Hypoxic-Ischemic Encephalopathy
Conditions
Keywords
caffeine citrate
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.
Interventions
DRUGCaffeine citrate 20 mg/kg
Following loading dose of 20 mg/kg of caffeine citrate IV, participants will receive 2 daily doses of 10 mg/kg caffeine citrate IV.
DRUGCaffeine citrate 30 mg/kg
Following loading dose of 30 mg/kg of caffeine citrate IV, participants will receive 2 daily doses of 10 mg/kg caffeine citrate IV.
Sponsors
University of North Carolina, Chapel Hill
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The first cohort of 8 infants will receive a lower loading dose of caffeine. Following a safety review, an additional 8 infants will receive a higher loading dose.
Eligibility
Sex/Gender
ALL
Age
No minimum to 24 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORWesley M Jackson, MD, MPH
University of North Carolina, Chapel Hill
Outcome results
None listed