Clinical trial NCT03913221: Caffeine for Hypoxic-Ischemic Encephalopathy
Official title: Pharmacokinetics and Safety of Caffeine in Neonates With Hypoxic-Ischemic Encephalopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hypoxic-Ischemic Encephalopathy
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: Thrasher Research Fund
First posted: 2019-04-12
Enrollment: 17
Sex: ALL
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Area Under Plasma Concentration-time at Time t (AUC0-t) for Caffeine
timeFrame: 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 outcomes:
measure: Number of Participants With Seizures Requiring >1 Anti-Epileptic Medication
timeFrame: From the first dose of caffeine to 7 days following the final dose.
measure: Number of Participants With Necrotizing Enterocolitis
timeFrame: From the first dose of caffeine to 7 days following the final dose.
measure: Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score
timeFrame: During initial hospitalization, approximately 7-14 postnatal days
measure: Number of Participants With a Bayley Scales of Infant Development (BSID-III) Cognitive, Language, or Motor Composite Score < 85
timeFrame: 18-24 months of age
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: The University of North Carolina at Chapel Hill Newborn Critical Care Center
state: North Carolina
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Wesley M Jackson, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.
citation: Jackson W, Gonzalez D, Greenberg RG, Lee YZ, Laughon MM. A phase I trial of caffeine to evaluate safety in infants with hypoxic-ischemic encephalopathy. J Perinatol. 2024 Apr;44(4):508-512. doi: 10.1038/s41372-023-01752-y. Epub 2023 Aug 16.