Azathioprine in MOGAD

Phase 3RecruitingNCT05349006

Hospices Civils de Lyon126 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

126

Conditions

Central Nervous System Inflammation MOG-IgG Associated Disease

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (17)

Department of Neurology, CHU de Bordeaux - GH Pellegrin

Bordeaux, France

RECRUITING

Department of Neurology, CHU of Lille, Hospital Roger Salengro

Lille, France

RECRUITING

Department of Neuro Ophthalmology, CHU of Lyon, Neurology Hospital Pierre Wertheimer

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

Lyon, France

RECRUITING

Department of Neurology University hospital Timone

Marseille, France

RECRUITING

Department of Neurology Montpellier Universitary Hospital

Montpellier, France

RECRUITING

CHRU de Nancy Hôpital Central

Nancy, France

RECRUITING

Department of Neurology, Hôpital Pasteur 2

Nice, France

NOT_YET_RECRUITING

Department of Neurology, Hôpital Caremeau

Nîmes, France

RECRUITING

National Hospital of Vision (15-20)

Paris, France

RECRUITING

...and 7 more locations

Outcomes

Primary Outcomes

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).

Time frame: During a randomized control period of a maximum of three years

Secondary Outcomes

Number and type of adverse events, including serious adverse events, related to azathioprine and/or steroids and placebo

Time frame: : 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.

Time frame: at baseline and at 36 months

Evaluation of global disability at 36 months

Worsening from baseline to 36 months of the EDSS

Time frame: 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.

Time frame: at baseline and at 36 months

Evaluation of global disability at 36 months

Worsening from baseline to 36 months of the Ambulation Score.

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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)

Time frame: 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).

Time frame: at baseline and at 36 months

Quality of life will be assessed using the EuroQOL EQ-5D-3L at 36 months

https://euroqol.org

Time frame: at 36 months

Compliance to treatment

percentage of untaken pills (left in the blisters) regarding each patient

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: at screening, at 6 months, at 12 months, at 36 months and in case of a relapse

Azathioprine in MOGAD

Overview

Conditions

Interventions

Eligibility

Locations (17)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts