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）

基本信息

批准号：
10390861
负责人：
Mariana Baserga
金额：
$ 24.39万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-14 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10390861
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 Hypoxia-Ischemia Brain Injuries 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 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 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

项目摘要

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.

项目概要右美托咪定用于因新生儿脑病而接受降温的婴儿（DICE 试验）缺氧缺血性脑病（HIE，通常称为“出生窒息”）是一种大脑尽管进行了早期干预，但每 1,000 名婴儿中就有 2 名患有 HIE。降温、死亡或严重残疾（例如脑瘫和智力低下）的结果仍然发生在近 30% 的婴儿已被证明没有其他疗法可以进一步减少这些婴儿的脑损伤。此外，同时使用吗啡等药物可能会导致额外的脑损伤。在动物模型中使用吗啡来治疗疼痛和镇静可以增加神经元凋亡。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。 HIE 是一项紧迫且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，可能是吗啡更好的替代品患有新生儿 HIE 的新生儿使用右美托咪定进行降温治疗，可提供镇静、镇痛和镇静作用。可以防止颤抖，但不会抑制呼吸。重要的是，右美托咪定已被证明具有保护作用。最近的临床研究也表明，脑损伤动物模型的大脑结果得到改善。尽管关于脑损伤的成年患者的右美托咪定给药的数据有限。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；血液中的药物水平） HIE 已越来越多地在许多中心进行管理。我们的中心假设是右美托咪定对患有 HIE 的足月婴儿进行镇静接受冷却是安全的（AIM 1），并且与改善短期和长期结果相关 (AIM 3) 为了检验这一假设，我们设计了一项 II 期多中心、随机、安全性和 PK 试验。 50 名患有 HIE 且需要镇静的婴儿（每组 n=25）将被随机分配接受右美托咪定（负荷剂量 1 μg/kg，随后连续输注 0.1 至 0.5 μg/kg/h）或吗啡（0.02-0.03 mg/kg/剂，间歇给药，每 4 小时 IV 次，或连续输注剂量 0.005-0.01 mg/kg/hr) 两个机会性 PK 样品（在常规实验室时）和一个 PRN PK 样品（随时）。测量右美托咪定血浆浓度 (AIM 2) 时将获得不良事件。有希望的初步数据表明，右美托咪定可以改善结果，但最佳剂量、安全性和我们建议通过收集数据来确认右美托咪定的最佳剂量。机会性血液样本的 PK 数据并确定右美托咪定在该人群中的安全性 II 期安全性试验将为更大规模的 III 期试验提供信息，以评估该疗法的疗效。降低新生儿期后存活的 HIE 婴儿长期残疾的风险。