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

May 8, 2024 updated by: University of Arkansas

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

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

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 Type

Interventional

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Arkansas
      • Little Rock, Arkansas, United States, 72205
        • University of Arkansas for Medical Sciences
      • Little Rock, Arkansas, United States, 72202
        • Arkansas Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 second to 1 day (Child)

Accepts Healthy Volunteers

No

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 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).
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.
Other Names:
  • Cafcit
Active Comparator: 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).
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.
Other Names:
  • Cafcit
Active Comparator: 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).
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.
Other Names:
  • Cafcit

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clearance of caffeine
Time Frame: 1 week
Clearance (mL h-1 kg-1)
1 week
Volume of distribution of caffeine
Time Frame: 1 week
Volume of distribution (ml/kg)
1 week
Peak plasma concentration (Cmax) of caffeine
Time Frame: 1 week
Peak plasma concentration (Cmax) (ng/mL)
1 week
Area under the plasma concentration-time curve of caffeine
Time Frame: 1 week
Area under the plasma concentration-time curve from 0 to infinity (AUC0-INF) (mg*h/L)
1 week
Seizure incidence
Time Frame: 2 weeks
Number of neonates who developed seizures based on continuous video electroencephalogram (VEEG) data
2 weeks
Seizure burden
Time Frame: 2 weeks
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
Time Frame: 10 days
AKI incidence utilizing KDIGO criteria based on urine output and SCr.
10 days
Renal near infrared spectroscopy (NIRS)
Time Frame: 5 days
Investigate changes in renal NIRS values during the therapeutic hypothermia and rewarming period.
5 days
Urine neutrophil gelatinase-associated lipocalin (NGAL) (ng/mL)
Time Frame: 3 days
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)
Time Frame: 3 days
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)
Time Frame: 3 days
Urine samples will be collected at 24, 48 and 72 hours after birth. Urine will be analyzed for IL-18.
3 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Arkansas

Investigators

  • Principal Investigator: Jennifer Rumpel, MD, University of Arkansas

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 8, 2024

Primary Completion (Actual)

May 8, 2024

Study Completion (Actual)

May 8, 2024

Study Registration Dates

First Submitted

February 21, 2022

First Submitted That Met QC Criteria

March 15, 2022

First Posted (Actual)

March 25, 2022

Study Record Updates

Last Update Posted (Actual)

May 10, 2024

Last Update Submitted That Met QC Criteria

May 8, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 260845

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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