Central Nervous System Inflammation, MOG-IgG Associated Disease
Conditions
Keywords
MOGAD, azathioprine, optic neuritis, myelitis, neuromyelitis optica, MOG-IgG associated disease
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.
Interventions
DRUGAzathioprine
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
OTHERPlacebo
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
Sponsors
Hospices Civils de Lyon
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
double blind
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to first relapse (in days), comparing azathioprine-treated vs placebo-treated patients during a randomized control period of a maximum of three years. | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of global disability at 36 months | at baseline and 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. |
| Evaluation of visual disability at 36 months | at baseline and at 36 months | Best-corrected high contrast visual acuity at 36 months measured (each eye tested separately) using the standard Snellen chart or equivalent. |
| Quality of life will be assessed using the EuroQOL EQ-5D-3L at 36 months | at 36 months | https://euroqol.org |
| 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 | — |
| Exploratory radiological features | at baseline and at 36 months | 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 |
| Exploratory biological features | at screening, at 6 months, at 12 months, at 36 months and in case of a relapse | In each group of treatment, association between MOG-Ab titer at first episode and the risk of relapse |
| Compliance to treatment | During a randomized control period of a maximum of three years | percentage of untaken pills (left in the blisters) regarding each patient |
Countries
France
Contacts
Primary ContactRomain MARIGNIER, MD PhD
Backup ContactLakhdar BENYAHYA, project manager
Outcome results
None listed