Immediate Versus Delayed Treatment With Azathioprine or Rituximab in Anti-MOG Antibodies Associated Acute Demyelinating Syndromes in Children: a Randomized Controlled Clinical Trial

NCT05545384 | Recruiting Phase 3 DMC

• 2 other identifiers: APHP2110572022-002385-32
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 9

Brief Summary

Among all non viral encephalitis, myelin oligodendrocytes glycoprotein antibody associated diseases (MOGAD) are the second most frequent diagnosis in children. Risk of relapses varies according to studied cohorts and cognitive and academic difficulties are more and more detected in children without knowing if these sequelae are related to the first attack or relapses. The hypothesis is that earlier treatment would induce reduction of sequelae after the first attack and the number of relapses which would be also associated with a subsequent reduction of disability occurrence on the long term.

Conditions

Acute Demyelinating Syndrome

Keywords

acute demyelinating syndrome

Outcome Measures

Primary Outcomes (1)

• annualized relapse rate (ARR) at 24 months

  To 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.

  at 24 months

Secondary Outcomes (8)

• Annualized relapse rate at 12 months

  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

  through study completion, an average of 2.5 years

• Percentage of patients free of relapses over 24 months

  through study completion, an average of 2.5 years

• Motor disability outcome will be assessed with Expanded Disability Status Scale (EDSS) score

  through study completion, an average of 2.5 years

• Visual Acuity, Optical Coherence Tomography

  at 3, 6, 12 and 24 months

Study Arms (3)

Immediate Azathioprine (1st attack)

EXPERIMENTAL

Treatment will be started at 2mg/kg or at 1mg/kg if the patient has a partial activity which would be increased slowly according the 6-TGN activity and clinical and biological tolerance at Week 2 for patient with partial activity or M1 for patient without TPMT activity deficit. Only for patient with partial deficit and whose 6-TGN activity is low, azathioprine would be increased at 3mg/kg/d at Week 6 and without exceeding a total daily dose of 150 mg.

Drug: Immediate Azathioprine (1st attack)

Immediate Rituximab (1st attack)

EXPERIMENTAL

Once the inclusion criteria are validated, the first injection will be performed according to the injection protocol (Annex 4). Fifteen day later, the second injection will be performed. The next visit during a consultation with PI or his collaborators will be scheduled 1 week ± 2 days later, and patients will be advised to contact the PI if any neurologic symptoms or symptoms of adverse event occurs in the meantime.

Drug: Immediate Rituximab (1st attack)

Standard Care: delayed treatment (2nd attack)

ACTIVE COMPARATOR

Patients will be treated according to standard of care after their 1st attack. In case of relapse: * before 3 months, IV methylprednisolone (30 mg/kg/j not exceeding 1g/day) will be administered for 3 days. There won't be any change of the initial treatment which will be pursued. * after 3 months, IV methylprednisolone (30 mg/kg/j not exceeding 1g/day) will be administered for 3 days with an oral relay of prednisolone (1mg/kg/day not exceeding 60 mg/day) during 3 months with then a slowly tapered dose (reduction of 25% every week for 4 weeks). Azathioprine or Rituximab might be proposed as per local clinician experience

Drug: Standard of care

Interventions

Immediate Azathioprine (1st attack) DRUG

Patients randomized in Immediate Azathioprine group will benefit from immediate treatment with azathioprine. Treatment will be started at 2mg/kg or at 1mg/kg if the patient has a partial activity which would be increased slowly according the 6-TGN activity and clinical and biological tolerance at Week 2 for patient with partial activity or M1 for patient without TPMT activity deficit. Only for patient with partial deficit and whose 6-TGN activity is low, azathioprine would be increased at 3mg/kg/d at Week 6 and without exceeding a total daily dose of 150 mg.

Immediate Azathioprine (1st attack)

Immediate Rituximab (1st attack) DRUG

Patients randomized in Immediate Rituximab group will benefit from immediate treatment with rituximab. Rituximab 375mg/m2 IV will be given at D1 and D15 and repeat every 6 months for 2 years. Once the inclusion criteria are validated, the first injection will be performed according to the injection protocol (Annex 4). Fifteen day later, the second injection will be performed. The next visit during a consultation with PI or his collaborators will be scheduled 1 week ± 2 days later, and patients will be advised to contact the PI if any neurologic symptoms or symptoms of adverse event occurs in the meantime.

Immediate Rituximab (1st attack)

Standard of care DRUG

Patients in this group will be treated according to standard care

Standard Care: delayed treatment (2nd attack)

Eligibility Criteria

• Age: 6 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• Current infection with SARS-COV2 (positive PCR)
• Any prior allergy to azathioprine or rituximab with hypersensitivity to active substances, murine proteins or to any of the excipients.
• Any prior history of uncontrolled 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 ml/min)
• Prior documented history of hemostase perturbation (TP and/or TCA more than twice of the witnesse's TP and/or TCA)
• Prior documented history of increased liver enzyme level (ASAT and/or ALAT) \> 2N.
• TP \<70%

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Institut National de la Santé Et de la Recherche Médicale, France: collaborator

Study Sites (9)

CHU Besançon

Besançon, France

NOT YET RECRUITING

CHU Bordeaux

Bordeaux, France

NOT YET RECRUITING

CHU Brest

Brest, France

NOT YET RECRUITING

HCL de Bron

Bron, France

NOT YET RECRUITING

Hôpital Bicêtre

Le Kremlin-Bicêtre, 94270, France

RECRUITING

CHRU Lille

Lille, France

NOT YET RECRUITING

CHU Monptellier

Montpellier, France

NOT YET RECRUITING

CHU Strasbourg

Strasbourg, France

NOT YET RECRUITING

CHU Toulouse Purpan

Toulouse, France

NOT YET RECRUITING

MeSH Terms

Interventions

Standard of Care

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Central Study Contacts

Kumaran DEIVA, phD

CONTACT

0145213112; kumaran.deiva@aphp.fr

Domitille MOLINARI

CONTACT

0145217138; domitille.molinari@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: The adjudication committee is responsible the evaluation of all relapses reported during the the follow-up period. Relapses assessments will use blinded data and will be performed in real time.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a multicentre, randomized controlled, open-labelled, parallel group study.

Study Record Dates

• First Submitted: September 6, 2022
• First Posted: September 19, 2022
• Study Start: April 1, 2025
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2030
• Last Updated: April 7, 2025

Record last verified: 2025-03

Locations

FR (9)