| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| myelin oligodendrocytes glycoprotein antibody associated diseases (MOGAD) |
| maladies démyélinisantes associées aux anticorps anti-myéline oligodendrocyte glycoprotéine (MOG). |
|
| E.1.1.1 | Medical condition in easily understood language |
| myelin oligodendrocytes glycoprotein antibody associated diseases |
| maladies démyélinisantes associées aux anticorps anti-myéline oligodendrocyte glycoprotéine |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- Compare the efficacy of immediate (at first attack) azathioprine (AZA) or rituximab (RTX) treatment in children with MOG antibodies positive diseases with delayed treatment (at second attack), on the annualized relapse rate at 24 months.
- The primary endpoint will be the annualized relapse rate (ARR) at 24 months.
|
- Comparer l’efficacité du traitement immédiat (à la première crise) par azathioprine (AZA) ou rituximab (RTX) versus le traitement retardé (à la seconde poussée), chez les enfants atteints de maladies à anticorps MOG positif, sur le taux annualisé de poussée, à 24 mois.
- Le critère de jugement principal sera le taux annualisé de rechute à 24 mois.
|
|
| E.2.2 | Secondary objectives of the trial |
• To compare the efficacy between azathioprine (AZA) and rituximab (RTX) in immediate (at first attack) treatment in children with MOGAD
• To compare separately the efficacy between immediate-AZA with dealayed-treatment and immediate-RTX with delayed treatment
• Evaluate the efficacy of immediate treatment with delayed treatment on other clinical outcomes:
o Annualized relapse rate at 12 months
o Time to first relapse after the first attack
o Percentage of patients free of relapses over 24 months
o Motor disability outcome
o Cognitive outcome
o Visual outcome
o Fatigue
o Depression
o Quality of life
• Evaluate the efficacy on MRI outcomes
• Evaluate the efficacy through modulation of immunological mechanism between treated and not treated patients
• Follow immunological markers of treatment efficacy such as neurofilament (Nfl)
• Verify the safety and tolerance of the treatment
|
• Comparer l’efficacité du traitement par AZA ou RTX immédiat (1ère crise) chez les enfants atteints de MOGAD
• Comparer séparément l’efficacité entre le traitement immédiat par AZA et le traitement retardé et entre le traitement immédiat par RTX et le traitement retardé
• Evaluer l’efficacité du traitement immédiat vs le traitement retardé sur d’autres critères cliniques :
o Taux de rechute annualisé à 12 mois
o Délai de 1ère rechute après la 1ère poussée
o Pourcentage de patients sans rechute sur les 24 mois
o Handicap moteur
o Difficultés cognitives
o Séquelles visuelles
o Fatigue
o Dépression
o Qualité de vie
• Evaluer l’efficacité sur les critères IRM
• Evaluer l’efficacité à travers la modulation des mécanismes immunologiques entre les patients traités rapidement et non traités rapidement
• Suivre les marqueurs immunologiques de l’efficacité du traitement comme les neurofilaments (nfl)
• Vérifier la tolérance et la sécurité du traitement.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Children 18 years old and 6 years old at baseline
- Children weight ≥ 20 kg
- All ADS with confirmed anti-MOG-Abs at onset including any acute neurologic symptom with a duration of more than 24H of inflammatory causes (including optic neuritis, transverse myelitis, rhombencephalitis, ADEM, NMOSD) Without any previous treatment other than steroids
- Informed consent signed by both parents and the child
- Expanded Disability Status Scale (EDSS) < 5.5
- Affiliated to French social security regime |
- Enfant de 6 ans ou plus et de moins de 18 ans à la baseline
- Poids ≥ 20 kg
- Tous les patients ayant un diagnostic d’une maladie démyélinisante avec présence confirmée d’anticorps anti-MOG au début de la maladie quelle que soit la présentation de la poussée clinique (névrite optique, encéphalomyélite aigue disséminée, myélite aigue transverse…) ayant durée plus de 24H et de cause inflammatoire sans traitement corticoïdes antérieur
- Consentement éclairé signé par les deux parents
- Score échelle Expanded Disability Status Scale (EDSS) < 5.5
- Affilié à un régime de sécurité sociale |
|
| E.4 | Principal exclusion criteria |
- Current infection with SARS-COV2 (positive PCR)
- Any prior allergy to azathioprine or rituximab
- Any prior history of uncontrolleduncontrolled cancer during the last 2 years
- Uncontrolled infections (Hepatitis B, C and HIV)
- Any prior history of cardiac dysfunction and/or hypertension
- Any progressive or non-relapsing form demyelinating diseases
- Any previous treatment with natalizumab, daclizumab, fingolimod, methotrexate, cyclosporine, mycophenolate mofetil, rituximab in the last 6 months, or determined by the treating physician to have residual immune suppression from these or other immunosuppressive treatments
- CD4+, CD8+, or CD19+ absolute cell count, wbc, neutrophiles in blood at screening below lower limits of normal (LLN)
- Creatinine>30µmol/L
- Platelets <70 000mm3
- Haemoglobin < 8g/dL
- Acute renal insufficiency (clearance < 30)
- Prior documented history of hemostase perturbation > 2 X witnesses
- Prior documented history of increased liver enzyme level (ASAT and/or ALAT) > 2N.
- TP <70%
- Total bilirubin > 2N
- Any patient with allopurinol treatment and immunosupressive treatment
- Patients with two inactive TPMT alleles (homozygous deficient or double heterozygote)
- Pregnancy or lactating woman or wish for future pregnancy
- Refusal to have a double effective contraception during the follow-up and until one year (12 months) after the end of the experimental treatment
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- Infection en cours par SARS-COV2 (PCR positive)
- Antécédent d’allergie à l’azathioprine ou au rituximab
- Antécédent de cancer non contrôlé durant les deux dernières années
- Infections non contrôlées (Hépatite B, C et VIH)
- Tout antécédent de dysfonction cardiaque et / ou d’hypertension
- Tout forme de maladie démyélinisante progressive ou ne rechutant pas |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| - Analysis of primary endpoint will be based on intent-to-treat analysis. The primary endpoint will be the annualized relapse rate (ARR) at 24 months. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints are other clinical, imaging, immunological and biological outcome and tolerance and safety of treatment.
• Comparison between immediate-AZA and immediate- RTX
- Annualized relapse rate at 12 and 24 months
• Comparison between immediate-AZA and delayed-treatment
- Annualized relapse rate at 12 and 24 months
• Comparison between immediate-RTX and delayed-treatment
- Annualized relapse rate at 12 and 24 months
• Other clinical outcome for comparing immediate- and delayed-treatment
- Annualized relapse rate at 12 months
- Time to first relapse (2nd attack) will be defined as time from randomization to the date of first relapse, with right-censoring in case of loss of follow-up
- Percentage of patients free of relapses over 24 months
- Motor disability outcome will be assessed with Expanded Disability Status Scale (EDSS) score (see section 18.5.1) every 6 months which is a frequently used score in pediatric MS for neurological disability40-42. The EDSS is an ordinal scale used for assessing neurologic impairment based on a neurological examination. It consists of scores in each of seven central functional systems (FSs) that are then combined to determine the EDSS steps (ranging from 0 (normal) to 10 (death due to MS)). The FSs are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel & Bladder, and Cerebral functions. EDSS is a widely used and accepted instrument to evaluate disability status at a given time and, longitudinally, to assess disability progression in clinical studies in MS other MOG-Abs-ADS related studies.
- Visual Acuity, Optical Coherence Tomography (OCT) at 3, 6, 12 and 24 months performed by a pediatric ophthalmologist.
- Cognitive function: Wechsler Intelligence Scale for Children (WISC)-V for children more than 6 years at 6 months of randomization and at 2 years43 would be performed by a neuropsychologist
- Fatigue: Fatigue Severity Scale (FSS) every 6 months43, this is an auto-questionnaire with 9 questions which would take aproximatly 10 min to fill. For children less than 6 the neuropsychologist would fill the questionnaire with the parents and the child
- Depression: Major Depression Inventory for Children (MDI-C) every 6 months, this is an auto-questionnaire with 79 questions and would take approximately 15 min to fill.
- Quality of life: Pediatric Quality of Life (PedsQL) inventory every 6 months43, this is an auto and hetero-questionnaire with 23 questions which would take approximately 10 min.
- All questionnaires will be filled with the neuropsychologist with child or the child alone and parents will fill it alone.
• Radiological outcome
• Immunological studies
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| To compare the efficacy of immediate (at first attack) azathioprine (AZA) or rituximab (RTX) treatme |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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