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NCT Number: NCT03913221

Caffeine for 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.

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Key information

Conditions

Hypoxic-Ischemic Encephalopathy Brain Diseases Brain Ischemia Cardiovascular Diseases Central Nervous System Diseases Cerebrovascular Disorders Hypoxia Hypoxia, Brain Hypoxia-Ischemia, Brain Nervous System Diseases Pathological Conditions, Signs and Symptoms Signs and Symptoms Signs and Symptoms, Respiratory Vascular Diseases

Age range

Up to 24 hour

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

The University of North Carolina at Chapel Hill Newborn Critical Care Center

Chapel Hill, North Carolina, 27599, United States

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Caffeine Citrate 5 mg/kg

Drug

Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 5 mg/kg IV.

Other names: Cafcit

Caffeine Citrate 10 mg/kg

Drug

Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 10 mg/kg IV.

Other names: Cafcit

Primary outcomes

  1. Area Under Plasma Concentration-time at Time t (AUC0-t) for Caffeine

    Time frame: 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.

    AUC0-t defines area under the plasma concentration-time curve (AUC) from administration to the last quantifiable concentration at time t.

Secondary outcomes

  1. Number of Participants With Seizures Requiring >1 Anti-Epileptic Medication

    Time frame: From the first dose of caffeine to 7 days following the final dose.

    As a potential complication of caffeine exposure, seizure activity requiring >1 anti-epileptic medication is reported.

  2. Number of Participants With Necrotizing Enterocolitis

    Time frame: From the first dose of caffeine to 7 days following the final dose.

    As a potential complication of caffeine exposure, the number of participants with necrotizing enterocolitis defined as Bell Stage II or III are reported.

  3. Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score

    Time frame: During initial hospitalization, approximately 7-14 postnatal days

    The National Institute of Child Health and Human Development (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. A higher score is considered a worse outcome.

    • 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

  4. Number of Participants With a Bayley Scales of Infant Development (BSID-III) Cognitive, Language, or Motor Composite Score < 85

    Time frame: 18-24 months of age

    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.

Sponsors and collaborators

Lead sponsor

University of North Carolina, Chapel Hill

Other

Collaborators

  • Thrasher Research Fund

Registry information

Official study title

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

Important dates

Study start
2019
Primary completion
2023
Study completion
2024
First posted
Apr 12, 2019
Registry last updated
Mar 27, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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