Dexmedetomidine Use in Infants undergoing Cooling due to Neonatal Encephalopathy (DICE trial)

项目总结 右美托咪定在新生儿脑病降温治疗中的应用(DICE试验) 缺氧缺血性脑病(HIE，俗称“新生儿窒息”)是一种脑部疾病 没有得到足够的氧气。每1000个婴儿中就有2个感染HIE。尽管早期使用Brain进行干预 降温、死亡或重大残疾的后果，如脑瘫和智力低下，仍然发生在 其中近30%的婴儿。还没有其他疗法被证明可以进一步减少这些高血糖患者的脑损伤。 有风险的婴儿。此外，同时使用吗啡等药物可能会造成额外的脑损伤。 在这个人群中治疗疼痛和镇静。在动物模型中使用吗啡可增加神经细胞凋亡 并对神经发育产生负面影响。开发可改善婴儿结局的辅助疗法 与HIE一起存在的是一个迫切的、未得到满足的公共卫生需求。 右美托咪定是一种有效的α2-肾上腺素能受体激动剂，可能是治疗吗啡的更好替代品 新生儿缺氧缺血性脑病降温治疗。右美托咪定提供镇静、止痛和 防止发抖，但不抑制呼吸。重要的是，右旋美托咪定已被证明具有保护作用 脑损伤动物模型中的大脑。最近的临床研究也表明，治疗后脑功能改善 右美托咪定在成人脑损伤患者中的应用。即使只有有限的数据 右美托咪定在婴儿中的安全性和有效性以及药代动力学(PK；血药浓度) 他说，许多中心越来越多地对它进行管理。 我们的中心假设是右美托咪定用于HIE足月儿的镇静治疗 降温将是安全的(目标1)，并将与改善短期和长期结果相关 (目标3)。为了验证这一假设，我们设计了一项第二阶段的多中心、随机、安全和PK试验。 50名患有HIE并需要镇静的婴儿(每只手臂n=25)将随机接受以下两种治疗之一 右美托咪定(负荷量1μg/kg，然后持续输注0.1至0.5μg/kg/h)或吗啡 (0.02-0.03 mg/kg/剂量，间断给药，q4小时静脉注射或连续输注剂量0.005-0.01) 毫克/公斤/小时)。两个机会主义PK样本(在常规实验室时)和一个PRN PK样本随时在那里 不良事件发生后将获得右旋美托咪定血药浓度(AIM2)的测量结果。 有希望的初步数据显示，右美托咪定可能会改善疗效，但最佳剂量、安全性和 疗效仍需确定。我们建议通过收集以下信息来确定右美托咪定的最佳剂量 PK数据的机会性血液样本，并确定右美托咪定在这一人群中的安全性 第二阶段安全性试验。这些数据将为一项更大的III期试验提供信息，以评估该疗法在 降低出生后存活的缺氧缺血性脑病婴儿长期残疾的风险。

PROJECT SUMMARY Dexmedetomidine Use in Infants undergoing Cooling due to Neonatal Encephalopathy (DICE trial) Hypoxia-ischemia encephalopathy (HIE, commonly called “birth asphyxia”) is a condition where the brain doesn’t get enough oxygen. HIE affects 2 out of every 1,000 babies. Despite early intervention using brain cooling, outcomes of death or major disability, such as cerebral palsy and mental retardation, still occurs in nearly 30% of these babies. No other therapies have been proven to further reduce brain injury for these high risk infants. Furthermore, additional brain injury may be caused by concomitant use of drugs such as morphine to treat pain and sedation in this population. Morphine use in animal models can increase neuronal apoptosis and negatively affect neurodevelopment. Developing adjunctive therapies that improve outcomes in infants with HIE is an urgent, unmet public health need. Dexmedetomidine is a potent α2-adrenergic receptor agonist that may be a better alternative to morphine for newborns with neonatal HIE treated with cooling. Dexmedetomidine provides sedation, analgesia, and prevents shivering but does not suppress breathing. Importantly, dexmedetomidine has been shown to protect the brain in animal models of brain injury. Recent clinical studies also suggest improved brain outcomes after dexmedetomidine administration in adult patients with brain injury. Even though there are limited data on dexmedetomidine safety and usefulness as well as pharmacokinetics (PK; drug levels in blood) in infants with HIE it has been increasingly administered in many centers. Our central hypothesis is that dexmedetomidine administered for sedation to full-term infants with HIE undergoing cooling will be safe (AIM 1) and will be associated with improved short and long-term outcomes (AIM 3). To test this hypothesis, we have designed a Phase II multicenter, randomized, safety and PK trial. Fifty infants (n=25 in each arm) with HIE and requiring sedation will be randomized to receive either dexmedetomidine (1 μg/kg for loading dose followed by 0.1 to 0.5 μg/kg/h continuous infusion) or morphine (0.02-0.03 mg/kg/dose intermittent dosing q 4 hours IV or as continuous infusion dose of 0.005- 0.01 mg/kg/hr). Two opportunistic PK samples (at time of routine laboratories) and a PRN PK sample any time there is an adverse event will be obtained for measurement of Dexmedetomidine plasma concentrations (AIM 2). Promising preliminary data show that dexmedetomidine may improve outcomes but optimal dosing, safety, and efficacy still need to be established. We propose to confirm dexmedetomidine optimal dosing by collecting opportunistic blood samples for PK data and determine safety of dexmedetomidine in this population in a phase II safety trial. These data will inform a larger phase III trial to assess the efficacy of this therapy in reducing the risk of long-term disabilities in infants with HIE who survive beyond the newborn period.