Phase II Trial of Interleukin-1 Receptor Antagonist in Intracerebral Haemorrhage: BLOcking the Cytokine IL-1 in ICH
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Oedema extension distance (OED)
研究概览
简要总结
This trial will help inform the development of a new treatment for intracerebral haemorrhage (ICH; also known as haemorrhagic stroke). ICH is a type of stroke caused by spontaneous bleeding into the brain. In the hours to days after bleeding occurs, inflammation develops in the brain around the haematoma (collection of blood in the brain). Inflammation is the body's natural response to injury, however when it continues unchecked there is a risk that the brain tissue around the haematoma will become swollen. This type of swelling can worsen existing stroke symptoms or cause new deficits such as speech disturbance and limb weakness, which can lead to long term disability.
The level of inflammation in the blood is high after ICH. The investigators want to investigate whether blocking this inflammation can improve overall recovery. The investigators research group has extensively investigated the use of a well-established anti-inflammatory drug, Kineret® in trials with patients who have suffered a stroke or brain haemorrhage. Kineret® is similar to a naturally-produced protein called interleukin-1 receptor antagonist (IL-1Ra) and is already licensed to treat patients with rheumatoid arthritis. The investigators have evidence from these previous studies that Kineret® reduced levels of inflammation in the blood after ischaemic stroke (caused by a blockage in an artery). However, in order to develop Kineret® as a treatment for ICH, the investigators need to know if it reduces levels of inflammation present in the blood following ICH and if it reduces swelling in the brain.
详细描述
The investigators know from previous studies that the level of inflammation in the blood is high after haemorrhagic stroke and want to investigate whether blocking this inflammation can improve outcomes. The only current treatments for haemorrhagic stroke are aimed at significantly reducing the blood pressure and reversing the action of any anticoagulants (e.g. warfarin) where necessary. Surgery to remove the blood clot is not an option for all participants and the benefits of this are not clear.
The investigators research group has extensively investigated the use of a well-established anti-inflammatory drug, Kineret® in trials with participants who have suffered a stroke or brain haemorrhage. Kineret® is similar to a naturally-produced protein called interleukin-1 receptor antagonist (IL-1Ra) and is already licensed to treat patients with rheumatoid arthritis. The investigators have evidence from these previous studies that Kineret® reduced levels of inflammation in the blood after ischaemic stroke (caused by a blockage in an artery). In another trial, the investigators collected samples of the haematoma blot clot removed during surgery in 47 participants who had suffered a haemorrhagic stroke. These participants were taking part in a trial of 'keyhole' surgery as a treatment for haemorrhagic stroke. The investigators found that higher levels of naturally occurring IL-1Ra in and around the haematoma blood clot is linked to less brain swelling a few days later. This suggests that Kineret® may reduce swelling in the brain after haemorrhagic stroke. However, in order to develop Kineret® as a treatment for haemorrhagic stroke, the investigators need to know if it reduces levels of inflammation present in the blood and if it reduces swelling in the brain.
The investigators also want to investigate whether blocking inflammation can improve outcomes following ICH. If the results of this trial show promise, it could support the decision to run a much larger trial to establish whether lowering inflammation improves recovery after haemorrhagic stroke.
Patients admitted to a neurosurgical centre within 8 hours of intracerebral haemorrhage (ICH) on brain imaging will be considered for study participation. Potential participants will be identified by the clinical team and will be referred to the research teams at the sites following usual and established pathways. These pathways may include potential participants being identified by; (i) Screening the acute referral databases/medical records, (ii) Attendance at ward round and, (iii) Referral by Accident and Emergency team. All members of the research teams at the sites have an existing working relationship with the clinical teams and are employed by the research site (hospital Trust). This procedure is employed at sites in order to identify potential participants for all acute and hyper acute research studies.
Capacity to consent may be an issue within this patient group. An appropriately trained member of the research team will carry out a formal assessment of capacity, where appropriate. Where it is not possible to obtain consent from the patient due to lack of capacity, the investigators will seek consent from their personal legal representative. If the patient lacks capacity to consent to participation and no personal legal representative exists, the decision to include the patient will be made by a senior member of the clinical team who is independent of the research team (professional legal representative).
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
- Double (Participant, Investigator)
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
- •Patients with spontaneous, non-traumatic, supratentorial ICH with no underlying macrovascular or neoplastic cause admitted to a participating centre within 8 hours of symptom onset.
- •No concomitant health problems that, in the opinion of the principle Investigator (PI) or designee, would interfere with participation, administration of study drug or assessment of outcomes including safety.
- •Willing and able to give informed consent or consent available from a patient representative for trial inclusion including agreement in principle to receive study drug and undergo all study assessments.
- •Male or female aged 18 years or above.
排除标准
- •Severe ICH, unlikely to survive to 72 hours scan, in the opinion of the treating clinician. For example, a GCS score < 6 at time of consent);
- •Confirmed or suspected structural abnormality as cause of ICH (including tumour, vascular malformation).
- •Confirmed or suspected haemorrhagic transformation of an arterial or venous infarct.
- •Acute neurosurgery planned within 72 hours of admission.
- •Known active tuberculosis or active hepatitis.
- •Known active malignancy.
- •Neutropenia (absolute neutrophil count (ANC) <1.5 x10^9/L).
- •Abnormal renal function (creatinine clearance or estimated Glomerular Filtration Rate (eGFR) < 30 ml/minute) documented in the last 3 months prior to this ICH.
- •Live vaccinations within the last 10 days prior to this ICH.
- •Previous or concurrent treatment with IL-1Ra known at the time of trial entry or previous participation in this trial.
- •Previous or current treatment with etanercept or any other tumour necrosis factor alpha (TNFα) antagonist.
- •Known to have participated in a clinical trial of an investigational agent or device in the 30 days prior to symptom onset.
- •Known to have participated in a clinical trial of an investigational agent or device within 5 half-lives (of the previous agent or device) prior to symptom onset.
- •Known to be pregnant or breast-feeding or inability to reliably confirm that the patient is not pregnant.
- •Known diagnosis of Still's disease.
- •Clinically significant serious concurrent medical condition, premorbid illnesses, or concurrent serious infection, at the PI's (or designee's) discretion, which could affect the safety or tolerability of the intervention.
- •Known allergy to IL-1Ra or any of the excipients listed in the drug summary of product characteristics (SmPC).
- •Known allergy to other products that are produced by DNA technology using the micro-organism E. coli (e.g. E.coli derived protein).
研究组 & 干预措施
IL-1Ra Kineret®
100mg doses of the trial drug Kineret® will be administered subcutaneously (SC) twice daily (12 hourly) starting within 8 hours of symptoms onset for a maximum of 3 days from symptoms onset (or sooner if discharged from neurosurgical centre).
干预措施: IL-1Ra Kineret® (Drug)
IL-1Ra Placebo
100mg doses of the placebo will be administered subcutaneously (SC) twice daily (12 hourly) starting within 8 hours of symptoms onset for a maximum of 3 days from symptoms onset (or sooner if discharged from neurosurgical centre).
干预措施: IL-1Ra Placebo (Other)
结局指标
主要结局
Oedema extension distance (OED)
时间窗: 72 hours (+/-12 hours) post symptoms onset
Perihaematomal OED on CT scan at 72 hours (+/-12 hours), which equates to the average distance that oedema extends beyond the haematoma border.
次要结局
- Early haematoma growth(between baseline and 72 hours post symptoms onset)
- Early Neurological Decline (END)(between baseline and 72 hours post symptoms onset)
- Inflammatory markers(from day 0 (baseline) to day 4 post randomisation)
- Stroke Impact Scale (SIS)(3 months post randomisation)
- Quantitative blood-brain barrier permeability(day 2-4 post randomisation)
- Fatigue severity score (FSS)(3 months post randomisation)
- modified Rankin Score (mRS)(3 months post randomisation)
- EQ-5D-5L(3 months post randomisation)
- Hospital Anxiety and Depression Scale (HADS)(3 months post randomisation)
研究者
Adrian Parry-Jones
NIHR Clinician Scientist & Honorary Consultant Neurologist
University of Manchester