Pharmacokinetics (PK) and Safety of Caffeine in Neonates With Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 2
- 主要终点
- Volume of distribution of caffeine
研究概览
简要总结
A phase 1 study investigating the tolerability and pharmacokinetics of caffeine citrate in neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia. This study is an essential first step to develop caffeine as a kidney protective medication in this in this vulnerable group of newborns.
详细描述
Neonatal acute kidney injury (AKI) is an unfortunate comorbidity in neonates with hypoxic ischemic encephalopathy (HIE) which is brain injury due to a lack of blood flow and oxygen delivery to a neonate around the time of delivery. Neonatal AKI increases the risk of death by 4 fold. AKI in neonates with HIE is associated with brain injury on brain MRI and worse neurodevelopmental outcomes at 2 years. Despite the increases in death and morbidity associated with AKI, limited therapeutic interventions currently exist.
Caffeine is a promising medication for kidney protection in neonates at high risk for AKI. Three retrospective studies in premature neonates identified a reduction in AKI in neonates exposed to caffeine. Theophylline, which is in the same drug class as caffeine, has been shown to improve urine output and decrease AKI in neonates with HIE. Limited centers worldwide utilize theophylline in neonates with HIE due to its side effects. Caffeine is a well-tolerated and is extensively utilized in neonatal intensive care units (NICUs) in the premature population for prevention of chronic lung disease and for apnea of prematurity (or immature breathing patterns). Therefore, dosing guidelines are well established for preterm neonates and neonatologists are comfortable administering the drug.
Specific Aim 1: Determine the pharmacokinetics (how an organism affects a drug) of caffeine in neonates ≥ 35 weeks GA with HIE receiving therapeutic hypothermia.
Specific Aim 2: Assess the preliminary safety and tolerability of caffeine in neonates with HIE receiving hypothermia including any impact on seizure burden.
Specific Aim 1: Characterize acute kidney injury (AKI) in neonates with HIE receiving therapeutic hypothermia with caffeine exposure using serum creatinine (SCr), urine output, renal near infrared spectroscopy (NIRS), and urinary biomarkers.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 0 Hours 至 24 Hours（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newborns ≥ 35 weeks GA
- •Admitted to the ACH NICU less than 24 hours of life
- •Receiving active or passive TH or whole-body cooling at 12 hours of life to treat hypoxic ischemic encephalopathy per institutional criteria based on National Institute of Child Health and Human Development criteria
排除标准
- •Genetic or congenital condition that affects renal function (e.g., congenital anomalies of the kidney and urinary tract (CAKUT), complex congenital heart disease)
- •Diminished capacity or autonomy of the neonate's parents that prevents their ability to give informed consent
- •Theophylline, aminophylline, or caffeine exposure prior to enrollment
- •Status epilepticus as defined by:
- •A seizure lasting longer than 30 minutes
- •Use of a continuous infusion of antiepileptic medication (i.e., midazolam)
- •The use of 3 or more antiepileptic medications for the indications of intractable seizures
研究组 & 干预措施
Arm 1: Low dose caffeine
Each neonate will receive a single dose of caffeine citrate in the first 24 hours of life. Arm 1 neonates will receive low dose intravenous caffeine citrate (5 mg/kg).
干预措施: Caffeine citrate (Drug)
Arm 2: Medium dose caffeine
Each neonate will receive a single dose of caffeine citrate in the first 24 hours of life. Arm 2 neonates will receive medium dose intravenous caffeine citrate (15 mg/kg).
干预措施: Caffeine citrate (Drug)
Arm 3: High dose caffeine
Each neonate will receive a single dose of caffeine citrate in the first 24 hours of life. Arm 3 neonates will receive high dose intravenous caffeine citrate (25 mg/kg).
干预措施: Caffeine citrate (Drug)
结局指标
主要结局
Volume of distribution of caffeine
时间窗: 1 week
Volume of distribution (ml/kg)
Peak plasma concentration (Cmax) of caffeine
时间窗: 1 week
Peak plasma concentration (Cmax) (ng/mL)
Clearance of caffeine
时间窗: 1 week
Clearance (mL h-1 kg-1)
Area under the plasma concentration-time curve of caffeine
时间窗: 1 week
Area under the plasma concentration-time curve from 0 to infinity (AUC0-INF) (mg\*h/L)
Seizure incidence
时间窗: 2 weeks
Number of neonates who developed seizures based on continuous video electroencephalogram (VEEG) data
Seizure burden
时间窗: 2 weeks
Electrographic seizures (in minutes per hour) based on continuous video electroencephalogram (VEEG) data
次要结局
- Acute kidney injury(10 days)
- Urine interleukin-18 (IL-18) (pg/mL)(3 days)
- Urine neutrophil gelatinase-associated lipocalin (NGAL) (ng/mL)(3 days)
- Renal near infrared spectroscopy (NIRS)(5 days)
- Urine kidney injury molecule-1 (KIM-1) (pg/mL)(3 days)