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| Name | Class |
|---|---|
| Thrasher Research Fund | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Low Dose Caffeine (5 mg/kg) | Active Comparator | Within 24 hours of delivery, participants will receive low dose administration of Caffeine citrate. |
|
| High Dose Caffeine (10 mg/kg) | Active Comparator | Within 24 hours of delivery, participants will receive high dose administration of Caffeine citrate. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Caffeine Citrate 5 mg/kg | Drug | Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 5 mg/kg IV. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | From the first dose of caffeine to 7 days following the final dose. |
| Number of Participants With Necrotizing Enterocolitis |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Wesley M Jackson, MD, MPH | University of North Carolina, Chapel Hill | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The University of North Carolina at Chapel Hill Newborn Critical Care Center | Chapel Hill | North Carolina | 27599 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26387012 | Background | 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. | |
| 16221780 |
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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.
Beginning 9 months and ending 36 months following article publication.
Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata.
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Low Dose Cohort |
| |||||||||||||
| High Dose Cohort |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | High Dose Caffeine (10 mg/kg) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Standard Deviation | mg*hr/L | 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. |
|
From the first dose of study intervention through 7 days after the last dose of study intervention, approximately 10 days.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Extracorporeal membrane oxygenation (ECMO) | Surgical and medical procedures | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute Kidney Injury | Renal and urinary disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Wesley Jackson, MD, MPH | University of North Carolina at Chapel Hill | 984-215-3449 | wesley.jackson@unc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 26, 2019 | Sep 19, 2023 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D020925 | Hypoxia-Ischemia, Brain |
| ID | Term |
|---|---|
| D002545 | Brain Ischemia |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| C026189 | caffeine citrate |
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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.
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| Caffeine Citrate 10 mg/kg | Drug | Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 10 mg/kg IV. |
|
|
As a potential complication of caffeine exposure, the number of participants with necrotizing enterocolitis defined as Bell Stage II or III are reported. |
| 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.
| 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. | 18-24 months of age |
| Background |
| 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. |
| 37587184 | Result | 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. |
| NOT COMPLETED |
|
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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | 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.
|
|
| 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. | Posted | Count of Participants | Participants | From the first dose of caffeine to 7 days following the final dose. |
|
|
|
| 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. | Posted | Count of Participants | Participants | 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 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.
| Two infants died during hospitalization and did not have MRI performed. | Posted | Count of Participants | Participants | 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. | 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. | Posted | 18-24 months of age |
|
|
| 1 |
| 9 |
| 3 |
| 9 |
| 8 |
| 9 |
| EG001 | 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. | 1 | 8 | 2 | 8 | 4 | 8 |
| Seizures | Nervous system disorders | Systematic Assessment | Seizures requiring more than 1 anti-convulsant medication |
|
| Bowel perforation | Gastrointestinal disorders | Systematic Assessment |
|
| Hepatic Dysfunction | Hepatobiliary disorders | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Pulmonary Hypertension | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Hypotension | Vascular disorders | Systematic Assessment |
|
| Supraventricular Tachycardia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Subcutaneous Fat Necrosis | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Hypertension | Vascular disorders | Systematic Assessment |
|
| Disseminated Intrvascular Coagulopathy | Hepatobiliary disorders | Systematic Assessment |
|
| Hypoglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyperglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Direct Hyperbilirubinemia | Hepatobiliary disorders | Systematic Assessment |
|
| Seizures | Nervous system disorders | Systematic Assessment |
|
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| D009422 | Nervous System Diseases |
| D002534 | Hypoxia, Brain |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D000860 | Hypoxia |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Score 1B |
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| Score 2A |
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| Score 2B |
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| Score 3 |
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