MICA: Optimising brain protection and reducing birth asphyxia disability: safety and efficacy of early high dose MELATONIN and COOLING with late EPO

出生时的问题导致婴儿缺氧，可能会导致被称为新生儿脑病(NE)的大脑功能紊乱，这可能导致长期的脑损伤和脑性瘫痪。已经证明，婴儿出生后尽快给婴儿降温3摄氏度3天是安全的，可以长期保护大脑，甚至可以改善结果，甚至到上学年龄也是如此。需要接受降温治疗以防止一人死亡或残疾的婴儿数量为6-7人。降温已得到英国国家临床卓越研究所(NICE)的认可，并被英国各地的新生儿重症监护病房采用，用于患有中到重度NE的婴儿。然而，尽管降温对患有NE的婴儿来说是向前迈出的一大步，但44%-53%的婴儿仍然有不良后果。在过去的5年里，N Robertson(Pi)和S Juul(共同申请人)的实验室分别对1.褪黑激素和2.促红细胞生成素(EPO)进行了研究；这些研究都表明，在降温过程中添加其中一种制剂是安全的，并在动物(褪黑激素)和动物和婴儿(EPO)中导致更好的结果。这些药物作用于缺氧后损伤级联反应的不同部分：1.褪黑激素是松果体产生的一种自然产生的激素，在生理水平上参与昼夜循环。在较高的水平(血浆水平是正常夜间水平的10,000倍)，褪黑素具有强大的非受体作用，可以清除破坏性的自由基。我们的研究表明，在受伤后尽快达到褪黑素的治疗范围对于最大限度地受益至关重要。我们与制药公司Chiesi的合作始于2013年，此前我们的初步研究显示，在缺氧10分钟后，褪黑素显著增强了脑保护。Chiesi开发了一种新的褪黑素配方，对婴儿是安全的；我们的实验室最近对这种新配方进行了评估，并计算出了在3小时而不是8小时达到治疗水平的最佳褪黑素速率和剂量。2.促红细胞生成素是一种蛋白质，最初被认为具有刺激红细胞生成的作用。EPO具有脑保护、修复和再生特性，已被证明在动物损伤后1周的亚急性阶段和婴儿降温16.5小时时具有保护作用。S Juul一直是EPO脑保护领域的领导者，对剂量反应和安全性具有独特的知识，并在美国进行的2项EPO脑保护临床试验中被PI。我们的目标是进行一项解决以下问题的研究：1.在伤后1小时早期以更快的输注速度给予优化的大剂量褪黑素与在复温后24小时晚给予EPO的组合是否比单独降温(三联疗法与单一疗法)更能带来更好的脑保护2.三联疗法(降温、褪黑素和EPO)是否比双重疗法(降温褪黑素或降温+EPO)更能带来更好的保护3.与我们之前的方案相比，优化的大剂量褪黑素与伤后3小时内达到的治疗水平是否能带来比我们之前的方案更好的保护效果，我们之前的方案是在受伤后8小时达到治疗水平。我们将使用已建立的NE仔猪重症监护模型来解决这些问题。可以对小猪进行重症监护和监测，其大小允许使用与婴儿相同的静脉导管和导管，药物均基于NICU的方案，小猪大脑的成熟阶段类似于人类大脑，大脑生长激增发生在出生前后。我们使用与NE婴儿相同的3Tesla MRI系统和相同的序列，使数据具有临床相关性和转换性。如果这些数据呈阳性，将被转化为婴儿临床试验，并可能对结果产生重大好处。

Problems around the time of birth causing a lack of oxygen to the baby can cause disordered brain function called neonatal encephalopathy (NE), which can result in long term brain damage and cerebral palsy. Cooling a baby by 3 degrees Celsius for three days as soon as possible after birth has been shown to be safe and leads to long term brain protection and improved outcome even to school age. The number of babies that need to be treated with cooling to prevent one from being dead or disabled is 6-7. Cooling has been endorsed by the National Institute for Clinical Excellence (NICE) and adopted in neonatal intensive care units around the UK for babies with moderate to severe NE. However, although cooling is a major step forward for babies with NE, 44-53% of babies still have adverse outcomes. Over the last 5 years, studies have been performed in the laboratory of N Robertson (PI) and S Juul (co-applicant) on 1. melatonin and 2. erythropoietin (Epo) respectively; these studies have both shown that adding one of these agents to cooling is safe and leads to better outcomes in animals (melatonin) and in animals and babies (Epo). These agents act at different parts of the cascade of injury after hypoxia: 1. Melatonin is a naturally occurring hormone produced by the pineal gland which entrains the day/night cycle at physiological levels. At higher levels (plasma levels 10,000 times higher than normal night time levels), melatonin has powerful non-receptor actions to scavenge damaging free radicals. Our studies have shown the critical importance of reaching the therapeutic range of melatonin as quickly as possible after the injury for most benefit. Our collaboration with the pharmaceutical company, Chiesi, started in 2013 following our initial study showing significant augmentation of brain protection with melatonin at 10 mins after hypoxia. Chiesi has developed a novel melatonin formulation which is safe for babies; this new formulation was assessed recently in our laboratory and the optimal rate and dosing of melatonin to achieve therapeutic levels at 3h rather than 8h has been calculated. 2. Epo is a protein originally identified for its role in stimulating red blood cell generation. Epo has brain protection and repair and regeneration properties and have been shown to be protective when starting in the subacute phase up to 1 week after the injury in animals and at 16.5 h in babies with cooling.S Juul has been a leader in the Epo brain protection field and has unique knowledge of dose response and safety and is PI on the 2 clinical trials of Epo brain protection in the USA. Our aim is to perform a study which addresses the following questions:1. Does the combination of an optimised high dose melatonin given early on at 1h after the injury and at a faster infusion rate and late Epo at 24h after rewarming lead to better brain protection than cooling alone (triple versus single therapy)2. Does triple therapy (Cooling, melatonin and Epo) lead to bettie protection than double therapy (Cooling play melatonin or cooling plus Epo)3. Does the optimised high dose melatonin with therapeutic levels achieved in 3h after injury lead to improved protection compared to our previous protocol where therapeutic levels were achieved at 8h after injury. We will use an established piglet intensive care model of NE to address these questions. Intensive care and monitoring can be given to the piglet, the size allows for the same intravenous lines and catheters to be used as in babies, the medications are all based on protocols from the NICU and the maturational stage of the piglet brain is similar to human brain with the brain growth spurt occurring around birth. We use the same 3 Tesla MRI system and same sequences as we do in babies with NE, making the data clinically relevant and translational. These data, if positive, will be translated to clinical trials in babies and could lead to significant benefit to outcomes.