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

Primary Purpose

Eosinophilic Granulomatosis With Polyangiitis

Status
Recruiting
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Mepolizumab
cyclophosphamide/azathioprine
Placebo
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 focused on measuring Eosinophilic Granulomatosis with Polyangiitis, Mepolizumab, Remission induction, Conventional therapeutic

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,
  • 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.

Sites / Locations

  • Service de Médecine Interne, Centre de référence " Maladies systémiques et autoimmunes rares, en particulier Vascularites nécrosantes et Sclérodermies systémiques "Hôpital CochinRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

Patients with FFS=0 - Mepolizumab

Patients with FFS=0 - Placebo

Patients with FFS≥1 - Mepolizumab

Patients with FFS≥1 - Placebo

Arm Description

Mepolizumab 300mg every 4 weeks until D336

Placebo of Mepolizumab every 4 weeks until D336

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Prednisone dosage at days 168 and 364
Area under the curve for corticosteroids at days 168 and 364
Proportion of participants with a prednisone dose of 4.0 mg or less per day for 0 weeks
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
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
Proportion of participants with a prednisone dose of 4.0 mg or less per day for at least 12 weeks
Proportion of participants with a prednisone dose of 4.0 mg or less per day at both days 168 and 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
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.
Time from inclusion to first relapse
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).
Vasculitis Damage Index (VDI)
HAQ questionnaire
SF-36 questionnaire
Evolution of ANCA titers (in UI/mL) and correlation with clinical events during follow-up
Evolution of eosinophils (in x10^9/L) and correlation with clinical events during follow-up

Full Information

First Posted
July 31, 2021
Last Updated
June 28, 2022
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
French Vasculitis Study Group, URC-CIC Paris Descartes Necker Cochin
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1. Study Identification

Unique Protocol Identification Number
NCT05030155
Brief Title
Study of Mepolizumab-based Regimen Compared to Conventional Therapeutic Strategy in Patients With Eosinophilic Granulomatosis With Polyangiitis (E-merge)
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Recruiting
Study Start Date
May 30, 2022 (Actual)
Primary Completion Date
May 2025 (Anticipated)
Study Completion Date
May 2025 (Anticipated)

3. Sponsor/Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Eosinophilic Granulomatosis With Polyangiitis
Keywords
Eosinophilic Granulomatosis with Polyangiitis, Mepolizumab, Remission induction, Conventional therapeutic

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Patients with FFS=0 - Mepolizumab
Arm Type
Experimental
Arm Description
Mepolizumab 300mg every 4 weeks until D336
Arm Title
Patients with FFS=0 - Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo of Mepolizumab every 4 weeks until D336
Arm Title
Patients with FFS≥1 - Mepolizumab
Arm Type
Experimental
Arm Description
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
Arm Title
Patients with FFS≥1 - Placebo
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Mepolizumab
Intervention Description
300 mg/month subcutaneous
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide/azathioprine
Intervention Description
Patients with FFS≥1 will receive cyclophosphamide then azathioprine
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Patients with FFS=0 will receive placebo
Primary Outcome Measure Information:
Title
Percentage of patients who achieved a prednisone dose of 4.0 mg or less per day at day 168, without experiencing a relapse
Description
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
Time Frame
Day 168
Secondary Outcome Measure Information:
Title
Prednisone dosage at days 168 and 364
Time Frame
Days 168 and 364
Title
Area under the curve for corticosteroids at days 168 and 364
Time Frame
Days 168 and 364
Title
Proportion of participants with a prednisone dose of 4.0 mg or less per day for 0 weeks
Time Frame
Days 168 and 364
Title
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
Time Frame
Days 168 and 364
Title
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
Time Frame
Days 168 and 364
Title
Proportion of participants with a prednisone dose of 4.0 mg or less per day for at least 12 weeks
Time Frame
Days 168 and 364
Title
Proportion of participants with a prednisone dose of 4.0 mg or less per day at both days 168 and 364.
Time Frame
Day 364
Title
Proportion of participants experiencing a relapse
Description
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
Time Frame
Day 364
Title
Number of relapse during the study period
Description
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.
Time Frame
Day 364
Title
Time from inclusion to first relapse
Time Frame
Day 364
Title
Number of adverse events that result in the cessation of further injections
Description
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).
Time Frame
Day 364
Title
Vasculitis Damage Index (VDI)
Time Frame
Days 168 and 364
Title
HAQ questionnaire
Time Frame
Days 168 and 364
Title
SF-36 questionnaire
Time Frame
Days 168 and 364
Title
Evolution of ANCA titers (in UI/mL) and correlation with clinical events during follow-up
Time Frame
Day 364
Title
Evolution of eosinophils (in x10^9/L) and correlation with clinical events during follow-up
Time Frame
Day 364

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, 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Benjamin TERRIER, MD, PhD
Phone
(+33)1 58 41 14 61
Email
benjamin.terrier@aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Karima MESBAHI
Phone
(+33)1 58 41 12 11
Email
karima.mesbahi@aphp.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Loic GUILLEVIN, MD, PhD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Study Director
Facility Information:
Facility Name
Service de Médecine Interne, Centre de référence " Maladies systémiques et autoimmunes rares, en particulier Vascularites nécrosantes et Sclérodermies systémiques "Hôpital Cochin
City
Paris
ZIP/Postal Code
75014
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Benjamin TERRIER, MD, PhD
Phone
(+33)1 58 41 14 61
Email
benjamin.terrier@aphp.fr

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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