Immediate Versus Delayed Treatment With Azathioprine or Rituximab in Anti-MOG Antibodies Associated Acute Demyelinating Syndromes in Children: a Randomized Controlled Clinical Trial (IDAR)
Acute Demyelinating Syndrome
About this trial
This is an interventional treatment trial for Acute Demyelinating Syndrome focused on measuring acute demyelinating syndrome
Eligibility Criteria
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
Exclusion Criteria:
- 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%
- Total bilirubin > 2N
- Any patient with allopurinol treatment and immunosupressive treatment with concomitant use of xanthine oxidase inhibitors (e.g. allopurinol, oxipurinol/thiopurinol, febuxostat)
- Patients with two inactive TPMT or NUDT15 alleles (homozygous deficient or double heterozygote)
- Pregnancy or lactating woman or wish for future pregnancy
- Refusal to have a highly effective contraception during traitment and for one year (12 months) after the end of the experimental treatment
- participation to another interventional study within 5 half-lives prior to baseline.
- Active, severe infections (including tuberculosis, HBV and HCV, HIV, herpes, VZV, EBV and CMV)
- Psychosis not controlled by treatment
- Patients with Lesch Nyhan syndrome
- Pheochromocytoma
- Scleroderma
- Untreated peptic ulcer
- Myasthenia gravis
- Any other medical illness or disability that, in the opinion of the investigator, would compromise effective trial participation
Sites / Locations
- CHU Besançon
- CHU Bordeaux
- CHU Brest
- HCL de Bron
- Hôpital Bicêtre
- CHRU Lille
- CHU Monptellier
- CHU Strasbourg
- CHU Toulouse Purpan
Arms of the Study
Arm 1
Arm 2
Arm 3
Experimental
Experimental
Active Comparator
Immediate Azathioprine (1st attack)
Immediate Rituximab (1st attack)
Standard Care: delayed treatment (2nd attack)
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.
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.
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