MOGwAI: Azathioprine in MOGAD

Sponsor

Hospices Civils de Lyon (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05349006

Collaborator

(none)

126

Enrollment

Locations

Arms

Anticipated Duration (Months)

8.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Central Nervous System Inflammation MOG-IgG Associated Disease	Drug: Azathioprine Other: Placebo	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

126 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

double blind

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Oct 1, 2022

Anticipated Primary Completion Date :

Oct 1, 2025

Anticipated Study Completion Date :

Oct 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azathioprine 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 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
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 <50 kg, 150 mg 50-100 kg, 200 mg for >100 kg) = 2 to 4 50mg oral caps, daily, during all the study period

Arm

Intervention/Treatment

Experimental: Azathioprine

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

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

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 <50 kg, 150 mg 50-100 kg, 200 mg for >100 kg) = 2 to 4 50mg oral caps, daily, during all the study period

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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 [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 global disability at 36 months [at baseline and at 36 months]
Worsening from baseline to 36 months of the EDSS
Evaluation of global disability at 36 months [at baseline and 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.
Evaluation of global disability at 36 months [at baseline and at 36 months]
Worsening from baseline to 36 months of the Ambulation Score.
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.
Evaluation of visual disability at 36 months [at baseline and 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).
Evaluation of visual disability at 36 months [at baseline and at 36 months]
Best-corrected low-contrast visual acuity at 36 months using the Sloan Charts at 2.5%, in each eye.
Evaluation of visual disability at 36 months [at baseline and at 36 months]
Worsening from baseline to 36 months of low-contrast visual acuity using the Sloan Charts at 2.5%, in each eye.
Evaluation of visual disability at 36 months [at baseline and at 36 months]
Inner retinal layers thicknesses at 36 months assessed by the spectral domain OCT (each eye tested separately)
Evaluation of visual disability at 36 months [at baseline and 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).
Quality of life will be assessed using the EuroQOL EQ-5D-3L at 36 months [at 36 months]
https://euroqol.org
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
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 radiological features [at baseline and at 36 months]
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
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
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 onset and the level of global disability assessed by the EDSS at 36 months.
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, prognostic value of longitudinal MOG-Ab-titers to predict relapse.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	Country
1	Department of Neurology, CHU de Bordeaux - GH Pellegrin	Bordeaux	France
2	Department of Neurology, CHU of Lille, Hospital Roger Salengro	Lille	France
3	Department of Neuro Ophthalmology, CHU of Lyon, Neurology Hospital Pierre Wertheimer	Lyon	France
4	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
5	Department of Neurology University hospital Timone	Marseille	France
6	Department of Neurology Montpellier Universitary Hospital	Montpellier	France
7	Department of Neurology, Hôpital Pasteur 2	Nice	France
8	Department of Neurology, Hôpital Caremeau	Nîmes	France
9	Department of Neurology APHP, Pitié Salpêtrière Hospital	Paris	France
10	Department of Neurology. Hôpital A. Fondation Rothschild	Paris	France
11	Department of Neurology, CHU de Rennes	Rennes	France
12	Department of Neurology, CHU de Rouen	Rouen	France
13	Department of Neurology, Hôpital g. Et r. Laennec	Saint-Herblain	France
14	Department of Neurology, Hôpital Hautepierre	Strasbourg	France
15	Department of Neurology, Toulouse Universitary Hospital	Toulouse	France