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

Phase 1

Withdrawn

• Conditions: Hypoxic-Ischemic Encephalopathy; Acute Kidney Injury; Caffeine
• Interventions: Drug: Caffeine citrate

• Registration Number: NCT05295784
• Lead Sponsor: University of Arkansas

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2022-02-21
• Study First Submitted QC: 2022-03-15
• Study First Posted: 2022-03-25
• Status Verified: 2024-04
• Study Start: 2024-05-08
• Primary Completion: 2024-05-08
• Study Completion: 2024-05-08
• Last Update Submitted: 2024-05-08
• Last Update Posted: 2024-05-10

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

1. Newborns ≥ 35 weeks GA
2. Admitted to the ACH NICU less than 24 hours of life
3. 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

1. Genetic or congenital condition that affects renal function (e.g., congenital anomalies of the kidney and urinary tract (CAKUT), complex congenital heart disease)

2. Diminished capacity or autonomy of the neonate's parents that prevents their ability to give informed consent

3. Theophylline, aminophylline, or caffeine exposure prior to enrollment

4. Status epilepticus as defined by:

   1. A seizure lasting longer than 30 minutes
   2. Use of a continuous infusion of antiepileptic medication (i.e., midazolam)
   3. The use of 3 or more antiepileptic medications for the indications of intractable seizures

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Arm 2: Medium dose caffeine	Caffeine citrate	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).
Arm 3: High dose caffeine	Caffeine citrate	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).
Arm 1: Low dose caffeine	Caffeine citrate	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).

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (2)

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States

University of Arkansas for Medical Sciences; 🇺🇸 Little Rock, Arkansas, United States