Clinical trial NCT05295784: PK and Safety of Caffeine in Neonates With Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia
Official title: Pharmacokinetics (PK) and Safety of Caffeine in Neonates With Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Acute Kidney Injury
Hypoxic-Ischemic Encephalopathy
Caffeine
Lead sponsor: University of Arkansas
Sponsor class: OTHER
First posted: 2022-03-25
Enrollment: 0
Sex: ALL
Minimum age (years): 0
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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).
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Clearance of caffeine
timeFrame: 1 week
measure: Volume of distribution of caffeine
timeFrame: 1 week
measure: Peak plasma concentration (Cmax) of caffeine
timeFrame: 1 week
measure: Area under the plasma concentration-time curve of caffeine
timeFrame: 1 week
measure: Seizure incidence
timeFrame: 2 weeks
measure: Seizure burden
timeFrame: 2 weeks
Secondary outcomes:
measure: Acute kidney injury
timeFrame: 10 days
measure: Renal near infrared spectroscopy (NIRS)
timeFrame: 5 days
measure: Urine neutrophil gelatinase-associated lipocalin (NGAL) (ng/mL)
timeFrame: 3 days
measure: Urine kidney injury molecule-1 (KIM-1) (pg/mL)
timeFrame: 3 days
measure: Urine interleukin-18 (IL-18) (pg/mL)
timeFrame: 3 days
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
Study officials:
affiliation: University of Arkansas
name: Jennifer Rumpel, MD
role: PRINCIPAL_INVESTIGATOR
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