PK and Safety of Caffeine in Neonates With Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia

Study Overview
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Brief Summary
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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.

Detailed Description
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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. General Experimental Approach: A total of 18 neonates will be enrolled over approximately 18 months. Each neonate will receive a single dose of caffeine in the first 24 hours of life. The first six neonates will receive low dose (5 mg/kg), the next six neonates will receive a medium dose (15 mg/kg), and the next six neonates will receive high dose or (25 mg/kg). Demographic data (birthdate, sex, ethnicity, race, gestational age) and clinical data (perinatal birth history, other diagnosis) will be collected from the electronic medical record input into a secure REDCap database created uniquely for this study. Laboratory (serum creatinine) and imaging (head ultrasound and brain MRIs) results will also be recorded. Blood samples will be obtained from the newborns to monitor the caffeine blood levels. Urine samples will be analyzed for biomarkers that detect kidney damage. Data on seizures and medications will be monitored closely. Blood flow and oxygen levels in the kidney will be monitored with a non-invasive technology called near infrared spectroscopy or NIRS. Data will be collected on urine output and blood creatinine levels to determine which newborns have acute kidney injury. In conclusion, this study will investigate the drug levels in the blood of caffeine in neonates with HIE receiving therapeutic hypothermia. Safety will also be monitored obtained. The investigators anticipate caffeine is a safe and effective therapy. This study is an essential first step to develop caffeine as a kidney protective medication in this in this vulnerable group of newborns.

Official Title
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Pharmacokinetics (PK) and Safety of Caffeine in Neonates With Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia

Conditions
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Acute Kidney Injury, Hypoxic-Ischemic Encephalopathy, Caffeine

Intervention / Treatment
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* Drug: Caffeine citrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 0 Hours
Maximum Age: 24 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Each neonate will receive a single dose of caffeine citrate in the first 24 hours of life. The first six neonates will receive low dose (5 mg/kg), the next six neonates will receive a medium dose (15 mg/kg), and the next six neonates will receive high dose or (25 mg/kg).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1: Low dose caffeine<br>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). | Drug: Caffeine citrate<br>* A single dose of intravenous caffeine citrate will be administered to neonates with hypoxic ischemic encephalopathy to determine the pharmacokinetics and tolerability.<br>* Other names: Cafcit;|
| Active Comparator: Arm 2: Medium dose caffeine<br>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). | Drug: Caffeine citrate<br>* A single dose of intravenous caffeine citrate will be administered to neonates with hypoxic ischemic encephalopathy to determine the pharmacokinetics and tolerability.<br>* Other names: Cafcit;|
| Active Comparator: Arm 3: High dose caffeine<br>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). | Drug: Caffeine citrate<br>* A single dose of intravenous caffeine citrate will be administered to neonates with hypoxic ischemic encephalopathy to determine the pharmacokinetics and tolerability.<br>* Other names: Cafcit;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clearance of caffeine | Clearance (mL h-1 kg-1) | 1 week | 
| Volume of distribution of caffeine | Volume of distribution (ml/kg) | 1 week | 
| Peak plasma concentration (Cmax) of caffeine | Peak plasma concentration (Cmax) (ng/mL) | 1 week | 
| Area under the plasma concentration-time curve of caffeine | Area under the plasma concentration-time curve from 0 to infinity (AUC0-INF) (mg*h/L) | 1 week | 
| Seizure incidence | Number of neonates who developed seizures based on continuous video electroencephalogram (VEEG) data | 2 weeks | 
| Seizure burden | Electrographic seizures (in minutes per hour) based on continuous video electroencephalogram (VEEG) data | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute kidney injury | AKI incidence utilizing KDIGO criteria based on urine output and SCr. | 10 days | 
| Renal near infrared spectroscopy (NIRS) | Investigate changes in renal NIRS values during the therapeutic hypothermia and rewarming period. | 5 days | 
| Urine neutrophil gelatinase-associated lipocalin (NGAL) (ng/mL) | Urine samples will be collected at 24, 48 and 72 hours after birth. Urine will be analyzed for NGAL. | 3 days | 
| Urine kidney injury molecule-1 (KIM-1) (pg/mL) | Urine samples will be collected at 24, 48 and 72 hours after birth. Urine will be analyzed for KIM-1. | 3 days | 
| Urine interleukin-18 (IL-18) (pg/mL) | Urine samples will be collected at 24, 48 and 72 hours after birth. Urine will be analyzed for IL-18. | 3 days |