A Randomized, Placebo-controlled Phase 3 Trial of Azathioprine for the Prevention of Relapse in Myelin-oligodendrocyte-glycoprotein (MOG)-Antibody Associated Disease
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 126
- 试验地点
- 17
- 主要终点
- Time to first relapse (in days), comparing azathioprine-treated vs placebo-treated patients during a randomized control period of a maximum of three years.
研究概览
简要总结
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.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
double blind
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •Female patients of childbearing potential should have effective contraception throughout the course of treatment and for at least three months after stopping treatment.
排除标准
- •Hypersensitivity to azathioprine or steroids
- •Active infections or cancer (including tuberculosis, hepatitis, herpes and VZV)
- •Psychosis not controlled by treatment
- •Seriously impaired bone marrow functions: Lymphocyte count < 1000/ml and or Polynuclear neutrophil count < 1500/ml
- •Seriously impaired hepatic functions: ALT and/or AST > 3N
- •Seriously impaired renal functions: GFR < 29 ml/min/1.73m²
- •Any live vaccine in the past 3 months or planned during the RCT and RCT+6months
- •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 a xanthine oxidase inhibitor (Allopurinol, Oxipurinol, Thiopurinol, Febuxotat,...)
- •Necessary use of angiotensin-converting-enzyme inhibitor, cotrimoxazole, cimetidine and indometacine
- •Necessary use of an aminosalicylate derivates
- •Necessary use of any another immunosuppressive therapy, different than azathioprine, or steroids
- •Necessary use of cytotoxic therapy
- •Necessary use of any other medical illness or disability that, in the opinion of the investigator, would compromise effective trial participation
- •Current enrollment or a plan to enroll in any interventional clinical study in which an investigational treatment or approved therapy is use within 5 half-lives prior to baseline. 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.
- •For subjects coming back from strongyloidiasis endemic regions, a parasitology screening examination will be performed on faeces, and that appropriate treatment will be performed prior to administration of corticosteroids
- •Patients with Lesch Nyhan syndrome
- •Asian patients (probable mutation of the gene NUDT1)
- •Female subjects who have a positive a positive urinary or blood pregnancy test result, are pregnant or are currently breast feeding
- •Inability to comply with study requirements
- •Person under legal protection or deprived of liberty
研究组 & 干预措施
Azathioprine
Azathioprine, dose related to weight (100 mg for weight ≤ 50 kg and 150 mg for weight > 50 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)
干预措施: Azathioprine (Drug)
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)
干预措施: Placebo (Other)
结局指标
主要结局
Time to first relapse (in days), comparing azathioprine-treated vs placebo-treated patients during a randomized control period of a maximum of three years.
时间窗: 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).
次要结局
- Evaluation of global disability at 36 months(at baseline and at 36 months)
- 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 visual disability at 36 months(at baseline and at 36 months)
- Quality of life will be assessed using the EuroQOL EQ-5D-3L at 36 months(at 36 months)
- Compliance to treatment(During a randomized control period of a maximum of three years)
- Exploratory radiological features(at baseline and at 36 months)
- Exploratory biological features(at screening, at 6 months, at 12 months, at 36 months and in case of a relapse)