First Submitted That Met QC Criteria: June 16, 2016
• First Posted (Estimated): June 21, 2016

Study Record Updates

• Last Update Posted (Actual): January 15, 2026
• Last Update Submitted That Met QC Criteria: January 14, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Rituximab; eosinophilic granulomatosis with polyangiitis; remission induction
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Autoimmune Diseases; Immune System Diseases; Skin Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Skin Diseases, Vascular; Vasculitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Granuloma; Systemic Vasculitis; Skin and Connective Tissue Diseases; Hemic and Lymphatic Diseases; Churg-Strauss Syndrome; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Hydrocarbons; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Inorganic Chemicals; Chlorine Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Antibodies, Monoclonal, Murine-Derived; Sodium Compounds; Chlorides; Hydrochloric Acid; Rituximab; Cyclophosphamide; Sodium Chloride
• Other Study ID Numbers: P140915; 2016-000275-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO