Trial Outcomes & Findings for Caffeine for Hypoxic-Ischemic Encephalopathy (NCT NCT03913221)
NCT ID: NCT03913221
Last Updated: 2025-03-27
Results Overview
AUC0-t defines area under the plasma concentration-time curve (AUC) from administration to the last quantifiable concentration at time t.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
17 participants
Primary outcome 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.
Results posted on
2025-03-27
Participant Flow
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.
Participant milestones
| Measure |
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.
|
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.
|
|---|---|---|
|
Low Dose Cohort
STARTED
|
9
|
0
|
|
Low Dose Cohort
COMPLETED
|
9
|
0
|
|
Low Dose Cohort
NOT COMPLETED
|
0
|
0
|
|
High Dose Cohort
STARTED
|
0
|
8
|
|
High Dose Cohort
COMPLETED
|
0
|
8
|
|
High Dose Cohort
NOT COMPLETED
|
0
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Caffeine for Hypoxic-Ischemic Encephalopathy
Baseline characteristics by cohort
| Measure |
Low Dose Caffeine (5 mg/kg)
n=9 Participants
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.
|
High Dose Caffeine (10 mg/kg)
n=8 Participants
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.
|
Total
n=17 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Customized
>/= 36 weeks gestational age
|
9 Participants
n=5 Participants
|
8 Participants
n=7 Participants
|
17 Participants
n=5 Participants
|
|
Sex: Female, Male
Female
|
6 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
10 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
3 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
7 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
0 Participants
n=5 Participants
|
3 Participants
n=7 Participants
|
3 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
9 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
14 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
5 Participants
n=5 Participants
|
3 Participants
n=7 Participants
|
8 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
3 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
8 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
9 Participants
n=5 Participants
|
8 Participants
n=7 Participants
|
17 Participants
n=5 Participants
|
PRIMARY outcome
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.AUC0-t defines area under the plasma concentration-time curve (AUC) from administration to the last quantifiable concentration at time t.
Outcome measures
| Measure |
Low Dose Caffeine (5 mg/kg)
n=9 Participants
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.
|
High Dose Caffeine (10 mg/kg)
n=8 Participants
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.
|
|---|---|---|
|
Area Under Plasma Concentration-time at Time t (AUC0-t) for Caffeine
AUC (0-72)
|
1137.36 mg*hr/L
Standard Deviation 324.96
|
1177.94 mg*hr/L
Standard Deviation 134.42
|
|
Area Under Plasma Concentration-time at Time t (AUC0-t) for Caffeine
AUC (0-infinity)
|
2213.26 mg*hr/L
Standard Deviation 540.81
|
2768.25 mg*hr/L
Standard Deviation 338.06
|
SECONDARY outcome
Timeframe: 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.
Outcome measures
| Measure |
Low Dose Caffeine (5 mg/kg)
n=9 Participants
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.
|
High Dose Caffeine (10 mg/kg)
n=8 Participants
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.
|
|---|---|---|
|
Number of Participants With Seizures Requiring >1 Anti-Epileptic Medication
|
1 Participants
|
0 Participants
|
SECONDARY outcome
Timeframe: 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.
Outcome measures
| Measure |
Low Dose Caffeine (5 mg/kg)
n=9 Participants
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.
|
High Dose Caffeine (10 mg/kg)
n=8 Participants
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.
|
|---|---|---|
|
Number of Participants With Necrotizing Enterocolitis
|
0 Participants
|
0 Participants
|
SECONDARY outcome
Timeframe: During initial hospitalization, approximately 7-14 postnatal daysPopulation: Two infants died during hospitalization and did not have MRI performed.
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
Outcome measures
| Measure |
Low Dose Caffeine (5 mg/kg)
n=8 Participants
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.
|
High Dose Caffeine (10 mg/kg)
n=7 Participants
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.
|
|---|---|---|
|
Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score
Score 0
|
3 Participants
|
2 Participants
|
|
Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score
Score 1A
|
2 Participants
|
2 Participants
|
|
Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score
Score 1B
|
1 Participants
|
3 Participants
|
|
Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score
Score 2A
|
0 Participants
|
0 Participants
|
|
Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score
Score 2B
|
2 Participants
|
0 Participants
|
|
Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score
Score 3
|
0 Participants
|
0 Participants
|
SECONDARY outcome
Timeframe: 18-24 months of agePopulation: 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.
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.
Outcome measures
Outcome data not reported
Adverse Events
Low Dose Caffeine (5 mg/kg)
Serious events: 3 serious events
Other events: 8 other events
Deaths: 1 deaths
High Dose Caffeine (10 mg/kg)
Serious events: 2 serious events
Other events: 4 other events
Deaths: 1 deaths
Serious adverse events
| Measure |
Low Dose Caffeine (5 mg/kg)
n=9 participants at risk
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.
|
High Dose Caffeine (10 mg/kg)
n=8 participants at risk
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.
|
|---|---|---|
|
Surgical and medical procedures
Extracorporeal membrane oxygenation (ECMO)
|
22.2%
2/9 • Number of events 2 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
12.5%
1/8 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Nervous system disorders
Seizures
|
11.1%
1/9 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
0.00%
0/8 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Gastrointestinal disorders
Bowel perforation
|
0.00%
0/9 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
12.5%
1/8 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
Other adverse events
| Measure |
Low Dose Caffeine (5 mg/kg)
n=9 participants at risk
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.
|
High Dose Caffeine (10 mg/kg)
n=8 participants at risk
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.
|
|---|---|---|
|
Renal and urinary disorders
Acute Kidney Injury
|
22.2%
2/9 • Number of events 2 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
12.5%
1/8 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Hepatobiliary disorders
Hepatic Dysfunction
|
22.2%
2/9 • Number of events 2 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
0.00%
0/8 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
55.6%
5/9 • Number of events 5 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
25.0%
2/8 • Number of events 2 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Respiratory, thoracic and mediastinal disorders
Pulmonary Hypertension
|
11.1%
1/9 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
0.00%
0/8 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Vascular disorders
Hypotension
|
11.1%
1/9 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
12.5%
1/8 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Respiratory, thoracic and mediastinal disorders
Supraventricular Tachycardia
|
11.1%
1/9 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
0.00%
0/8 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Skin and subcutaneous tissue disorders
Subcutaneous Fat Necrosis
|
11.1%
1/9 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
0.00%
0/8 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Vascular disorders
Hypertension
|
11.1%
1/9 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
0.00%
0/8 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Hepatobiliary disorders
Disseminated Intrvascular Coagulopathy
|
11.1%
1/9 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
0.00%
0/8 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Metabolism and nutrition disorders
Hypoglycemia
|
22.2%
2/9 • Number of events 2 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
12.5%
1/8 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Metabolism and nutrition disorders
Hyperglycemia
|
0.00%
0/9 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
12.5%
1/8 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Hepatobiliary disorders
Direct Hyperbilirubinemia
|
11.1%
1/9 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
0.00%
0/8 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
|
Nervous system disorders
Seizures
|
0.00%
0/9 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
12.5%
1/8 • Number of events 1 • From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
|
Additional Information
Wesley Jackson, MD, MPH
University of North Carolina at Chapel Hill
Phone: 984-215-3449
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place