A RANDOMIZED DOUBLE BLIND, PLACEBO-CONTROLLED NATIONAL MULTICENTER PHASE 3 TRIAL TO EVALUATE THE EFFICACY OF AZATHIOPRINE FOR THE PREVENTION OF RELAPSE IN PATIENTS WITH MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODY ASSOCIATED DISEASE (MOG-AD) AFTER A FIRST ATTACK : MOGWAI

The primary objective of this study is to evaluate the **efficacy** of azathioprine in preventing relapse in patients with Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease (MOGAD) after a first attack. This is assessed by measuring the time to first relapse in azathioprine-treated patients compared to those receiving a placebo over a maximum period of three years. This objective is clinically relevant as it aims to determine the potential of azathioprine to reduce the frequency of relapses, which can significantly impact the long-term prognosis and quality of life for patients with MOGAD.

Secondary objectives include: - Assessing the tolerability and safety of azathioprine in an adult MOGAD population. - Evaluating the prevention of accrual of global and visual disability in MOGAD at three years, comparing azathioprine to placebo. - Comparing the quality of life at three years between the azathioprine and control groups. - Assessing compliance to treatment. These objectives are crucial for understanding the broader impact of azathioprine on patient health and its potential role in long-term management strategies for MOGAD.

The clinical trial involves participants diagnosed with a **neurological** condition, specifically focusing on individuals who have experienced their first attack of an acute demyelinating syndrome of the central nervous system within the past three months. The study population includes both male and female subjects aged 18 years and older. Participants must have tested positive for MOG-Ab, confirmed in a centralized laboratory. The trial does not target a vulnerable population, and all participants are required to have health care coverage under the social security system. Female participants of childbearing potential are required to use effective contraception during the study and for at least three months after treatment cessation. The sponsor has not provided information regarding the total number of participants in the trial. The selection criteria ensure that participants are capable of understanding the study's purpose and risks, and they must provide signed and dated written informed consent.

The clinical trial is a **randomized**, **double-blind**, placebo-controlled, national multicenter Phase 3 study designed to evaluate the efficacy of **azathioprine** in preventing relapse in patients with Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease (MOG-AD) following a first attack. The primary endpoint is the time to first relapse, comparing azathioprine-treated versus placebo-treated patients over a maximum period of three years. The trial is expected to conclude by December 2028, with recruitment having commenced in December 2023.

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), a recent first attack of acute demyelinating syndrome, and a positive test for MOG-Ab. Following the screening, participants will be randomized to receive either azathioprine or placebo. The study involves regular follow-up visits to monitor the participants' health, assess the occurrence of any adverse events, and evaluate the primary and secondary endpoints, including global disability and visual acuity. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted.

The expected duration of participant involvement is up to three years, contingent upon the occurrence of a relapse or the completion of the study period. Conditions that may lead to early termination from the study include the development of serious adverse events or non-compliance with the study protocol. The trial will ensure that all participants are provided with appropriate health care coverage and that female participants of childbearing potential maintain effective contraception throughout the study and for at least three months post-treatment.

The clinical trial involves the administration of **azathioprine**, a chemical compound with the ATC code L04AX01. Azathioprine is provided in an oral pharmaceutical form, identified by the code PHF00082MIG. The maximum daily dose is 100 mg, with a total maximum dose of 200 mg over the treatment period. The treatment duration is set for a maximum of 36 months. Participants will receive azathioprine orally, and compliance will be monitored throughout the trial period to ensure adherence to the dosing schedule.

**Prednisolone** is used as an auxiliary treatment in the trial. It is a chemical substance with the ATC code H02AB07, provided in an oral form, coded as PHF00245MIG. The maximum daily dose of prednisolone is 40 mg, with a total maximum dose of 600 mg. The treatment period for prednisolone is limited to 6 months. Administration is oral, and participant compliance will be monitored to ensure proper dosing.

**Hydrocortisone** is another auxiliary treatment included in the study. It is a chemical compound with the ATC code H02AB09, available in an oral form, identified by the code PHF00099MIG. The maximum daily dose is 20 mg, with a total maximum dose of 40 mg. The treatment period for hydrocortisone is restricted to 1 month. Participants will receive hydrocortisone orally, and adherence to the dosing schedule will be monitored.

The trial also includes a placebo group, which will receive a non-active treatment to serve as a comparator for the efficacy of azathioprine. The placebo is administered in a manner consistent with the active treatments to maintain the double-blind nature of the study. Compliance monitoring will be conducted to ensure the integrity of the trial data.

Efficacy in this clinical trial will be assessed primarily by measuring the time to first relapse in patients with **Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease (MOG-AD)**. This will involve comparing patients treated with azathioprine to those receiving a placebo over a randomized control period of up to three years. The primary endpoint is specifically focused on this time-to-event analysis.

Secondary endpoints will include the evaluation of adverse events, both general and serious, related to azathioprine and/or steroids. Global disability will be assessed at month 36 (M36) using the Expanded Disability Status Scale (EDSS), with particular attention to any worsening from baseline. Ambulation status will also be evaluated at M36 through the Ambulation Score, which measures the distance a patient can walk, and any changes from baseline will be noted.

Visual acuity assessments will be conducted at M36, using the standard Snellen chart for high-contrast visual acuity and the Sloan Charts at 2.5% for low-contrast visual acuity. Changes from baseline in visual disability will be recorded. Quality of life will be measured using the EuroQOL EQ-5D-3L at M36. Additionally, compliance with treatment will be monitored by calculating the percentage of untaken tablets left in the blisters, relative to each patient's participation time in the study.