Acute High Dose Melatonin for Encephalopathy of the Newborn (ACUMEN):Phase I Study

出生前后的问题导致婴儿严重缺氧，导致大脑功能紊乱，可能导致脑损伤。在过去的20年里，医生已经为出生时可能有脑损伤的婴儿引入了冷却。冷却是一种安全有效的治疗方法，婴儿的身体在三天内冷却3度。冷却改善结果，然而，尽管冷却，许多婴儿在学龄前后仍然存在身体发育，学习，行为和记忆方面的问题。在过去的10年里，已经研究了几种治疗方法，但是，到目前为止，除了冷却之外，还没有针对这些婴儿的治疗方法。褪黑激素是一种很有希望的疗法，它是大脑在夜间自然产生的一种激素。众所周知，褪黑激素调节睡眠-觉醒周期;在高剂量（高于身体分泌）褪黑激素“扫荡”循环血液中的有害化学物质，阻止细胞死亡。褪黑激素是安全的，多年来一直在儿童中使用高剂量，没有副作用。我们已经在动物中表明，在冷却中加入高剂量的褪黑激素（20 mg/kg）比单独冷却产生更好的保护作用; 20 mg/kg的负荷剂量对于尽可能快地递送褪黑激素是必要的，脑保护与在6小时内达到高褪黑激素水平（15- 30 mg/L）有关。因此，褪黑激素有可能对婴儿有益。当褪黑激素溶解在少量酒精中时，保护效果更好。我们已经与英国监管机构MHRA进行了交谈，他们认为只要将酒精保持在推荐的安全水平以下，就可以为这一高危人群提供巨大的治疗益处。这项研究的第一个里程碑是将褪黑激素药物（含酒精）的生产外包给我们，使其达到我们可以用于婴儿的标准。制药公司将进行测试，以确保药物是纯净和稳定的几个月。在里程碑2，在药物生产后，我们将评估褪黑激素在4个剂量水平的安全性在25-40婴儿在“剂量递增研究”中有脑损伤的风险。我们将从三家英国大型医院（UCLH，曼彻斯特和爱丁堡）和三家爱尔兰大型医院（都柏林和科克的Coombe和Rotunda医院）招募12个月以上的婴儿。我们将从估计的有效褪黑激素剂量的四分之一开始;该四分之一剂量将在出生后6小时内给予5 mg/kg负荷，然后从24- 72小时给予2.5mg/kg 12小时维持剂量（共6次剂量）。剂量递增研究的最小样本量为25名婴儿，每个剂量水平（四分之一、半剂量、四分之三和全剂量）的队列为5名婴儿。在允许评估下一个褪黑激素水平之前，安全委员会将仔细评估临床数据。将测量褪黑激素和乙醇的水平;这些值将用于预测模型，以告知安全委员会预期的水平。使用这些模型，我们将避免血液酒精水平超过0.25g/L的安全限值（美国儿科学会1984年的安全建议）。我们将评估“剂量限制性事件”，包括：1.褪黑激素输注期间血压严重下降，对两种改善血压的疗法无反应2。死亡最大耐受剂量将是这些事件发生在<33%的婴儿中的剂量。在等待安全委员会的时候，允许使用较低的安全剂量。在剂量递增研究和确定褪黑激素的推荐剂量后，我们将在相同的6家医院加上澳大利亚的2家医院（合作研究中心）进行为期6个月的“队列扩展研究”。这将进一步证实安全性，招募的可行性，探索同意过程和跨站点的成像。在里程碑3中，在数据分析和撰写之后，如果结果是积极的，我们将为未来的褪黑激素II期研究寻求资金。

Problems around birth leading to a critical lack of oxygen to the baby leads to disordered brain function which can result in brain damage. Over the last 2 decades, doctors have introduced cooling for babies with likely brain damage at birth. Cooling is a safe and effective treatment where a baby's body is cooled by 3 degrees for three days. Cooling improves outcomes, however, despite cooling, many babies still have problems with physical development, learning, behaviour and memory around school age. New therapies to improve outcomes with cooling are urgently needed.Over the last 10y, several therapies have been studied but, as yet, no therapy apart from cooling exists for these babies. One promising therapy is melatonin, a naturally occurring hormone produced in the brain at night. Melatonin is known to regulate the sleep-wake cycle; at high dose (higher than the body secretes) melatonin "mops-up" damaging chemicals in the circulating blood and stops cells dying. Melatonin is safe and has been used in children at high dose for long periods of years with no side effects. We have shown in animals that adding high doses of melatonin (20mg/kg) to cooling leads to better protection than cooling alone; a loading dose of 20mg/kg is necessary to deliver melatonin as rapidly as possible with brain protection related to achieving high melatonin levels (15-30mg/L) within 6h. Melatonin therefore has the potential to benefit babies. When melatonin is dissolved in a small amount of alcohol, the protection is better. We have spoken to the UK regulatory body, the MHRA, who see the large potential of treatment benefit given this high risk population as long as alcohol is kept below recommended safe levels.The first milestone of this study is to outsource the manufacture of the melatonin medicine (with alcohol) to a standard we can use in babies. The pharmaceutical company will run tests to ensure the medicine is pure and stable over several months.In milestone 2, following manufacture of the medicine, we will assess safety of melatonin at 4 dose levels in 25-40 babies at risk of brain injury in the "Dose Escalation Study". We will recruit babies from three large UK hospitals (UCLH, Manchester and Edinburgh) and three large Irish hospitals (Coombe and Rotunda Hospitals in Dublin and Cork) over 12 months. We will start with one quarter of the estimated effective melatonin dose; this quarter dose will be 5mg/kg loading given within 6h of birth, followed by 2.5mg/kg 12hrly maintenance doses from 24-72h (total of 6 doses). The minimum sample size in the dose escalation study will be 25 babies, with cohorts of 5 babies at each dose level (quarter, half, three quarters and full dose). A safety committee will carefully assess the clinical data, before allowing the next melatonin level to be assessed. Levels of melatonin and ethanol will be measured; these values will be used in the predictive models to inform the safety board of expected levels. Using such models we will avoid blood alcohol levels over the safety limit of 0.25g/L (safety recommendation from the American Academy of Paediatrics 1984). We will assess "dose limiting events" which include: 1. Severe drop in blood pressure during the melatonin infusion unresponsive to two therapies to improve blood pressure2. Death The maximum tolerated dose will be the dose where these events occur in <33% of babiesWhile waiting for the safety committee, backfilling to a lower safe dose is allowed. Following the dose escalation study and identification of the recommended dose of melatonin, we will perform a "Cohort expansion Study" for 6 months in the same 6 hospitals plus 2 hospitals in Australia (collaborator sites). This will further confirm safety, feasibility of recruitment, explore consent processes and imaging across sites.In milestone 3, after data analysis and write up, if results positive, we will pursue funding for a future phase II study of melatonin.