Immediate Versus Delayed Treatment With Azathioprine or Rituximab in Anti-myelin Oligodendrocytes Glycoprotein (Anti-MOG) Antibodies Associated Acute Demyelinating Syndromes in Children: a Randomized Controlled Clinical Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 86
- 试验地点
- 10
- 主要终点
- annualized relapse rate (ARR) at 24 months
研究概览
简要总结
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.
详细描述
Acquired Demyelinating Syndrome (ADS) are rare immune-mediated central nervous system (CNS) disorders that contribute to significant neurological morbidity in Europe and worldwide. ADS can affect adult and children, and the clinical spectrum is heterogenous. It begins as monophasic diseases, as often observed in acute demyelinating encephalomyelitis (ADEM), optic neuritis (ON) and transverse myelitis (TM); or as multiphasic disease with relapses such as multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD).
MOG-Abs-ADS are a frequent disease in children with ADS with specific clinical and MRI pattern.
Recently, myelin oligodendrocyte glycoprotein (MOG) antibodies (MOG-Abs) have been found implicated in ADS affecting children with a frequency up to 30%-45% according to tested cohorts.
Studies have shown that in MOG-Abs positive ADS, the most frequent clinical phenotype in children are ADEM-like presentations (ADEM, ADEM-optic neuritis, multiphasic demyelinating encephalomyelitis (MDEM) and encephalitis) and optic neuritis (ON). These presentations may vary according to the age and young children < or = 10 years old, most often, present with ADEM, whereas optic neuritis is the most common feature in children older than 10 years of age. Fewer patients present with myelitis, brainstem features, or the more recently described encephalitis with steroid-responsive seizures11.
Cerebro-spinal fluid parameters are normal in most patients, although up to 50% had pleiocytosis or increased protein levels. Oligoclonal bands were present in only 10% of patients and their presence in the context of relapsing disease would rather suggest MS 5.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
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.
入排标准
- 年龄范围
- 6 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
- •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
研究组 & 干预措施
Standard Care: delayed treatment (2nd attack)
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
干预措施: Standard of care (Drug)
Immediate Azathioprine (1st 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.
干预措施: Immediate Azathioprine (1st attack) (Drug)
Immediate Rituximab (1st attack)
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.
干预措施: Immediate Rituximab (1st attack) (Drug)
结局指标
主要结局
annualized relapse rate (ARR) at 24 months
时间窗: 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.
次要结局
- Annualized relapse rate at 12 months(at 12 months)
- 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)
- Fatigue Severity Scale (FSS)(at 6, 12, 18 and 24 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)
- Visual Acuity, Optical Coherence Tomography(at 3, 6, 12 and 24 months)
- Cognitive function: Wechsler Intelligence Scale for Children (WISC)-5(at 6 and 24 months)
- Cumulative number of new or newly enlarged lesions detected on T2-weighted MRI and of T1 gadolinium enhancing lesions(at 6, 12, 18 and 24 months)