Anakinra in Cerebral Haemorrhage to Target Secondary Injury Resulting From Neuroinflammation - a Phase II Clinical Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 75
- 试验地点
- 1
- 主要终点
- Perihematomal oedema
研究概览
简要总结
The goal of this clinical trial] is to determine if anakinra can ameliorate the formation of perihaematomal oedema in patients with spontaneous intracerebral haemorrhage (ICH). The main aims are:
- To determine the effect of high-dose versus low-dose anakinra compared to standard medical management on perihaematomal oedema formation in the first week after ICH.
- Determine the safety profile of anakinra in these patients
- Study the effect of anakinra treatment on inflammation markers, blood-brain-barrier permeability and functional outcome.
Researchers will compare treatment with anakinra for three days, in either a low or high dose, with standard medical care after ICH. Participants will:
- Be randomized to receive anakinra during three days, or receive standard medical care
- Undergo a MRI scan seven days after their ICH
- Take part in a telephone interview their functional performance three months later.
详细描述
Spontaneous intracerebral haemorrhage (sICH) is the deadliest stroke subtype yearly affecting over 6000 patients in the Netherlands. Treatment options are very limited. Inflammation plays a vital role in the development of sICH-related secondary brain injury (SBI). Within 4 hours after sICH onset, blood components and thrombin induce the release of cytokines and other inflammatory molecules, with subsequent microglial activation, blood brain barrier (BBB) damage and the formation of perihaematomal oedema (PHO). Among the released cytokines, interleukin 1 beta (IL-1β) has a pivotal role. Recombinant human interleukin-1 receptor antagonist (IL-1Ra, anakinra) effectively antagonizes IL-1β through competitive binding to the IL-1 receptor. Anakinra is available for treatment of rheumatoid arthritis, other inflammatory diseases and has been studied in acute sepsis. We hypothesize that anakinra safely reduces SBI after sICH, and that its effect is dose-dependent.
Objective: To determine the effect of high-dose versus low-dose anakinra compared to standard medical management on oedema extension distance (OED) determined with MRI on day 7±1. Second, to study the safety profile of anakinra. Furthermore, to assess its effect on 1) serum inflammatory markers IL-1β, IL-6, hsCRP, neutrophil and total white blood cell counts at day 1, 3 and 7 compared to baseline; 2) dynamic contrast enhanced (DCE-) MRI measurement of BBB transfer constant (Ktrans) on day 7±1, and; 3) to estimate an effect on functional outcome in patients with sICH.
Study design: Multicentre, prospective, randomized, three-armed (1:1:1) trial with open label treatment and blinded end-point assessment (PROBE design) .
Study population: 75 patients with supratentorial sICH admitted within 8 hours after symptom onset.
Intervention: Patients will receive anakinra in either a high dose (loading dose 500mg i.v., followed by infusion with 2mg/kg/h over 3 days; n=25) or in a low dose (loading dose 100mg s.c.., followed by subcutaneous administration of 100mg twice a day for 3 days; n=25), started within 8 hours of symptom onset. The control group (n=25) will receive standard medical management.
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
- Single (Outcomes Assessor)
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;
- •Supratentorial non-traumatic ICH confirmed by CT, without a confirmed causative lesion on admission CT-angiography (e.g. aneurysm, AVM, DAVF, cerebral venous sinus thrombosis) or other known underlying lesion (e.g. tumour, cavernoma);
- •Minimal intracerebral haemorrhage volume of 10 mL;
- •Intervention can be started within 8 hours from symptoms onset;
- •Patient's or legal representative's informed consent.
排除标准
- •Severe ICH, unlikely to survive the first 72 hours (defined as Glasgow Coma Scale score < 6 at time of consent);
- •Confirmed or suspected haemorrhagic transformation of an arterial or venous infarct;
- •Planned neurosurgical haematoma evacuation;
- •Severe infection at admission, requiring antibiotic treatment;
- •Known active tuberculosis or active hepatitis;
- •Use of immunosuppressive or immune-modulating therapy at admission (see 15.1 Appendix A);
- •Neutropenia (Absolute Neutrophil Count (ANC) <1.5 x 109/L );
- •Pre-stroke modified Rankin Scale score ≥ 3;
- •Pregnancy or breast-feeding;
- •Standard contraindications to MRI (see 15.2 Appendix B);
- •Known prior allergic reaction to gadolinium contrast or one of the constituents of its solution for administration;
- •Known allergy to anakinra or other products that are produced by DNA technology using the micro-organism E. coli;
- •Live vaccinations within the last 10 days prior to this ICH;
- •Severe renal impairment (eGFR <30ml/min/1.73m)
- •Active malignancy
研究组 & 干预措施
Anakinra High dose
500mg i.v. loading dose, followed by continuous iv infusion with 2mg/kg/h over 3 days
干预措施: Anakinra (Drug)
Anakinra Low dose
100mg s.c. loading dose, followed by subcutaneous administration of 100mg twice daily for 3 days.
干预措施: Anakinra (Drug)
结局指标
主要结局
Perihematomal oedema
时间窗: 7 days after ICH onset
Measured as Oedema Extension Distance (OED/EED)
次要结局
- Blood brain barriere leakage(7 days)
- Adverse events of special interest (AESI) and serious adverse events (SAE)(90 days)
- Levels of serum inflammatory markers (IL-1β, IL-6, hsCRP)(7 days)
- Functional outcome(90 days)