NCT06855108

Caffeine for Hypoxic Ischemic Encephalopathy

Caffeine for Hypoxic Ischemic Encephalopathy (CHIME Trial)

• Status: Not Yet Recruiting
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 830 (estimated)
• Sponsor: NICHD Global Network for Women's and Children's Health · Network
• Sex: All
• Age: 6 Hours
• Healthy volunteers: Not accepted

Summary

CHIME is a randomized, parallel-arm, double-blind, placebo-controlled trial focused on infants with hypoxic ischemic encephalopathy (HIE). The trial will recruit neonates who are diagnosed with HIE within six hours after birth based on physiologic criteria (acidosis noted on an umbilical cord or early \[\<1 hour\] postnatal blood sample) and neurologic criteria (modified Sarnat exam consistent with encephalopathy). Following informed consent, and by six hours after birth, neonates with HIE will be randomized to one of two treatment arms and subsequently receive one 20 mg/kg dose of oral caffeine followed by two additional 10 mg/kg doses at 24-hour intervals or placebo of the same regimen (three total doses). The goal of this clinical trial is to compare the incidence of all-cause mortality OR moderate to severe neurodevelopmental impairment (NDI) at 18-22 months between neonates with HIE who are randomized to oral caffeine or placebo. Our hypothesis is that neonates with HIE who receive oral caffeine will have 10% lower incidence of all-cause mortality or moderate to severe NDI at 18-22 months compared to placebo.

Detailed description

Background: One million newborns die annually due to intrapartum-related events (formerly referred to as birth asphyxia). Among survivors, intrapartum related events often lead to organ dysfunction with lasting consequences, including severe morbidity and neurodevelopmental impairment (NDI). Newborns exposed to significant intrapartum-related events can have brain injury, referred to as hypoxic ischemic encephalopathy (HIE). HIE is routinely treated with therapeutic hypothermia. However, a recent multi-national randomized controlled trial demonstrated that therapeutic hypothermia increased mortality from HIE in some contexts. Therefore, there is an urgent, unmet public health need to develop effective strategies for the treatment of HIE to prevent morbidity and mortality. Caffeine, a low-cost, readily available medication is a promising strategy for treatment of HIE given its neuroprotective, anti-inflammatory, and anti-oxidative properties. Furthermore, caffeine might have physiologic benefits beyond HIE, because a single dose of a methylxanthine (caffeine's drug class) reduces acute kidney injury in infants with HIE in settings where therapeutic hypothermia is not available. Objective: To compare the incidence of all-cause mortality OR moderate to severe NDI at 18-22 months between neonates with HIE who are randomized to oral caffeine or placebo. Hypothesis: Neonates with HIE who receive oral caffeine will have 10% lower incidence of all-cause mortality or moderate to severe NDI at 18-22 months compared to placebo. Study Design: 1:1 individually randomized, parallel-arm, double-blind, placebo-controlled trial Population: ≥ 36 week gestation and ≥1800 grams liveborn neonates who meet both physiologic and neurologic criteria for moderate to severe HIE and live in the Global Network research sites Intervention: The intervention arm will receive one 20 mg/kg loading dose of caffeine given within 6 hours of delivery, followed by a daily dose of 10 mg/kg, given every 24 hours for 2 doses (total of 3 doses). Comparison: The comparison arm will receive placebo using an identical dosing regimen. Primary outcomes: All-cause mortality or moderate to severe NDI at 18-22 months of age Sub-Studies: In conjunction with the CHIME Trial, we will embed 3 sub-studies to be conducted within subsets of CHIME participants. A sample will be chosen by convenience for each sub-study. Pharmacokinetics Sub-study: For approximately 40 participants per Global Network research site, we will collect 2-3 blood samples during the birth hospitalization for pharmacokinetic (PK) analysis of caffeine. We will use a population PK approach to characterize the PK of infants with HIE, and to relate caffeine exposure to mortality or moderate to severe disability. Neuro-imaging Sub-Study: For participants who are born at or follow-up in a facility with the capability of performing ultra-low-field (ULF) magnetic resonance imaging (MRI), we will obtain ULF MRI brain images during the birth hospitalization and at the 6-month follow-up visit. We will relate the findings on ULF MRI to the severity of HIE at enrollment and to the neurodevelopmental outcomes. Omics Sub-Study: For participants for whom cord blood is available, we will obtain a sample of cord blood to be stored for future multi-omic analyses (e.g., genomic, transcriptomic, proteomic, and metabolomic). We will use multi-omics to identify molecular signatures associated with HIE.

Conditions

• Hypoxic Ischemic Encephalopathy (HIE)

Interventions

Type	Name	Description
DRUG	Caffeine citrate oral solution	Caffeine citrate oral solution will be used and administered by enteral route (oral or by gavage tube). The loading dose (20 mg/kg) will be administered once followed by daily doses of 10 mg per kg body weight every 24 hours for two doses. The study Standard Operating Procedures (SOPs) includes details regarding caffeine preparation based on the participant's body weight.
DRUG	Oral placebo solution	Identical placebo oral solution

Timeline

• Start date: 2025-06-01
• Primary completion: 2029-12-01
• Completion: 2030-07-01
• First posted: 2025-03-03
• Last updated: 2025-03-03

Locations

7 sites across 6 countries: Bangladesh, Democratic Republic of the Congo, Guatemala, India, Pakistan, Zambia