Caffeine for Hypoxic-Ischemic Encephalopathy

Study Overview
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Brief Summary
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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.

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

Conditions
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Hypoxic-Ischemic Encephalopathy

Intervention / Treatment
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* Drug: Caffeine Citrate 5 mg/kg
* Drug: Caffeine Citrate 10 mg/kg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 24 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The first cohort of 9 infants will receive a lower maintenance dose of caffeine. Following a safety review, an additional 9 infants will receive a higher maintenance dose.
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |