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

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Brief Title

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

Official Title

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

Brief Summary

      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

      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.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Percentage of patients who achieved a prednisone dose of 4.0 mg or less per day at day 168, without experiencing a relapse

Secondary Outcome

 Prednisone dosage at days 168 and 364

Condition

Eosinophilic Granulomatosis With Polyangiitis

Intervention

Mepolizumab

Study Arms / Comparison Groups

 Patients with FFS=0 - Mepolizumab
Description:  Mepolizumab 300mg every 4 weeks until D336

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

100

Start Date

December 2021

Completion Date

December 2024

Primary Completion Date

December 2024

Eligibility Criteria

        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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Loic GUILLEVIN, MD, PhD, (+33)1 58 41 14 61, [email protected]

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT05030155

Organization ID

D20180135

Secondary IDs

2020-003318-10

Responsible Party

Sponsor

Study Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

 French Vasculitis Study Group

Study Sponsor

Loic GUILLEVIN, MD, PhD, Study Director, Assistance Publique - Hôpitaux de Paris


Verification Date

August 2021