Hypoxic-Ischemic Encephalopathy
Conditions
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.
Interventions
Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 5 mg/kg IV.
DRUGCaffeine Citrate 10 mg/kg
Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 10 mg/kg IV.
Sponsors
Thrasher Research Fund
University of North Carolina, Chapel Hill
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
No minimum to 24 Hours
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 * Any condition which would make the participant, in the opinion of the investigator, unsuitable for the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Plasma Concentration-time at Time t (AUC0-t) for Caffeine | 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. | AUC0-t defines area under the plasma concentration-time curve (AUC) from administration to the last quantifiable concentration at time t. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Seizures Requiring >1 Anti-Epileptic Medication | From the first dose of caffeine to 7 days following the final dose. | As a potential complication of caffeine exposure, seizure activity requiring \>1 anti-epileptic medication is reported. |
| Number of Participants With Necrotizing Enterocolitis | From the first dose of caffeine to 7 days following the final dose. | As a potential complication of caffeine exposure, the number of participants with necrotizing enterocolitis defined as Bell Stage II or III are reported. |
| Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score | During initial hospitalization, approximately 7-14 postnatal days | The National Institute of Child Health and Human Development (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. A higher score is considered a worse outcome. * 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 |
| Number of Participants With a Bayley Scales of Infant Development (BSID-III) Cognitive, Language, or Motor Composite Score < 85 | 18-24 months of age | 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. |
Countries
United States
Participant flow
Recruitment details
17 infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy were enrolled at the University of North Carolina at Chapel Hill Newborn Critical Care Center between August 2019 and December 2022.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Caffeine (5 mg/kg) Within 24 hours of delivery, participants will receive low dose administration of Caffeine citrate.
Caffeine Citrate 5 mg/kg: Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 5 mg/kg IV. | 9 |
| High Dose Caffeine (10 mg/kg) Within 24 hours of delivery, participants will receive high dose administration of Caffeine citrate.
Caffeine Citrate 10 mg/kg: Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 10 mg/kg IV. | 8 |
| Total | 17 |
Baseline characteristics
| Characteristic | Low Dose Caffeine (5 mg/kg) | Total | High Dose Caffeine (10 mg/kg) |
|---|---|---|---|
| Age, Customized >/= 36 weeks gestational age | 9 Participants | 17 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 14 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 8 Participants | 5 Participants |
| Region of Enrollment United States | 9 Participants | 17 Participants | 8 Participants |
| Sex: Female, Male Female | 6 Participants | 10 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 9 | 1 / 8 |
| other Total, other adverse events | 8 / 9 | 4 / 8 |
| serious Total, serious adverse events | 3 / 9 | 2 / 8 |
Outcome results
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose Caffeine (5 mg/kg) | Area Under Plasma Concentration-time at Time t (AUC0-t) for Caffeine | AUC (0-72) | 1137.36 mg*hr/L | Standard Deviation 324.96 |
| Low Dose Caffeine (5 mg/kg) | Area Under Plasma Concentration-time at Time t (AUC0-t) for Caffeine | AUC (0-infinity) | 2213.26 mg*hr/L | Standard Deviation 540.81 |
| High Dose Caffeine (10 mg/kg) | Area Under Plasma Concentration-time at Time t (AUC0-t) for Caffeine | AUC (0-72) | 1177.94 mg*hr/L | Standard Deviation 134.42 |
| High Dose Caffeine (10 mg/kg) | Area Under Plasma Concentration-time at Time t (AUC0-t) for Caffeine | AUC (0-infinity) | 2768.25 mg*hr/L | Standard Deviation 338.06 |
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.
Time frame: 18-24 months of age
Population: Bayley-III examinations were planned at the beginning of the study per institutional standard of care. However, during the study period, clinical practice changed, and due to COVID-19 pandemic-related staff turnover, Bayley-III examinations were no longer routinely obtained in Hypoxic-ischemic encephalopathy (HIE) patients. As Bayley-III exams were not included in the study budget and were not a primary study aim, these data were not collected. The protocol was not amended with this change.
Secondary
Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score
The National Institute of Child Health and Human Development (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. A higher score is considered a worse outcome. * 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
Time frame: During initial hospitalization, approximately 7-14 postnatal days
Population: Two infants died during hospitalization and did not have MRI performed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Caffeine (5 mg/kg) | Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score | Score 0 | 3 Participants |
| Low Dose Caffeine (5 mg/kg) | Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score | Score 1A | 2 Participants |
| Low Dose Caffeine (5 mg/kg) | Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score | Score 1B | 1 Participants |
| Low Dose Caffeine (5 mg/kg) | Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score | Score 2A | 0 Participants |
| Low Dose Caffeine (5 mg/kg) | Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score | Score 2B | 2 Participants |
| Low Dose Caffeine (5 mg/kg) | Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score | Score 3 | 0 Participants |
| High Dose Caffeine (10 mg/kg) | Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score | Score 2B | 0 Participants |
| High Dose Caffeine (10 mg/kg) | Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score | Score 0 | 2 Participants |
| High Dose Caffeine (10 mg/kg) | Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score | Score 2A | 0 Participants |
| High Dose Caffeine (10 mg/kg) | Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score | Score 1A | 2 Participants |
| High Dose Caffeine (10 mg/kg) | Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score | Score 3 | 0 Participants |
| High Dose Caffeine (10 mg/kg) | Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score | Score 1B | 3 Participants |
Secondary
Number of Participants With Necrotizing Enterocolitis
As a potential complication of caffeine exposure, the number of participants with necrotizing enterocolitis defined as Bell Stage II or III are reported.
Time frame: From the first dose of caffeine to 7 days following the final dose.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Dose Caffeine (5 mg/kg) | Number of Participants With Necrotizing Enterocolitis | 0 Participants |
| High Dose Caffeine (10 mg/kg) | Number of Participants With Necrotizing Enterocolitis | 0 Participants |
Secondary
Number of Participants With Seizures Requiring >1 Anti-Epileptic Medication
As a potential complication of caffeine exposure, seizure activity requiring \>1 anti-epileptic medication is reported.
Time frame: From the first dose of caffeine to 7 days following the final dose.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Dose Caffeine (5 mg/kg) | Number of Participants With Seizures Requiring >1 Anti-Epileptic Medication | 1 Participants |
| High Dose Caffeine (10 mg/kg) | Number of Participants With Seizures Requiring >1 Anti-Epileptic Medication | 0 Participants |