Caffeine for Hypoxic-Ischemic Encephalopathy

Pharmacokinetics and Safety of Caffeine in Neonates With Hypoxic-Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy (HIE) due to perinatal asphyxia is common and often fatal. Therapeutic hypothermia reduces mortality and morbidity in infants with HIE. Even with the widespread use of therapeutic hypothermia, ~60% of infants with HIE die or have neurodevelopmental impairment. As a result, there is an urgent, unmet public health need to develop adjuvant therapies to improve survival and neurodevelopmental outcomes in this population.

Caffeine may offer neuroprotection for infants with HIE by blocking adenosine receptors in the brain and reducing neuronal cell death. In animal models of HIE, caffeine reduces white matter brain injury. Drugs in the same class as caffeine (i.e., methylxanthines) have been shown to be protective against acute kidney injury in the setting of HIE. However, their safety and efficacy have not been studied in the setting of therapeutic hypothermia and their effect on neurological outcomes is not known. Since these drugs reduce injury to the kidney in infants with HIE, they may also reduce injury to the brain.

This phase I study will evaluate the pharmacokinetics, safety, and preliminary effectiveness of caffeine as an adjuvant therapy to improve neurodevelopmental outcomes in infants with HIE.

Study Overview

• Status: Active, not recruiting
• Conditions: Hypoxic-Ischemic Encephalopathy
• Intervention / Treatment: Drug: Caffeine Citrate 5 mg/kg; Drug: Caffeine Citrate 10 mg/kg

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • The University of North Carolina at Chapel Hill Newborn Critical Care Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 day (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Documented informed consent from parent or guardian
• ≥ 36 weeks gestational age at birth
• Receiving therapeutic hypothermia for a diagnosis of HIE
• Intravenous (IV) access
• Postnatal age < 24 hours

Exclusion Criteria:

• Receiving > 1 anti-epileptic drug for seizures
• Sustained (>4 hours) heart rate > 180 beats per minute
• Known major congenital anomaly
• Any condition which would make the participant, in the opinion of the investigator, unsuitable for the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Low Dose Caffeine (5 mg/kg); Within 24 hours of delivery, participants will receive low dose administration of Caffeine citrate.	Drug: Caffeine Citrate 5 mg/kg; Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 5 mg/kg IV.; Other Names: Cafcit
Active Comparator: High Dose Caffeine (10 mg/kg); Within 24 hours of delivery, participants will receive high dose administration of Caffeine citrate.	Drug: Caffeine Citrate 10 mg/kg; Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 10 mg/kg IV.; Other Names: Cafcit

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under Plasma Concentration-time at Time t (AUC0-t) for Caffeine	AUC0-t defines area under the plasma concentration-time curve (AUC) from administration to the last quantifiable concentration at time t.	7 samples will be collected with the following optimal sampling windows: 0-15 minutes, 30-60 minutes, 1-3 hours, 3-6 hours, 6-12 hours, 12-18 hours, 15 minutes prior to next dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of seizures and necrotizing enterocolitis, which are potential complications of caffeine exposure	Incidence of seizure activity requiring >1 anti-epileptic medication. Necrotizing enterocolitis defined as Bell Stage II or III.	From the first dose of caffeine to 7 days following the final dose.
Number of participants with abnormal MRI brain findings based on NICHD Neonatal Research Network score	The NICHD Neonatal Research Network developed and validated an MRI scoring system that categorizes severity of brain injury in the Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy.; Score 0: Normal T2 MRI; Score 1A: Minimal cerebral lesions only with involvement of basal ganglia, thalamus; Score 1B: Extensive cerebral lesions; Score 2A: Basal ganglia thalamic, anterior or posterior limb of internal capsule, or watershed infarction; Score 2B: 2A with cerebral lesions; Score 3: Hemispheric devastation	During initial hospitalization, approximately 7-14 postnatal days
Number of participants with a Bayley Scales of Infant Development (BSID-III) cognitive, language, or motor composite score < 85	The BSID--III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The composite scores are scaled to a metric with a range of 40 to 160, a mean of 100, and a standard deviation of 15. Therefore, children with a composite score < 85 are 1 standard deviation below the mean in that area.	18-24 months of age

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: Thrasher Research Fund
• Investigators: Principal Investigator: Wesley M Jackson, MD, MPH, University of North Carolina, Chapel Hill

Publications and helpful links

General Publications

• Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005 Oct 13;353(15):1574-84. doi: 10.1056/NEJMcps050929.
• Shankaran S, McDonald SA, Laptook AR, Hintz SR, Barnes PD, Das A, Pappas A, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy. J Pediatr. 2015 Nov;167(5):987-93.e3. doi: 10.1016/j.jpeds.2015.08.013. Epub 2015 Sep 16.

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2019
• Primary Completion (Actual): January 1, 2023
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: April 10, 2019
• First Submitted That Met QC Criteria: April 10, 2019
• First Posted (Actual): April 12, 2019

Study Record Updates

• Last Update Posted (Estimate): January 11, 2023
• Last Update Submitted That Met QC Criteria: January 10, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Respiratory; Hypoxia, Brain; Brain Ischemia; Ischemia; Brain Diseases; Hypoxia; Hypoxia-Ischemia, Brain; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Purinergic Antagonists; Purinergic Agents; Anticoagulants; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Chelating Agents; Sequestering Agents; Central Nervous System Stimulants; Calcium Chelating Agents; Caffeine; Citric Acid; Sodium Citrate; Caffeine citrate
• Other Study ID Numbers: 19-0348

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication.
• IPD Sharing Access Criteria: Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata.
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No