Caffeine for Hypoxic-Ischemic Encephalopathy

Hypoxic-Ischemic Encephalopathy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03913221
• Other study ID #: 19-0348
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: July 12, 2019
• Est. completion date: December 2024

Study information

• Verified date: January 2023
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 17
• Est. completion date: December 2024
• Est. primary completion date: January 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 24 Hours

Eligibility

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

Related Conditions & MeSH terms

• Brain Diseases
• Brain Ischemia
• Hypoxia
• Hypoxia-Ischemia, Brain
• Hypoxic-Ischemic Encephalopathy
• Ischemia

Intervention

Drug:
• Caffeine Citrate 5 mg/kg
Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 5 mg/kg IV.
• Caffeine Citrate 10 mg/kg
Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 10 mg/kg IV.

Locations

Country	Name	City	State
United States	The University of North Carolina at Chapel Hill Newborn Critical Care Center	Chapel Hill	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	Thrasher Research Fund

Country where clinical trial is conducted

United States, 

References & Publications (2)

Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005 Oct 13;353(15):1574-84. doi: 10.1056/NEJMcps050929. — View Citation

Shankaran S, McDonald SA, Laptook AR, Hintz SR, Barnes PD, Das A, Pappas A, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy. J Pediatr. 2015 Nov;167(5):987-93.e3. doi: 10.1016/j.jpeds.2015.08.013. Epub 2015 Sep 16. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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
Secondary	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