Azathioprine in MOGAD (MOGwAI)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Central Nervous System Inflammation; MOG-IgG Associated Disease
• Intervention / Treatment: Drug: Azathioprine; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 126
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Romain MARIGNIER, MD PhD; Phone Number: +334 72 35 75 22; Email: romain.marignier@chu-lyon.fr
• Study Contact Backup: Name: Lakhdar BENYAHYA, project manager; Phone Number: +334 72 68 49 07; Email: lakhdar.benyahya@chu-lyon.fr

Study Locations

• France
  • Bordeaux, France
    • Recruiting
    • Department of Neurology, CHU de Bordeaux - GH Pellegrin
    • Contact: Aurélie RUET, Pr; Phone Number: +33 (0)5 56 79 55 21; Email: aurelie.ruet@chu-bordeaux.fr
  • Lille, France
    • Recruiting
    • Department of Neurology, CHU of Lille, Hospital Roger Salengro
    • Contact: Helene ZEPHIR, Pr; Phone Number: +33 (0)3 20 44 68 46; Email: thi-helene.zephir@chru-lille.fr
  • Lyon, France
    • Recruiting
    • Department of Neuro Ophthalmology, CHU of Lyon, Neurology Hospital Pierre Wertheimer
    • Contact: Caroline FROMENT, Pr; Phone Number: +33 (0)472118012; Email: caroline.froment01@chu-lyon.fr
  • Lyon, France
    • Recruiting
    • Service de Neurologie sclérose en plaques, pathologies de la myéline et neuro-inflammation - Centre de référence des maladies inflammatoires rares du cerveau et de la moelle (MIRCEM) - Hôpital Neurologique Pierre Wertheimer - Hospices Civils de Lyon
    • Contact: Romain MARIGNIER, Pr; Phone Number: +33 4 72 35 75 22; Email: romain.marignier@chu-lyon.fr
  • Marseille, France
    • Recruiting
    • Department of Neurology University hospital Timone
    • Contact: Bertrand AUDOIN, Pr; Phone Number: +33 (0)4 91 38 59 39; Email: bertrand.audoin@ap-hm.fr
  • Montpellier, France
    • Recruiting
    • Department of Neurology Montpellier Universitary Hospital
    • Contact: Xavier AYRIGNAC, Dr; Phone Number: +33 (0)4 67 33 94 69; Email: x-ayrignac@chu-montpellier.fr
  • Nancy, France, 54035
    • Recruiting
    • CHRU de Nancy Hôpital Central
    • Contact: Guillaume MATHEY, md; Phone Number: 03.83.85.16.88; Email: g.mathey@chru-nancy.fr
  • Nice, France
    • Not yet recruiting
    • Department of Neurology, Hôpital Pasteur 2
    • Contact: Mikael COHEN, Dr; Phone Number: +33 (0)4 92 03 98 93; Email: cohen.m@chu-nice.fr
  • Nîmes, France
    • Recruiting
    • Department of Neurology, Hôpital Caremeau
    • Contact: Eric THOUVENOT, Pr; Phone Number: +33 (0)4 66 68 32 61; Email: eric.thouvenot@chu-nimes.fr
  • Paris, France, 75012
    • Recruiting
    • National Hospital of Vision (15-20)
    • Contact: Jennifer ABOAB, MD; Phone Number: 06 20 35 14 56; Email: jaboab@15-20.fr
  • Paris, France
    • Recruiting
    • Department of Neurology APHP, Pitié Salpêtrière Hospital
    • Contact: Elisabeth MAILLART, Dr; Phone Number: +33 (0)1 42 16 19 75; Email: elisabeth.maillart@aphp.fr
  • Paris, France
    • Recruiting
    • Department of Neurology. Hôpital A. Fondation Rothschild
    • Contact: Romain DESCHAMPS, Dr; Phone Number: +33 (0)1 48 03 68 52; Email: rdeschamps@for.paris
  • Rennes, France
    • Recruiting
    • Department of Neurology, CHU de Rennes
    • Contact: Laure MICHEL, Dr; Phone Number: +33 (0)2 99 28 98 42; Email: laure.michel@chu-rennes.fr
  • Rouen, France
    • Recruiting
    • Department of Neurology, CHU de Rouen
    • Contact: Bertrand BOURRE, Dr; Phone Number: +33 (0)2 32 88 67 49; Email: bertrand.bourre@chu-rouen.fr
  • Saint-Herblain, France
    • Recruiting
    • Department of Neurology, Hôpital g. Et r. Laennec
    • Contact: David LAPLAUD, Pr; Phone Number: +33 (0)2 40 16 52 12; Email: david.laplaud@chu-nantes.fr
  • Strasbourg, France
    • Recruiting
    • Department of Neurology, Hôpital Hautepierre
    • Contact: Nicolas COLLONGUES, Dr; Phone Number: +33 (0)88 12 85 44; Email: nicolas.collongues@chru-strasbourg.fr
  • Toulouse, France
    • Recruiting
    • Department of Neurology, Toulouse Universitary Hospital
    • Contact: Jonathan CIRON, Dr; Phone Number: +33 (0)5 61 77 91 06; Email: ciron.j@chu-toulouse.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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
• Female patients of childbearing potential should have effective contraception throughout the course of treatment and for at least three months after stopping treatment.

Exclusion Criteria:

• Hypersensitivity to azathioprine or steroids
• Active infections or cancer (including tuberculosis, hepatitis, herpes and VZV)
• Psychosis not controlled by treatment
• Seriously impaired bone marrow functions: Lymphocyte count < 1000/ml and or Polynuclear neutrophil count < 1500/ml
• Seriously impaired hepatic functions: ALT and/or AST > 3N
• Seriously impaired renal functions: GFR < 29 ml/min/1.73m²
• Any live vaccine in the past 3 months or planned during the RCT and RCT+6months
• 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 a xanthine oxidase inhibitor (Allopurinol, Oxipurinol, Thiopurinol, Febuxotat,…)
• Necessary use of angiotensin-converting-enzyme inhibitor, cotrimoxazole, cimetidine and indometacine
• Necessary use of an aminosalicylate derivates
• Necessary use of any another immunosuppressive therapy, different than azathioprine, or steroids
• Necessary use of cytotoxic therapy
• Necessary use of any other medical illness or disability that, in the opinion of the investigator, would compromise effective trial participation
• Current enrollment or a plan to enroll in any interventional clinical study in which an investigational treatment or approved therapy is use within 5 half-lives prior to baseline. 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.
• For subjects coming back from strongyloidiasis endemic regions, a parasitology screening examination will be performed on faeces, and that appropriate treatment will be performed prior to administration of corticosteroids
• Patients with Lesch Nyhan syndrome
• Asian patients (probable mutation of the gene NUDT1)
• Female subjects who have a positive a positive urinary or blood pregnancy test result, are pregnant or are currently breast feeding
• Inability to comply with study requirements
• Person under legal protection or deprived of liberty

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 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; Dose related to weigh (100 mg for weight ≤ 50 kg and 150 mg for weight > 50 kg) = 2 to 4 50mg oral caps, daily, during all the study period
Experimental: Azathioprine; Azathioprine, dose related to weight (100 mg for weight ≤ 50 kg and 150 mg for weight > 50 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; Dose related to weigh (100 mg for weight ≤ 50 kg and 150 mg for weight > 50 kg) = 2 to 4 50mg oral caps, daily, during all the study period

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Study Director: Romain MARIGNIER, MD PhD, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2023
• Primary Completion (Estimated): December 12, 2026
• Study Completion (Estimated): December 12, 2029

Study Registration Dates

• First Submitted: April 15, 2022
• First Submitted That Met QC Criteria: April 21, 2022
• First Posted (Actual): April 27, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 31, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: MOGAD; azathioprine; optic neuritis; myelitis; neuromyelitis optica; MOG-IgG associated disease
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Azathioprine
• Other Study ID Numbers: 69HCL21_1065

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No