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

右美托咪定用于因新生儿脑病而接受降温的婴儿（DICE 试验）

• 批准号: 10571839
• 负责人: Mariana Baserga
• 金额: $ 19.24万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-14 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571839
• 关键词: Absence of pain sensation; Acute Kidney Failure; Adrenergic Agonists; Adult; Adverse event; Affect; Age; Agitation; Animal Model; Animals; Arrhythmia; Asphyxia Neonatorum; Birth trauma; Blood; Blood specimen; Bradycardia; Brain; Brain Injuries; Brain Ischemia; Breathing; Cerebral Palsy; Cessation of life; Childhood; Clinical; Clinical Research; Continuous Infusion; Data; Depressed mood; Development; Dexmedetomidine; Dose; Drug Kinetics; Drug usage; Early Intervention; Encephalopathies; Failure; Gestational Age; Hospitalization; Hour; Human; Hypertension; Hypotension; Impaired cognition; Infant; Inflammation; Injury; Intensive Care Units; Ischemia; Laboratories; Learning; Life; Liver Failure; Measurement; Measures; Mental Retardation; Modeling; Morphine; Motor; Motor Skills; Movement; Neonatal; Neurodevelopmental Impairment; Neurologic; Newborn Infant; Normal Range; Opioid; Outcome; Oxygen; Pain; Pain management; Parents; Patients; Performance; Pharmaceutical Preparations; Phase; Plasma; Population; Property; Public Health; Questionnaires; Randomized; Reperfusion Therapy; Research; Risk; Risk Reduction; Safety; Sampling; Sedation procedure; Seizures; Severities; Shivering; Survivors; Testing; Therapeutic; Therapeutic Uses; Time; Toxic effect; Traumatic Brain Injury; Treatment Efficacy; Visit; Weaning; appropriate dose; arm; design; disability; efficacy evaluation; high risk infant; improved; improved outcome; motor disorder; natural hypothermia; negative affect; neonatal death; neonatal encephalopathy; neonatal hypoxic-ischemic brain injury; neonatal period; neurodevelopment; neuron apoptosis; neuroprotection; phase III trial; pre-clinical; prevent; sedative; side effect; study population; ventilation

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.

项目摘要 由于新生儿脑病（骰子试验），在接受冷却的婴儿中使用右美托咪定（骰子） 低氧 - 缺血性脑病（Hie，通常称为“出生窒息”）是大脑 没有足够的氧气。 Hie每1000名婴儿中有2个影响。尽管早期干预了大脑 冷却，死亡或重大残疾的结果，例如脑瘫和智力低下，仍然发生在 这些婴儿中有将近30％。尚无其他疗法被证明可以进一步减少这些高的脑损伤 风险婴儿。此外，额外的脑损伤可能是由伴随使用（例如吗啡）的使用引起的 治疗该人群中的疼痛和镇静。在动物模型中使用吗啡可以增加神经元细胞凋亡 并对神经发育产生负面影响。开发改善婴儿预后的辅助疗法 Hie是一个紧急，未满足的公共卫生需求。 右美托汀是一种潜在的α2-肾上腺素受体激动剂，可能是吗啡的更好替代品 带有新生儿的新生儿用冷却治疗。右美咪定提供镇静，镇痛和 防止发抖，但不会抑制呼吸。重要的是，右美托咪定已证明可以保护 动物损伤动物模型中的大脑。最近的临床研究还表明，在 成人脑损伤患者的右美咪定给药。即使数据有限 右美托咪定的安全性和有用性以及药代动力学（PK；血液中的药物水平） hie越来越多地在许多中心管理。 我们的核心假设是给镇静剂给予的右美托咪定致Hie的完美婴儿 进行冷却将是安全的（AIM 1），并将与改进的短期和长期结局有关 （目标3）。为了检验这一假设，我们设计了II期多中心，随机，安全性和PK试验。 五十个婴儿（每只手臂中的n = 25个）和hie需要镇静 右美托咪定（用于加载剂量的1μg/kg，然后是0.1至0.5μg/kg/h连续输注）或吗啡 （0.02-0.03 mg/kg/剂量间歇性剂量Q 4小时IV或连续输注剂量为0.005- 0.01 mg/kg/hr）。两个机会主义的PK样品（在常规实验室时）和一个PRN PK样品 对于测量右美托胺血浆浓度，将获得不良事件（AIM 2）。 有希望的初步数据表明，右美托咪定可能会改善结果，但最佳剂量，安全性和 仍然需要确定功效。我们建议通过收集来确认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胺在该人群中的安全性 II期安全试验。这些数据将为大型III期试验提供信息，以评估该疗法的效率 降低了与新生儿时期生存的HIE的婴儿长期残疾的风险。