Clinical trial NCT05349006: Azathioprine in MOGAD
Official title: A Randomized, Placebo-controlled Phase 3 Trial of Azathioprine for the Prevention of Relapse in Myelin-oligodendrocyte-glycoprotein (MOG)-Antibody Associated Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Central Nervous System Inflammation
MOG-IgG Associated Disease
Keywords: MOGAD
azathioprine
optic neuritis
myelitis
neuromyelitis optica
MOG-IgG associated disease
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2022-04-27
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Time to first relapse (in days), comparing azathioprine-treated vs placebo-treated patients during a randomized control period of a maximum of three years.
timeFrame: During a randomized control period of a maximum of three years
Secondary outcomes:
measure: Number and type of adverse events, including serious adverse events, related to azathioprine and/or steroids and placebo
timeFrame: : During a randomized control period of a maximum of three years
measure: Evaluation of global disability at 36 months
timeFrame: at baseline and at 36 months
measure: Evaluation of global disability at 36 months
timeFrame: at baseline and at 36 months
measure: Evaluation of global disability at 36 months
timeFrame: at baseline and at 36 months
measure: Evaluation of global disability at 36 months
timeFrame: at baseline and at 36 months
measure: Evaluation of visual disability at 36 months
timeFrame: at baseline and at 36 months
measure: Evaluation of visual disability at 36 months
timeFrame: at baseline and at 36 months
measure: Evaluation of visual disability at 36 months
timeFrame: at baseline and at 36 months
measure: Evaluation of visual disability at 36 months
timeFrame: at baseline and at 36 months
measure: Evaluation of visual disability at 36 months
timeFrame: at baseline and at 36 months
measure: Evaluation of visual disability at 36 months
timeFrame: at baseline and at 36 months
measure: Quality of life will be assessed using the EuroQOL EQ-5D-3L at 36 months
timeFrame: at 36 months
measure: Compliance to treatment
timeFrame: During a randomized control period of a maximum of three years
measure: Exploratory radiological features
timeFrame: at baseline and at 36 months
measure: Exploratory radiological features
timeFrame: at baseline and at 36 months
measure: Exploratory biological features
timeFrame: at screening, at 6 months, at 12 months, at 36 months and in case of a relapse
measure: Exploratory biological features
timeFrame: at screening, at 6 months, at 12 months, at 36 months and in case of a relapse
measure: Exploratory biological features
timeFrame: at screening, at 6 months, at 12 months, at 36 months and in case of a relapse
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Department of Neurology, CHU de Bordeaux - GH Pellegrin
city: Lille
country: France
facility: Department of Neurology, CHU of Lille, Hospital Roger Salengro
city: Lyon
country: France
facility: Department of Neuro Ophthalmology, CHU of Lyon, Neurology Hospital Pierre Wertheimer
city: Lyon
country: France
facility: 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
city: Marseille
country: France
facility: Department of Neurology University hospital Timone
city: Montpellier
country: France
facility: Department of Neurology Montpellier Universitary Hospital
city: Nancy
country: France
facility: CHRU de Nancy Hôpital Central
city: Nice
country: France
facility: Department of Neurology, Hôpital Pasteur 2
city: Nîmes
country: France
facility: Department of Neurology, Hôpital Caremeau
city: Paris
country: France
facility: National Hospital of Vision (15-20)
city: Paris
country: France
facility: Department of Neurology APHP, Pitié Salpêtrière Hospital
city: Paris
country: France
facility: Department of Neurology. Hôpital A. Fondation Rothschild
city: Rennes
country: France
facility: Department of Neurology, CHU de Rennes
city: Rouen
country: France
facility: Department of Neurology, CHU de Rouen
city: Saint-Herblain
country: France
facility: Department of Neurology, Hôpital g. Et r. Laennec
city: Strasbourg
country: France
facility: Department of Neurology, Hôpital Hautepierre
city: Toulouse
country: France
facility: Department of Neurology, Toulouse Universitary Hospital
Study officials:
affiliation: Hospices Civils de Lyon
name: Romain MARIGNIER, MD PhD
role: STUDY_DIRECTOR
References: