Caffeine for Hypoxic-Ischemic Encephalopathy

NCT03913221 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 19-0348
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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.

Conditions

Hypoxic-Ischemic Encephalopathy

Outcome Measures

Primary Outcomes (1)

• 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.

Secondary Outcomes (4)

• Number of Participants With Seizures Requiring >1 Anti-Epileptic Medication

  From the first dose of caffeine to 7 days following the final dose.

• Number of Participants With Necrotizing Enterocolitis

  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

  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

  18-24 months of age

Study Arms (2)

Low Dose Caffeine (5 mg/kg)

ACTIVE COMPARATOR

Within 24 hours of delivery, participants will receive low dose administration of Caffeine citrate.

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.

Drug: Caffeine Citrate 10 mg/kg

Interventions

Caffeine Citrate 5 mg/kg DRUG

Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 5 mg/kg IV.

Also known as: Cafcit

Low Dose Caffeine (5 mg/kg)

Caffeine Citrate 10 mg/kg DRUG

Loading dose of caffeine 20 mg/kg IV followed by two daily doses of 10 mg/kg IV.

Also known as: Cafcit

High Dose Caffeine (10 mg/kg)

Eligibility Criteria

• Age: Up to 24 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• Thrasher Research Fund: collaborator

Study Sites (1)

The University of North Carolina at Chapel Hill Newborn Critical Care Center

Chapel Hill, North Carolina, 27599, United States

Location

Related Publications (3)

• 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.

  PMID: 26387012 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.

  PMID: 16221780 BACKGROUND

• 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.

  PMID: 37587184 RESULT

MeSH Terms

Conditions

Hypoxia-Ischemia, Brain

Interventions

caffeine citrate

Condition Hierarchy (Ancestors)

Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypoxia, Brain; Vascular Diseases; Cardiovascular Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Wesley Jackson, MD, MPH
• Organization: University of North Carolina at Chapel Hill

wesley.jackson@unc.edu

984-215-3449

Study Officials

• Wesley M Jackson, MD, MPH

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: April 10, 2019
• First Posted: April 12, 2019
• Study Start: August 14, 2019
• Primary Completion: January 1, 2023
• Study Completion: December 31, 2024
• Last Updated: March 27, 2025
• Results First Posted: September 19, 2024

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Beginning 9 months and ending 36 months following article publication.
• Access Criteria: 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.

Locations

US (1)