Dose Optimization of Caffeine for HIE

Phase 1

Recruiting

• Conditions: Hypoxic-Ischemic Encephalopathy
• Interventions: Drug: Caffeine citrate 20 mg/kg; Drug: Caffeine citrate 30 mg/kg

• Registration Number: NCT06448780
• Lead Sponsor: University of North Carolina, Chapel Hill

Brief Summary

This is a phase Ib, open-label, dose-validating and safety study of caffeine in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia.

Detailed Description

In a previous phase I trial (NCT03913221), the investigators characterized the pharmacokinetics (PK) of caffeine in the setting of HIE and therapeutic hypothermia using a population PK model. This is an open-label study of caffeine citrate in neonates with HIE to validate the population PK model and determine optimal dosing for HIE.

Study Timeline

• Status Verified: 2024-06
• Study First Submitted: 2024-06-03
• Study First Submitted QC: 2024-06-03
• Study First Posted: 2024-06-07
• Study Start: 2024-07-26
• Last Update Submitted: 2024-07-26
• Last Update Posted: 2024-07-29
• Primary Completion: 2026-12
• Study Completion: 2028-11

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 16

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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Lower loading dose (20 mg/kg)	Caffeine citrate 20 mg/kg	Within 24 hours after delivery, participants will receive a loading dose of 20 mg/kg caffeine citrate IV.
Higher loading dose (30 mg/kg)	Caffeine citrate 30 mg/kg	Within 24 hours after delivery, participants will receive a loading dose of 30 mg/kg caffeine citrate IV.

Primary Outcome Measures

Name	Time	Method
Apparent Caffeine Clearance	7 samples will be collected after the first dose of study drug and up to 72 hours after final dose of study drug	Clearance is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Caffeine concentrations will be used to calculate population estimates of caffeine clearance, with inter-individual variabilty and residual variabilty .
Volume of Distribution of Caffeine	7 samples will be collected after the first dose of study drug and up to 72 hours after final dose of study drug	Caffeine concentrations will be used to calculate population estimates of volume of distribution with inter-individual variability and residual variability.

Secondary Outcome Measures

Name	Time	Method
Number of Participants with Pre-Specified Adverse Events	From the first dose of caffeine to 7 days following the final dose.	Safety will be determined by the number of participants with the following: seizures requiring \> 1 anti-epileptic drug, necrotizing enterocolitis defined as Bell Stage II or higher, hypoglycemia defined as point-of-care blood glucose \< 30 mg/dL, and hyperglycemia defined as point-of-care blood glucose \>200 mg/dL.
Number of Participants with Abnormal MRI Brain Finding Score	During initial hospitalization, typically 3-5 postnatal days	Preliminary effectiveness assessed using the NICHD Neonatal Research Network MRI scoring system that categorizes severity of brain injury in the Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy. Abnormal MRI is defined as any score \>0.; * Score 0: Normal 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 Death or Neurodevelopmental Impairment	18-24 months of age	Preliminary effectiveness assessed based on death or neurodevelopmental impairment defined as: diagnosis of cerebral palsy, hearing impairment requiring hearing aids, blindness, or cognitive, language, or motor score \< 85 on the Bayley Scales of Infant and Toddler Development- Fourth Edition.

Trial Locations

Locations (1)

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