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

Acute Kidney Injury Clinical Trial

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT05295784
• Other study ID #: 260845
• Status: Withdrawn
• Phase: Phase 1
• Start date: May 8, 2024
• Est. completion date: May 8, 2024

Study information

• Verified date: April 2024
• Source: University of Arkansas
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: May 8, 2024
• Est. primary completion date: May 8, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Hours to 24 Hours

Eligibility

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

Related Conditions & MeSH terms

• Acute Kidney Injury
• Brain Diseases
• Brain Ischemia
• Caffeine
• Hypothermia
• Hypoxia
• Hypoxia-Ischemia, Brain
• Hypoxic-Ischemic Encephalopathy
• Ischemia

Intervention

Drug:
• Caffeine citrate
A single dose of intravenous caffeine citrate will be administered to neonates with hypoxic ischemic encephalopathy to determine the pharmacokinetics and tolerability.

Locations

Country	Name	City	State
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas

Sponsors (1)

Lead Sponsor	Collaborator
University of Arkansas

Country where clinical trial is conducted

United States, 

References & Publications (33)

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* Note: There are 33 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clearance of caffeine	Clearance (mL h-1 kg-1)	1 week
Primary	Volume of distribution of caffeine	Volume of distribution (ml/kg)	1 week
Primary	Peak plasma concentration (Cmax) of caffeine	Peak plasma concentration (Cmax) (ng/mL)	1 week
Primary	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
Primary	Seizure incidence	Number of neonates who developed seizures based on continuous video electroencephalogram (VEEG) data	2 weeks
Primary	Seizure burden	Electrographic seizures (in minutes per hour) based on continuous video electroencephalogram (VEEG) data	2 weeks
Secondary	Acute kidney injury	AKI incidence utilizing KDIGO criteria based on urine output and SCr.	10 days
Secondary	Renal near infrared spectroscopy (NIRS)	Investigate changes in renal NIRS values during the therapeutic hypothermia and rewarming period.	5 days
Secondary	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
Secondary	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
Secondary	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