Study of Mepolizumab-based Regimen Compared to Conventional Therapeutic Strategy in Patients With Eosinophilic Granulomatosis With Polyangiitis (E-merge)

Study Overview
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Brief Summary
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The purpose of this study is to compare mepolizumab-based regimen to conventional therapeutic strategy for remission induction in patients with Eosinophilic Granulomatosis with Polyangiitis.

Detailed Description
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Eosinophilic granulomatosis with polyangiitis (EGPA), formerly called Churg-Strauss syndrome, is a rare systemic small-vessel vasculitis, associated with asthma and blood and tissue eosinophilia. EGPA belongs to the group of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), and commonly involves upper and lower respiratory tracts, the lungs, the peripheral nerve and the heart. Therapeutic management is based on glucocorticoids alone or in combination with conventional immunosuppressive agents, mainly azathioprine, methotrexate or cyclophosphamide, according to disease severity assessed by the Five Factor Score. Such treatments, in addition to their common side effects, are frequently insufficiently effective to control chronic asthma and/or rhinosinusitis, requiring long-term high-dose corticosteroids. Because EGPA shares common pathophysiological features with eosinophilic disorders and asthma, new therapeutic options used in these conditions could be of interest, in particular mepolizumab, a monoclonal anti-interleukin (IL)-5 antibody, which has shown promising results in two small preliminary studies to control disease activity and decrease glucocorticoids in cortico-dependant patients. In addition, mepolizumab has been recently evaluated in a prospective trial, the MIRRA trial, targeting a small niche of patients, i.e. those with corticodependent asthma unable to achieve disease control with low dose of glucocorticoids. Results published revealed that mepolizumab led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had ≥24 weeks of accrued remission; odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P<0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P<0.001). However, these studies did not evaluate the interest of mepolizumab during EGPA flare associating asthma, eosinophilic and vasculitis lesions, in order to induce remission of the disease and rapidly decrease and discontinue glucocorticoids. Also, recent pathophysiological date strongly support in addition to previous therapeutic studies the major interest to target IL-5 as soon as EGPA is diagnosed: 1) genetic association studies demonstrated that polymorphisms in the IL-5 pathway are associated with EGPA in comparison with controls, 2) increased expression of IL-5 in mice model are able to induce vasculitis lesions as observed in the human diseases. Patients will receive a standardized glucocorticoid tapering schedule. From day 28 post-baseline onwards, if the subject's BVAS=0 their oral prednisone dose should be tapered downwards. A standardized glucocorticoid tapering schedule provided in the protocol enables a reduction in oral prednisone dose every 2 weeks, with the intention of achieving a prednisone dose of 4 mg/day or less. Once a subject has achieved a dose of 4 mg/day prednisone, the investigator is encouraged to continue tapering downwards, if clinically warranted, at dose increments of 1.0 mg every week. Upwards dose adjustments within the 0-4.0 mg range are permitted without necessarily being considered a relapse.

Official Title
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Evaluation of MEpolizumab-based Regimen Compared to Conventional Therapeutic Strategy For Remission Induction In Patients With Eosinophilic Granulomatosis With Polyangiitis. Prospective, Randomized, Controlled, Double-blind Study

Conditions
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Eosinophilic Granulomatosis With Polyangiitis

Intervention / Treatment
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* Drug: Mepolizumab
* Drug: cyclophosphamide/azathioprine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a diagnosis of EGPA independently of ANCA status, Patients 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) Patients having given their written informed consent prior to participation in the study. Patients affiliated with social security or CMU (profit or being entitled) Exclusion Criteria: Patients with GPA, MPA, or other vasculitis, 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 Association Patients with acute infections or chronic active infections (including HIV, HBV or HCV and checked in the last 12 months), 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 mepolizumab within the previous 12 months, Patients with hypersensitivity to a monoclonal antibody or biologic agent, Patients with contraindication to use mepolizumab, cyclophosphamide, mesna, azathioprine or maintenance therapy used for vasculitis, 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 Patients under tutorship or curatorship and protected adults.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with FFS=0 - Mepolizumab<br>Mepolizumab 300mg every 4 weeks until D336 | Drug: Mepolizumab<br>* 300 mg/month subcutaneous<br>|
| Placebo Comparator: Patients with FFS=0 - Placebo<br>Placebo of Mepolizumab every 4 weeks until D336 | Drug: Placebo<br>* Patients with FFS=0 will receive placebo<br>|
| Experimental: Patients with FFS≥1 - Mepolizumab<br>Mepolizumab 300mg every 4 weeks until D336 and placebo of Azathioprine 1mg/kg/day from D126 until D360 and placebo of cyclophosphamide/mesna at D1, D15, D28, D56, D84 and D112 | Drug: Mepolizumab<br>* 300 mg/month subcutaneous<br>Drug: Placebo<br>* Patients with FFS=0 will receive placebo<br>|
| Placebo Comparator: Patients with FFS≥1 - Placebo<br>Placebo of Mepolizumab every 4 weeks until D336, cyclophosphamide and mesna at D1, D15, D28, D56, D84 and D112 and Azathioprine 1mg/kg/day from D126 until D360 | Drug: cyclophosphamide/azathioprine<br>* Patients with FFS≥1 will receive cyclophosphamide then azathioprine<br>Drug: Placebo<br>* Patients with FFS=0 will receive placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients who achieved a prednisone dose of 4.0 mg or less per day at day 168, without experiencing a relapse | EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterized by: a) active vasculitis (BVAS >0); OR b) active asthma symptoms; OR c) active nasal and/or sinus disease, warranting: i) an increased dose of prednisone compared to previous dosage and at least >4 mg/day prednisone total daily dose or equivalent; OR ii) an increased dose or addition of immunosuppressive therapy; OR iii) hospitalisation related to EGPA worsening. A BVAS evaluation will be conducted at the time of a relapse, or as soon as possible afterwards | Day 168 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prednisone dosage at days 168 and 364 |  | Days 168 and 364 | 
| Area under the curve for corticosteroids at days 168 and 364 |  | Days 168 and 364 | 
| Proportion of participants with a prednisone dose of 4.0 mg or less per day for 0 weeks |  | Days 168 and 364 | 
| Proportion of participants with a prednisone dose of 4.0 mg or less per day for more than 0 weeks but less than 4 weeks |  | Days 168 and 364 | 
| Proportion of participants with a prednisone dose of 4.0 mg or less per day for more than 4 weeks but less than 12 weeks |  | Days 168 and 364 | 
| Proportion of participants with a prednisone dose of 4.0 mg or less per day for at least 12 weeks |  | Days 168 and 364 | 
| Proportion of participants with a prednisone dose of 4.0 mg or less per day at both days 168 and 364. |  | Day 364 | 
| Proportion of participants experiencing a relapse | EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterized by: a) active vasculitis (BVAS >0); OR b) active asthma symptoms; OR c) active nasal and/or sinus disease, warranting: i) an increased dose of prednisone compared to previous dosage and at least >4 mg/day prednisone total daily dose or equivalent; OR ii) an increased dose or addition of immunosuppressive therapy; OR iii) hospitalisation related to EGPA worsening. A BVAS evaluation will be conducted at the time of a relapse, or as soon as possible afterwards | Day 364 | 
| Number of relapse during the study period | EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterized by: a) active vasculitis (BVAS >0); OR b) active asthma symptoms; OR c) active nasal and/or sinus disease, warranting: i) an increased dose of prednisone compared to previous dosage and at least >4 mg/day prednisone total daily dose or equivalent; OR ii) an increased dose or addition of immunosuppressive therapy; OR iii) hospitalisation related to EGPA worsening. A BVAS evaluation will be conducted at the time of a relapse, or as soon as possible afterwards. | Day 364 | 
| Time from inclusion to first relapse |  | Day 364 | 
| Number of adverse events that result in the cessation of further injections | Number of adverse events is expressed as adverse events according to the CTCAE toxicity grading system per patient-year at days 168 and 364 for the following adverse events combined: death (all causes), grade 2 or higher leukopenia or thrombocytopenia, grade 3 or higher infections, hemorraghic cystitis, malignancies, venous thromboembolic events, hospitalization resulting either from the disease or from a complication due to the study treatment, injection reactions (within 24 hours of injection). | Day 364 | 
| Vasculitis Damage Index (VDI) |  | Days 168 and 364 | 
| HAQ questionnaire |  | Days 168 and 364 | 
| SF-36 questionnaire |  | Days 168 and 364 | 
| Evolution of ANCA titers (in UI/mL) and correlation with clinical events during follow-up |  | Day 364 | 
| Evolution of eosinophils (in x10^9/L) and correlation with clinical events during follow-up |  | Day 364 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eosinophilic Granulomatosis with Polyangiitis, Mepolizumab, Remission induction, Conventional therapeutic