A Randomized Phase III Multicenter Trial Comparing the Efficacy and Safety of Anakinra Versus Intravenous Immunoglobulin (IVIG) Retreatment, in Patients With Kawasaki Disease Who Failed to Respond to Initial Standard IVIG Treatment
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 84
- 试验地点
- 1
- 主要终点
- Fever
研究概览
简要总结
Kawasaki disease (KD) is the most frequent vasculitis in younger children <5years, and the first cause of acquired ischemic myocardiopathy in childhood. Exceptionally, KD may cause early death during the acute phase by myocardial infarction, but may compromise the long-term cardiovascular outcome by accelerating atherosclerotic disease.
The incidence of KD is high in far-Eastern countries and Hawaii but KD is relatively rare in other regions (10/100000 children <5years in northern Europe) which makes it difficult to develop research on these rare population.
Early recognition and treatment by intravenous immunoglobulins (IVIG) influences the prognosis positively. IVIG are the standard of care and decrease significantly the risk of coronary aneurysms. However, despite a first infusion of IVIG, 20% of KD patients remain febrile and have high risk of coronary vasculitis. Recent Japanese research group assessed additional cyclosporine treatment in first line KD treatment but failed preventing relapse. To date there is no agreement for a more effective second line treatment.
Based on the auto-inflammatory pattern of KD, the investigators hypothesize that anti IL-1 blocking agents could bring a rapid and sustained effect on systemic and coronary inflammation in patients with KD.
Our hypotheses are:
- Anakinra treatment may reduce the early and long-term mortality of patients with Kawasaki Disease (KD), by a rapid and sustained effect on vascular inflammation.
- The safety of anakinra is good, as the drug has a very short half-life, which allows its rapid withdrawal in case of serious adverse event.
The use of anakinra is not associated with the risk of contamination by infectious agents, which remain even minimal, a possibility with the use of IVIG.
详细描述
It is a multicentric national randomized controlled, parallel-group in a 1:1 ratio, open labelled trial of superiority.
The main objective is to compare the efficacy of Anakinra (Interleukin 1 receptor type 1 - receptor antagonist) with 2nd IVIG infusion, in second line, on fever in patients with KD, who failed to respond to one infusion of IVIG(standard treatment).
The main criterion-evaluating efficacy in both groups is: the patient must reach a body (axillary (+0.5°C), tympanic, oral) temperature <38˚C within 2 days after initiation of treatment (i.e. a binary outcome: success/failure).
The secondary objectives are to compare Anakinra with IVIG retreatment in terms of:
- Efficacy on fever at 72h
- Efficacy on disease activity
- Efficacy on KD symptoms
- Efficacy on coronary lesions (e.g.: dilatation and aneurysm)
- Efficacy on inflammation
- Safety and tolerability Secondary End Points (linked with the secondary objectives)
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
入排标准
- 年龄范围
- 3 Months 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Children, male and female, from 3 months to <18 years old
- •Patient ≥ 5 kg
- •Patient with KD according to the American Heart Association definition for complete or incomplete KD. (Fever ≥ 5 days (or at least 3 days if KD with American Heart Association criteria since the third days of fever) and ≥ 4 of 5 main clinical signs: modification of the extremities, polymorphic exanthema, and bilateral bulbar not exudative conjunctivitis, erythema of the lips or oral cavity, and cervical lymph nodes usually unilateral > 1.5 cm in diameter.
- •Patients who failed to respond to the standard therapy of KD, e.g. Persistence or recrudescence of fever ≥ 38°C, 48 hours after the infusion of 2g/kg of IV Ig. Patients may be screened 24h after the end of the first infusion if they remain febrile 24h after the end of the first infusion.
- •Patient, parents or legal guardian's written informed consent is required
- •Patient with health insurance (SS or CMU).
- •Efficient contraception for the duration of participation in the research for childbearing aged women
排除标准
- •Preterm and neonates, pregnancy, pregnancy and breast feeding
- •Suspicion of another diagnosis
- •Patient with overt concomitant bacterial, viral or fungal infection
- •Patient previously treated with steroids and/or another biotherapy
- •Patient with increased risk of tuberculosis infection
- •Recent tuberculosis infection or with active tuberculosis
- •Patient with any type of immunodeficiency or cancer
- •Patients with severe renal impairment (CLcr < 30 ml/minute)
- •Patients with hepatic insufficiency
- •Patients with neutropenia (ANC<1.5 x109/l)
- •Patients included in another interventional protocol
- •Patient under the following treatments:
- •Preventive Antipyretics (paracetamol, NSAIDs other than aspirin 30-50mg/kg given for purpose of KD inflammation), as long as the patient receives the study medication
- •Immunosuppressive medications given in a period less than twice of their half-life prior the patient receives the study medication (systemic steroids, cyclosporine, tacrolimus, azathioprine, cyclophosphamide, interferon, mycophenolate, other anti-IL-1, anti IL-6, anti CD20 and anti TNF (Tumor Necrosis Factor)), plasmapheresis)
- •Hypersensitivity to anakinra or excipients (citric acid, sodium chloride, disodium EDTA (Ethylene Diamine Tetra Acetic), polysorbate 80, sodium hydroxide, in water for injection)
- •Hypersensitivity to IV Ig, or excipients (L-proline and water for injection), hypersensitivity to human normal immunoglobulin, in particular if the patient have anti-IgA antibodies (IgA: Immunoglobulin A)
- •Patients with type I or II hyperprolinemia
- •Live vaccines within 1 month prior to enrollment
- •Hypersensitivity to anakinra or to immunoglobulins or to excipients of Kineret® or Privigen® or to E.coli proteins
- •Contraindication for administration of anakinra or IVIG listed in the Summary of Products Characteristics (SmPC) of Kineret® and Privigen®
- •Ongoing or recent use of any other medication Known inhibitors/inducers of cytochrome P450 as listed on the link below: http://medicine.iupui.edu/clinpharm/ddis/main-table
研究组 & 干预措施
KINERET
The patients will receive anakinra, an analogue of the IL-1 receptor antagonist, at a starting dose of 4 mg/kg. If patients are still febrile with 12 hours (H12) of treatment, they will receive a supplementary dose of 2 mg/Kg; otherwise, they will remain at a starting dose of 4 mg/kg. If they are still febrile at H24, they will receive a dose of 8mg/kg; otherwise, they will maintain their dose of 6 mg/kg. Patients with temperature <38°C at any point between initiation and day 14, but who develop secondary fever due to KD could have further escalation dose of anakinra until a maximum dose of 8mg/Kg. Patients will receive anakinra during 14 days independently of the period of escalation dose if any. After the last escalation dose, if any necessary, the primary criteria will be measured. Patients not responding to anakinra will follow usual standard care and will complete information related to all the study visits
干预措施: ANAKINRA (Drug)
Intravenous Immunoglobulin
The patients will receive a standard therapy, IVIG infusion of 2g/kg, and their treatment will follow usual standard care. Patients in the IVIG treatment will complete information related to the study visits.
干预措施: Intravenous immunoglobulin (Drug)
结局指标
主要结局
Fever
时间窗: 48 hours
The main criterion-evaluating efficacy in both groups is: the patient must reach a body (axillary (+0.5°C), tympanic, oral) temperature \<38˚C within 2 days after initiation of treatment (i.e. a binary outcome: success/failure).
次要结局
- Coronary abnormalities(Day 45)
- Fever(day 3, day 4, day 6, day 7, day 14, day 30, day 45, day 60)
- CRP(day 3 (or day 4) day 7, day 14, day 30 and day 45.)
- Disease activity (physician assessment)(day 2, day 3, day 4, day 6, day 7, day 14, day 30, day 45, day 60)
- Disease activity (patient's parent's assessment)(day 2, day 3, day 4, day 6, day 7, day 14, day 30, day 45, day 60)
- Safety and tolerability(From baseline to day 60 (day 2, day 3, day 4, day 6, day 7, day 14, day 30, day 45 and day 60))