Evaluation of Mepolizumab-Based Regimen Versus Conventional Therapy for Remission Induction in Eosinophilic Granulomatosis with Polyangiitis

The primary objective of this study is to evaluate the **glucocorticoid**-sparing effect of a mepolizumab-based regimen in patients with newly-diagnosed or relapsing **eosinophilic granulomatosis with polyangiitis (EGPA)**. This is defined as achieving a prednisone dose of 4.0 mg or less per day by day 168. This objective is clinically relevant as it aims to reduce the dependency on glucocorticoids, which are associated with significant side effects, thereby potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Measuring the glucocorticoid dose and cumulative dose at days 168 and 364 when comparing mepolizumab to conventional therapy.
• Comparing the proportions of participants with a prednisone dose of 4.0 mg or less per day over various time intervals and at specific days.
• Assessing the proportion of participants experiencing a relapse and the number of relapses during the study period.
• Evaluating the number of asthma and sinonasal exacerbations, as well as asthma control and sinonasal manifestations during the study period.
• Comparing the safety profile of mepolizumab and conventional treatment, and assessing sequelae using the Vasculitis Damage Index.
• Evaluating functional disability and quality of life, and the evolution of ANCA titers and eosinophils, correlating these with clinical events during follow-up.

The clinical trial involves participants diagnosed with **Eosinophilic granulomatosis with polyangiitis (EGPA)**, a condition previously known as Churg-Strauss syndrome. The study population includes both male and female subjects aged 18 years or older. Participants are required to have either newly-diagnosed or relapsing EGPA with active disease, as indicated by a Birmingham Vasculitis Activity Score (BVAS) of 3 or higher. The trial does not involve a vulnerable population. Participants must be within the first 21 days following the initiation or increase of corticosteroids at a dose of 1 mg/kg/day or less, with allowances for pulses of methylprednisolone before oral corticosteroid therapy. The sponsor has not provided information regarding the total number of participants. All participants must provide written informed consent and have an affiliation to social security or CMU. The selection criteria ensure a focus on individuals with active disease, allowing for the assessment of the glucocorticoid-sparing effect of a mepolizumab-based regimen.

The clinical trial is designed to evaluate the efficacy of a **mepolizumab**-based regimen compared to a conventional therapeutic strategy for remission induction in patients with **eosinophilic granulomatosis with polyangiitis** (EGPA). This study is a prospective, randomized, controlled, double-blind trial. The primary objective is to determine the glucocorticoid-sparing effect of the mepolizumab-based regimen, specifically achieving a prednisone dose of 4.0 mg or less per day by day 168 in patients with newly diagnosed or relapsing EGPA. The trial is expected to run from May 30, 2022, to January 30, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 years or older), diagnosis of EGPA, and active disease status. Following the screening, participants will be randomized to receive either the mepolizumab-based regimen or a conventional treatment strategy. The study includes follow-up visits at specified intervals to monitor treatment efficacy and safety, with assessments of prednisone dosage and disease activity. The end-of-study visit will evaluate the primary and secondary endpoints, including the percentage of patients achieving the target prednisone dose without relapse and the number of relapses during the study period.

The expected length of participant involvement is approximately 34 weeks, with conditions for early termination including withdrawal of consent, significant adverse events, or non-compliance with the study protocol. The trial will utilize a double-blind design to ensure unbiased results, with both participants and investigators unaware of the treatment assignments. The study will employ a placebo and comparator groups, with treatments administered via subcutaneous injection, oral tablets, or infusion as appropriate. The trial's endpoints will be assessed at days 168 and 364, with secondary endpoints including prednisone dosage, relapse rates, and quality of life measures.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Mepolizumab**, marketed as Nucala, is an experimental medication used in this study. It is provided in the form of a **powder for solution for injection**. The active substance, mepolizumab, is a protein-based therapeutic agent. The medication is administered via the **subcutaneous route**. The maximum daily dose is 300 mg, with a total maximum dose of 3900 mg over a treatment period of 13 weeks. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Azathioprine**, marketed as IMUREL, serves as a comparator treatment in the trial. It is available as a **film-coated tablet** and is administered **orally**. The active substance, azathioprine, is of chemical origin. The maximum daily dose is 200 mg, with a total maximum dose of 47.6 g over a treatment period of 34 weeks. Compliance is monitored through pill counts and patient diaries to ensure accurate dosing.

**Cyclophosphamide** is another comparator treatment used in the study. It is provided as a **powder for solution for injection** and is administered via **injection**. The active substance, cyclophosphamide, is chemically derived. The maximum daily dose is 700 mg/m², with a total maximum dose of 3900 mg/m² over a treatment period of 112 weeks. Compliance is assessed through regular clinical evaluations and patient reporting.

**Sodium chloride** is used as a non-experimental treatment in the form of a **solution for infusion**. It is administered **subcutaneously** with a maximum daily dose of 3 ml and a total maximum dose of 39 ml over a 13-week period. This treatment serves as a standard-of-care therapy to maintain hydration and electrolyte balance during the trial.

A **placebo** for azathioprine is also utilized in the study to maintain the double-blind design. The placebo is administered in a manner consistent with the azathioprine dosing schedule, ensuring that neither the participants nor the investigators are aware of the treatment assignments. Compliance with the placebo regimen is monitored similarly to the active treatments, using pill counts and patient diaries.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percentage of patients who achieve a prednisone dose of 4.0 mg or less per day at day 168 without experiencing a relapse. This endpoint is designed to evaluate the glucocorticoid-sparing effect of the mepolizumab-based regimen in patients with newly-diagnosed or relapsing **Eosinophilic Granulomatosis with Polyangiitis (EGPA)**.

Secondary endpoints include various measures to further assess the efficacy of the treatment. These include prednisone dosage at days 168 and 364, the area under the curve for corticosteroids at these timepoints, and the proportion of participants maintaining a prednisone dose of 4.0 mg or less per day for specified durations. Additionally, the trial will evaluate the proportion of participants experiencing a relapse, the number of relapses, and the number of asthma and sinonasal exacerbations during the study period. Other secondary measures include the time from inclusion to first relapse, scores from the Asthma Control Questionnaire (ACQ) and Sino-Nasal Outcome Test (SNOT-22), and the Vasculitis Damage Index at days 168 and 364.

Further assessments will involve the number of adverse events per patient-year, categorized by severity according to the CTCAE toxicity grading system, and the evolution of ANCA titers and eosinophil levels, with correlation to clinical events during follow-up. The Health Assessment Questionnaire (HAQ) and the SF-36 will also be used to evaluate patient-reported outcomes at days 168 and 364. These comprehensive measures will provide a robust evaluation of the treatment's efficacy in managing EGPA.