A Randomised Double Blind Placebo Controlled Dose-range Study Using Placebo, 1.5g and 3.0g of Intravenous Recombinant Interleukin-1 Receptor Antagonist (Anakinra) for Patients With Moderate-to-severe TBI
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Decrease of pro-inflammatory cytokines in brain extracellular fluid (ECF)
研究概览
简要总结
Traumatic brain injury (TBI) is a common condition with high degree of morbidity and mortality (Hyder et al., 2007). Current treatment paradigms for TBI focus on mitigating secondary injury and maintaining cerebral physiology (Carney et al., 2016), however, there are currently no approved drugs that target the underlying conditions for patients suffering from TBI (Bullock et al., 1999). It is increasingly recognised that the innate inflammatory response to TBI may inflict injury (Lucas et al., 2006), and one of the most prominent mediators of inflammation in the injured brain is the Interleukin-1 (IL-1) receptor pathway (Allan et al., 2005). An endogenous antagonist to IL-1, is available in recombinant form (IL-1ra, Kineret), and is known to be safe in TBI (Helmy et al., 2014).
In order to fully understand, and potentially optimize, the effect of Kineret, the investigators wish to conduct a dose-response study by giving three cohorts (n=20 per group) either placebo (isotonic saline), 1.5g or 3.0g of active substance administered intravenously in a double-blind, randomized setting. The concentrations have in previous studies not been shown to present any side-effects (Singh et al., 2014). The drug will be provided within 12 hours after trauma. The goal will be to provide a dose-response effect on the cerebral inflammatory response. As secondary goals, the investigators will assess the brain damage by measuring proteins in blood and cerebrospinal fluid, functional outcome and inflammation in the brain using positron emission tomography.
详细描述
Aim
The hypothesis is that an increasing dose of the anti-inflammatory drug recombinant human Interleukin-1 receptor antagonist (IL-1ra, Kineret) will modulate the inflammatory state of the traumatically injured brain, which will attenuate the injurious processes that occur following TBI.
Study Design
While different doses of Anakinra have been used in trials, there is no knowledge of what constitutes an optimized concentration of the drug. To address this limitation, the current study will be a dose-response study in a double blind randomised clinical fashion, using placebo (n=20), 1.5 g ("intermediate dose") or (n=20) and 3.0 g ("high dose")(n=20) of Anakinra provided the first 48 hours (drug/placebo administered initially as 500 mg infusion bolus and later as an 1g or 2.5g infusion for 48 hours). Thus, a total of n=60 patients will be included. Sample-size analyses have indicated that the number of patients is sufficient to detect differences in the inflammatory response as gauged with cytokine measurements using cerebral microdialysis.
As surrogate markers of outcome for these patients, several protein biomarkers of brain injury and proteins of the innate immune responses will be quantified using techniques called ELISA and multiplex assay technology. The investigators also wish to use radiological techniques, such as magnetic resonance imaging to study damages in white matter tracts in the brain and positron emission tomography to assess the degree of microglial activation. All these methods will be used to assess the potential benefit of the treatment vs placebo.
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)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Suffer from a TBI, present with a Glasgow Coma Scale (GCS) of 3-13 and be deemed to be in need of neuro-critical care and intracranial monitoring for at least 72 hours.
- •Be aged 18-65
- •The first dose of Kineret (or placebo) must be provided within 12 hours after trauma.
排除标准
- •Head injury unlikely to survive 5 days (radiological evidence of above as judged by clinical team, bilateral fixed and dilated pupils).
- •Follow up not possible
- •Not suitable for insertion of cranial access device to monitor the brain (such as bleeding complications)
- •Active immunosuppression therapy (evidence of neutropenia, immunosuppression secondary to immunomodulatory medications, chemotherapy or radiation therapy in the 3 months preceding study entry)
- •Severe Renal Insufficiency or End Stage Renal Disease (defined as a creatinine clearance <30 ml/min)
- •Pregnancy/Nursing mothers
- •Known hypersensitivity to E. coli derived products
- •Administration of live vaccine
研究组 & 干预措施
Placebo
Isotonic saline administered as an injection and infusion
干预措施: Isotonic saline (Drug)
1.5 g Kineret
Kineret provided as a 500 mg injection followed by a 1g infusion.
干预措施: Anakinra Prefilled Syringe (Drug)
3.0 g Kineret
Kineret provided as a 500 mg injection followed by a 2.5g infusion.
干预措施: Anakinra Prefilled Syringe (Drug)
结局指标
主要结局
Decrease of pro-inflammatory cytokines in brain extracellular fluid (ECF)
时间窗: First 48 hours
Decrease of Tumor necrosis factor alpha and interferon gamma cytokines in brain ECF
次要结局
- Biochemical outcome - Tau(During the first 7 days)
- Biochemical outcome - APP(During the first 7 days)
- Patient outcome GOSe(6 months and 12 months)
- Patient outcome SF36(6 months and 12 months)
- Imaging outcome - DTI-MRI(During the first 14 days)
- Biochemical outcome - S100B(During the first 7 days + at 6 months and 12 months)
- Biochemical outcome - NF-L(During the first 7 days)
- Imaging outcome - PET-MRI(During the first 14 days)
- Monitoring outcome - Cerebral Metabolism LPR(First 7 days)
- Biochemical outcome - Autoreactivity versus MBP(During the first 7 days + at 6 months and 12 months)
- Monitoring outcome - ICP(First 7 days)
- Monitoring outcome - CPP(First 7 days)
- Monitoring outcome - Brain tissue oxygenation(First 7 days)
- Monitoring outcome - PRx(First 7 days)
- Pharmacological outcome - Concentration of IL1ra in brain tissue(First week)
- Pharmacological outcome - Concentration of IL1ra in serum(First week)
- Side effects of the IL1ra(First week + up to 12 months follow-up)
研究者
Adel Helmy
MA, MB BChir, PhD, FRCS (SN)
University of Cambridge