Caffeine for Hypoxic-Ischemic Encephalopathy

Phase 1

Active, not recruiting

• Conditions: Hypoxic-Ischemic Encephalopathy
• Interventions: Drug: Caffeine Citrate 10 mg/kg; Drug: Caffeine Citrate 5 mg/kg

• Registration Number: NCT03913221
• Lead Sponsor: University of North Carolina, Chapel Hill

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-04-10
• Study First Submitted QC: 2019-04-10
• Study First Posted: 2019-04-12
• Study Start: 2019-07-12
• Status Verified: 2023-01
• Primary Completion: 2023-01-01
• Last Update Submitted: 2023-01-10
• Last Update Posted: 2023-01-11
• Study Completion: 2024-12

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 17

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
High Dose Caffeine (10 mg/kg)	Caffeine Citrate 10 mg/kg	Within 24 hours of delivery, participants will receive high dose administration of Caffeine citrate.
Low Dose Caffeine (5 mg/kg)	Caffeine Citrate 5 mg/kg	Within 24 hours of delivery, participants will receive low dose administration of Caffeine citrate.

Primary Outcome Measures

Name	Time	Method
Area Under Plasma Concentration-time at Time t (AUC0-t) for Caffeine	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 Outcome Measures

Name	Time	Method
Number of Participants With Seizures Requiring >1 Anti-Epileptic Medication	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.
Number of Participants With Necrotizing Enterocolitis	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.
Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score	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
Number of Participants With a Bayley Scales of Infant Development (BSID-III) Cognitive, Language, or Motor Composite Score < 85	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.

Trial Locations

Locations (1)

The University of North Carolina at Chapel Hill Newborn Critical Care Center; 🇺🇸 Chapel Hill, North Carolina, United States