Clinical trial NCT02807103: Rituximab in Eosinophilic Granulomatosis With Polyangiitis
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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Eosinophilic Granulomatosis With Polyangiitis (EGPA)
Keywords: Rituximab
remission induction
eosinophilic granulomatosis with polyangiitis
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: French Vasculitis Study Group
First posted: 2016-06-21
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: The percentage of patients who obtained a BVAS=0 and prednisone dose ≤7.5 mg/day at day 180.
timeFrame: 180 days
Secondary outcomes:
measure: Number of adverse events
timeFrame: 180 days
measure: Number of adverse events
timeFrame: 360 days
measure: Area under the curve for corticosteroids
timeFrame: 180 days
measure: Area under the curve for corticosteroids
timeFrame: 360 days
measure: Number of sequelae assessed by the Vasculitis Damage Index
timeFrame: 180 days
measure: Number of sequelae assessed by the Vasculitis Damage Index
timeFrame: day 180 and day 360
measure: ANCA titers and CD19+cells
timeFrame: day 180 and day 360
measure: Health Assessment Questionnaire (HAQ) score
timeFrame: 180 days
measure: Health Assessment Questionnaire (HAQ) score
timeFrame: 360 days
measure: Short Form-36 score
timeFrame: 180 days
measure: Short Form-36 score
timeFrame: 360 days
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Cochin
Study officials:
affiliation: Centre de référence " Maladies systémiques et autoimmunes rares, en particulier Vascularites nécrosantes et Sclérodermies systémiques "
name: Xavier PUECHAL, MD, PhD
role: STUDY_CHAIR
References: