Hypoxic-Ischemic EncephalopathyPhase 1NCT03913221
Caffeine for Hypoxic-Ischemic Encephalopathy
A Phase 1 study testing Caffeine Citrate 5 mg/kg and Caffeine Citrate 10 mg/kg in people with Hypoxic-Ischemic Encephalopathy, run by University of North Carolina, Chapel Hill at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages Up to 24 hours
- Conditions the study is for
- Hypoxic-Ischemic Encephalopathy
- What is being tested?
- Caffeine Citrate 5 mg/kg and Caffeine Citrate 10 mg/kg
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Aug 2019to 31 Dec 2024
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 24 hours
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
The University of North Carolina at Chapel Hill Newborn Critical Care Center
Chapel Hill, North Carolina, 27599
About this study
Official title: Pharmacokinetics and Safety of Caffeine in Neonates With Hypoxic-Ischemic Encephalopathy
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.
- Conditions
- Hypoxic-Ischemic Encephalopathy
- Being tested
- Caffeine Citrate 5 mg/kg, Caffeine Citrate 10 mg/kg
- Medical subject headings
- Hypoxia-Ischemia, Brain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Caffeine Citrate 5 mg/kgDrug
Also called Cafcit
Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 5 mg/kg IV.
Caffeine Citrate 10 mg/kgDrug
Also called Cafcit
Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 10 mg/kg IV.
| Study group | Role | What they receive |
|---|---|---|
| Low Dose Caffeine (5 mg/kg) | Active comparator | Within 24 hours of delivery, participants will receive low dose administration of Caffeine citrate. Receives: Drug: Caffeine Citrate 5 mg/kg |
| High Dose Caffeine (10 mg/kg) | Active comparator | Within 24 hours of delivery, participants will receive high dose administration of Caffeine citrate. Receives: Drug: Caffeine Citrate 10 mg/kg |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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 (4)
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.
Measured: From the first dose of caffeine to 7 days following the final dose.
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.
Measured: From the first dose of caffeine to 7 days following the final dose.
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
Measured: During initial hospitalization, approximately 7-14 postnatal days
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.
Measured: 18-24 months of age
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Apr 2019
- Study start14 Aug 2019
- Primary completion1 Jan 2023
- Study completion31 Dec 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Hypoxic-Ischemic EncephalopathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- 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.
- Masking
- None (open label)
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of North Carolina, Chapel Hill
- Sponsor type
- University, hospital or other
- Collaborators
- Thrasher Research Fund
- Responsible party
- Sponsor
- Investigators
- Wesley M Jackson, MD, MPH, Principal investigator, University of North Carolina, Chapel Hill
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03913221
- Sponsor's protocol ID
- 19-0348
- Status last verified
- Jan 2025
- First submitted
- 10 Apr 2019
- Last updated
- 27 Mar 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
Publications
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.
PubMed 26387012Shankaran 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.
PubMed 16221780Jackson 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.
PubMed 37587184
Study at a glance
From the registry record, last updated by the sponsor on 27 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetics and Safety of Caffeine in Neonates With Hypoxic-Ischemic Encephalopathy
- ClinicalTrials.gov ID
- NCT03913221
- Acronym / sponsor ID
- 19-0348
- Conditions
- Hypoxic-Ischemic Encephalopathy
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- University of North Carolina, Chapel HillUniversity, hospital or other
- Collaborators
- Thrasher Research Fund
- Study start
- 14 Aug 2019 (actual)
- Primary completion
- 1 Jan 2023 (actual)
- Study completion
- 31 Dec 2024 (actual)
- First posted
- 12 Apr 2019 (actual)
- Results
- Posted 19 Sep 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Low Dose Caffeine (5 mg/kg) | Active comparator | Drug: Caffeine Citrate 5 mg/kgWithin 24 hours of delivery, participants will receive low dose administration of Caffeine citrate. |
| High Dose Caffeine (10 mg/kg) | Active comparator | Drug: Caffeine Citrate 10 mg/kgWithin 24 hours of delivery, participants will receive high dose administration of Caffeine citrate. |
Who may qualify
- Ages
- Up to 24 hours
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (4 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Caffeine Citrate 5 mg/kgAlso: CafcitLoading dose of caffeine 20 mg/kg IV followed by two daily doses of 5 mg/kg IV. | Drug | Low Dose Caffeine (5 mg/kg) |
| Caffeine Citrate 10 mg/kgAlso: CafcitLoading dose of caffeine 20 mg/kg IV followed by two daily doses of 10 mg/kg IV. | Drug | High Dose Caffeine (10 mg/kg) |
Primary outcome
Area Under Plasma Concentration-time at Time t (AUC0-t) for Caffeine
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.
AUC0-t defines area under the plasma concentration-time curve (AUC) from administration to the last quantifiable concentration at time t.
4 secondary outcomes
Number of Participants With Seizures Requiring >1 Anti-Epileptic Medication
Time frame: From the first dose of caffeine to 7 days following the final dose.
Number of Participants With Necrotizing Enterocolitis
Time frame: From the first dose of caffeine to 7 days following the final dose.
Number of Participants With Abnormal MRI Brain Findings Based on NICHD Neonatal Research Network Score
Time frame: During initial hospitalization, approximately 7-14 postnatal days
Number of Participants With a Bayley Scales of Infant Development (BSID-III) Cognitive, Language, or Motor Composite Score < 85
Time frame: 18-24 months of age
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Mar 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 26387012Shankaran 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.
- Background: PubMed 16221780Shankaran 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.
- Results publication: PubMed 37587184Jackson 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.
- Individual participant dataSharing planned: Yes. Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
Related trials for Hypoxic-Ischemic Encephalopathy
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Levetiracetam as an Adjuvant Therapy to Hypothermia in Neonatal Asphyxia
Hypoxic Ischemic Encephalopathy of Newborn, Neuro-protection
Recruiting
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Out-of-Hospital Cardiac Arrest, Hypoxic-Ischemic Brain Injury
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The PROTECT-HIE Pilot Trial
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Recruiting
Neuro-MoD: Neuroplasticity With Motor Development
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Wesley M Jackson, MD, MPH principal investigator
University of North Carolina, Chapel Hill
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Caffeine Citrate 5 mg/kg and Caffeine Citrate 10 mg/kg in people with Hypoxic-Ischemic Encephalopathy, run by University of North Carolina, Chapel Hill at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Sep 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Area Under Plasma Concentration-time at Time t (AUC0-t) for Caffeine (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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03913221, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Mar 2025.