Azathioprine in MOGAD

Study Overview
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Brief Summary
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MOG-IgG associated disease (MOGAD) is a rare inflammatory disease of the central nervous system recently described. Initially reported as monophasic, data from incident cohorts suggests that around 50% of adult patients with MOG-Ab may relapse within the first two years of the disease, with most of relapses occurring early after disease onset. No randomized controlled trial has ever been performed and therapeutic guidelines for this disease remain unclear especially after a single event. In short-sized and mainly retrospective study, azathioprine, an immunosuppressant drug, have showed promising results on preventing the risk of relapse in MOGAD patients. The hypothesis is that the initiation of a treatment after a first attack of MOGAD should prevent further relapse and disability accrual. The investigators propose herein the first randomized controlled trial in MOGAD, to evaluate the efficacy of azathioprine to prevent relapses, after a first attack, in a placebo double-blinded design.

Official Title
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A Randomized, Placebo-controlled Phase 3 Trial of Azathioprine for the Prevention of Relapse in Myelin-oligodendrocyte-glycoprotein (MOG)-Antibody Associated Disease

Conditions
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Central Nervous System Inflammation, MOG-IgG Associated Disease

Intervention / Treatment
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* Drug: Azathioprine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years First attack of documented acute demyelinating syndrome of the central nervous system, within the past 3 months, whatever the severity or the clinical phenotype Tested positive for MOG-Ab, confirmed in a centralized lab (Lyon referral centre) Ability of the subject to understand the purpose and risks of the study and provide signed and dated written informed consent. Patients should be beneficiary of health care coverage under the social security system Exclusion Criteria: Hypersensitivity to azathioprine or steroids Active infections or cancer Seriously impaired hepatic or bone marrow functions: Lymphocyte count < 1000/ml and or Polynuclear neutrophil count < 1500/ml ALT and/or AST > 3N Any live vaccine in the past 3 months Thiopurine methyltransferase (TPMT) phenotype deficient or intermediate, with enzymatic activity < 16 nmol/h/ml Unable to complete an MRI (e.g. due to pacemaker, severe claustrophobia, hypersensitivity to contrast media, or who lack adequate peripheral venous access) Necessary use of allopurinol and febuxostat Necessary use of any another immunosuppressive therapy different than azathioprine or steroids Current enrollment or a plan to enroll in any interventional clinical study in which an investigational treatment or approved therapy is use. Participation in a non-interventional study can be allowed as long as this participation does not interfere with this protocol or is not likely to affect the subject's ability to comply with the protocol. Female subjects who have a positive blood pregnancy test result, are pregnant or are currently breast feeding. All female subjects of childbearing potential must practice effective contraception during the study. Inability to comply with study requirements Vulnerable patients (defined by articles L1121-5 to L1121-8 and L1122-1-2 from French Public Health Code)

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: Azathioprine<br>Azathioprine, dose related to weight (100 mg for <50 kg, 150 mg 50-100 kg, 200 mg for >100 kg), oral, daily Associated to oral corticosteroid, prednisone : 40 mg per day during three months, and progressively tapered during three months until stop (- 30 mg during 15 days, 20mg during 15 days, 15 mg during 15 days, 10 mg during 15 days, 5 mg during 15 days and introduction of hydrocortisone 20 mg + Stop prednisone; hydrocortisone 20mg during 15 days, Stop hydrocortisone) | Drug: Azathioprine<br>* Dose related to weigh (100 mg for <50 kg, 150 mg 50-100 kg, 200 mg for >100 kg) = 2 to 4 50mg oral caps, daily, during all the study period<br>|
| Placebo Comparator: Placebo<br>Placebo, once a day, oral, number of caps related to weight Associated to oral corticosteroid: prednisone 40 mg per day during three months and progressively tapered during three months until stop (- 30 mg during 15 days, 20mg during 15 days, 15 mg during 15 days, 10 mg during 15 days, 5 mg during 15 days and introduction of hydrocortisone 20 mg + Stop prednisone; hydrocortisone 20mg during 15 days, Stop hydrocortisone) | Other: Placebo<br>* Dose related to weigh (100 mg for <50 kg, 150 mg 50-100 kg, 200 mg for >100 kg) = 2 to 4 50mg oral caps, daily, during all the study period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first relapse (in days), comparing azathioprine-treated vs placebo-treated patients during a randomized control period of a maximum of three years. | A definite relapse will be defined as such: When a patient is diagnosed as experiencing a relapse by the local investigator, the anonymized file will be reviewed within 4 days by a second investigator neurologist, not aware of the randomization group nor of the center treating the patient. If this second neurologist also considers the patient as experiencing a relapse, the patient will be considered as relapsing for the main analysis. If the second neurologist disagrees, the opinion of a third neurologist will be asked and the majority opinion will be retained. As to ensure a maximum of homogeneity, we also propose a protocol-defined criteria for a MOGAD relapse, validated by the steering committee and available to every investigator (see Annex 2). | During a randomized control period of a maximum of three years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and type of adverse events, including serious adverse events, related to azathioprine and/or steroids and placebo |  | : During a randomized control period of a maximum of three years | 
| Evaluation of global disability at 36 months | Global disability at 36 months assessed by EDSS: The EDSS scale is a method of quantifying disability and monitoring changes in the level of disability over time. It is widely used in clinical trials and in the assessment of patients with inflammatory disorders of the central nervous system. The EDSS scale ranges from 0 to 10 in 0.5-unit increments (20 values) that represent higher levels of disability. Scoring is based on an examination by a neurologist. | at baseline and at 36 months | 
| Evaluation of global disability at 36 months | Worsening from baseline to 36 months of the EDSS | at baseline and at 36 months | 
| Evaluation of global disability at 36 months | Ambulation status at 36 months assessed by the Ambulation Score. Scoring is based on a measurement of the distance the patient is able to walk (in meters) and then classified in 12 levels. | at baseline and at 36 months | 
| Evaluation of global disability at 36 months | Worsening from baseline to 36 months of the Ambulation Score. | at baseline and at 36 months | 
| Evaluation of visual disability at 36 months | Best-corrected high contrast visual acuity at 36 months measured (each eye tested separately) using the standard Snellen chart or equivalent. | at baseline and at 36 months | 
| Evaluation of visual disability at 36 months | Worsening from baseline to 36 months of visual disability assessed by change of the best- corrected high-contrast visual acuity using the standard Snellen chart or equivalent (each eye tested separately). | at baseline and at 36 months | 
| Evaluation of visual disability at 36 months | Best-corrected low-contrast visual acuity at 36 months using the Sloan Charts at 2.5%, in each eye. | at baseline and at 36 months | 
| Evaluation of visual disability at 36 months | Worsening from baseline to 36 months of low-contrast visual acuity using the Sloan Charts at 2.5%, in each eye. | at baseline and at 36 months | 
| Evaluation of visual disability at 36 months | Inner retinal layers thicknesses at 36 months assessed by the spectral domain OCT (each eye tested separately) | at baseline and at 36 months | 
| Evaluation of visual disability at 36 months | Worsening from baseline to 36 months of the peripapillary retinal nerve fiber layer thickness (μm) and the ganglion cell complex thickness (μm) assessed with spectral domain OCT (each eye tested separately). | at baseline and at 36 months | 
| Quality of life will be assessed using the EuroQOL EQ-5D-3L at 36 months | https://euroqol.org | at 36 months | 
| Compliance to treatment | percentage of untaken pills (left in the blisters) regarding each patient | During a randomized control period of a maximum of three years | 
| Exploratory radiological features | Description, and comparison between the two groups, of worsening of MRI (brain and spinal cord and visual) from baseline to 36 months assessed by number of new/enlarging T2 lesions | at baseline and at 36 months | 
| Exploratory radiological features | Description and comparison between the two groups of worsening of MRI (brain and/or spinal cord and/or visual) from baseline to 36 months assessed by number of new T1 gadolinium enhancing lesions | at baseline and at 36 months | 
| Exploratory biological features | In each group of treatment, association between MOG-Ab titer at first episode and the risk of relapse | at screening, at 6 months, at 12 months, at 36 months and in case of a relapse | 
| Exploratory biological features | In each group of treatment, association between MOG-Ab titer at onset and the level of global disability assessed by the EDSS at 36 months. | at screening, at 6 months, at 12 months, at 36 months and in case of a relapse | 
| Exploratory biological features | In each group of treatment, prognostic value of longitudinal MOG-Ab-titers to predict relapse. | at screening, at 6 months, at 12 months, at 36 months and in case of a relapse | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neuromyelitis optica, MOGAD, azathioprine, optic neuritis, myelitis, MOG-IgG associated disease