A Phase 3 interventional study of Caffeine citrate oral solution and Oral placebo solution in Hypoxic Ischemic Encephalopathy (HIE), sponsored by NICHD Global Network for Women's and Children's Health. Recruiting at 7 sites in 6 countries. Open to participants aged Up to 6 Hours. Per ClinicalTrials.gov, last updated 2026-06-24.
Sponsored by NICHD Global Network for Women's and Children's Health · Phase 3, Interventional, and Treatment
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.
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.
261 studies on the registry are indexed under Hypoxia-Ischemia, Brain; 95 are open to participants now.
This study's planned enrollment of 830 is above the median of 50 across 156 interventional studies indexed under Hypoxia-Ischemia, Brain.
Browse Hypoxia-Ischemia, Brain studies →NICHD Global Network for Women's and Children's Health is the lead sponsor of 33 studies on the registry; 3 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Participant Inclusion Criteria:
Infants who meet all the following criteria are eligible for enrollment as study participants:
Meets physiologic criteria for moderate to severe HIE, defined as meeting either of the following two criteria:
Criterion #1: Severe acidosis, defined as an umbilical cord sample or neonatal serum sample within one hour after birth demonstrating any of following criteria:
i. Moderate acidosis, defined as an umbilical cord sample or neonatal serum sample within one hour after birth demonstrating any of following criteria:
ii. Evidence of an acute perinatal event (i.e., placental abruption, intrapartum hemorrhage, cord prolapse, severe fetal heart rate abnormality, uterine rupture).
iii. Any of the following criteria:
Meets neurologic criteria for moderate to severe HIE, defined as a physical exam conducted between one and six hours after birth that meets either of the following criteria:
Participant Exclusion Criteria:
Infants who meet any of the following criteria are not eligible for enrollment as study participants:
Participants randomized to the oral caffeine arm will receive a single 20 mg/kg loading dose of caffeine citrate administered enterally within 6 hours after delivery, followed by a 10 mg/kg dose every 24 hours for two additional doses.
Drug: Caffeine citrate oral solution
Participants randomized to the oral placebo arm will receive a single identical placebo administered enterally within 6 hours after delivery, followed by an identical placebo dose every 24 hours for two additional doses.
Drug: Oral placebo 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.
Identical placebo oral solution
Also known as: Oral placebo
Composite outcome, defined by the occurrence of any of the following:
All-cause infant mortality or moderate to severe neurodevelopmental impairment
Time frame: 18-22 months
Secondary composite outcome, defined by the occurrence of any of the following:
All-cause infant mortality or severe neurodevelopmental impairment
Time frame: 18-22 months
All-cause neonatal mortality
Death from any cause to 28 days after delivery
Time frame: 28 days after delivery
All-cause infant mortality
Death from any cause before first birthday
Time frame: 12 months
All-cause mortality
Death from any cause
Time frame: 18 months
Time to all-cause mortality
Timespan from randomization to death from any cause
Time frame: 18-22 months
Severe neurodevelopmental impairment
Time frame: 18-22 months
Moderate neurodevelopmental impairment
Time frame: 18-22 months
Composite cognitive, language, and motor scores on the Bayley Scales of Infant and Toddler Development-Fourth Edition
Cognitive Scale on the Bayley Scales of Infant and Toddler Development - Fourth Edition \- Scale ranges from 55-145 such that higher scores indicate a better cognitive outcome. Language Scale on the Bayley Scales of Infant and Toddler Development - Fourth Edition - Scale ranges from 45-155 such that higher scores indicate a better language outcome. Motor Scale on the Bayley Scales of Infant and Toddler Development - Fourth Edition \- Scale ranges from 45-155 such that higher scores indicate a better motor outcome.
Time frame: 18-22 months
Hammersmith Infant Neurological Exam score
Ranges from 0 to 78 where higher scores indicate a better neurological outcome.
Time frame: 6 months
Global Scale for Early Development D-score and DAZ
Global Scale for Early Development D-score: Ranges from 0 to 100 where higher scores indicate a higher level of overall development. Global Scale for Early Development DAZ: Ranges from -5 to 5 where higher scores indicate a higher level of overall development.
Time frame: 12 months
Global Scale for Early Development Short Form D-score and DAZ
Global Scale for Early Development D-score: Ranges from 0 to 100 where higher scores indicate a higher level of overall development. Global Scale for Early Development DAZ: Ranges from -5 to 5 where higher scores indicate a higher level of overall development.
Time frame: 18-22 months
Acute kidney injury within the first postnatal week
Defined as an increase in serum creatinine of 0.3 mg/dL or more on 2 measurements
Time frame: Postnatal days 2-4
Manual blood pressure (systolic and diastolic)
Systolic and diastolic blood pressure taken using manual measurement
Time frame: 18-22 months
Hypertension
Based on the systolic blood pressure at the ≥95% for age related normative values
Time frame: 18-22 months
Serum creatinine
Measured using serum creatinine testing.
Time frame: 18-22 months
Serious adverse events (SAEs)
An SAE form will be completed for any event meeting the following criteria: * Results in participant death; * Is life-threatening; * Requires hospitalization or prolongs existing hospitalization; * Results in persistent or significant disability or incapacity; * Any other serious or unexpected AE that the study investigator(s) feels should be reported.
Time frame: Discharge or 7 days after administration of the last study drug (whichever occurs first)
Adverse events of special interest (AESIs)
To include: * Clinically diagnosed seizures * Receipt of any antiepileptic drug * Seizures not controlled on one antiepileptic drug * Hypoglycemia (BG \<30 mg/dL) * Hyperglycemia (BG \>200 mg/dL) * Heart rate \[HR\] \>180 beats per minute \[bpm\] within 30 minutes of study drug administration * Necrotizing enterocolitis (NEC): as defined by feeding intolerance, bloody stool and abdominal distension
Time frame: Discharge or 7 days after administration of the last study drug (whichever occurs first)
Length/height and length/height-for-age z-score
Length/height and length/height-for-age z-score
Time frame: Birth, 1 month, 6 months, 12 months, and 18-22 months
Weight and weight-for-age z-score
Weight and weight-for-age z-score
Time frame: Birth, 1 month, 6 months, 12 months, and 18-22 months
Head circumference and Head circumference-for-age z-score
Head circumference and Head circumference-for-age z-score
Time frame: Birth, 1 month, 6 months, 12 months, and 18-22 months
Plan to share: No — Only aggregate and deidentified data will be shared.
No publications or documents are linked to this record.
Eligibility is decided by the study team. Share this record with your doctor or contact the team directly.
Contact study teamGet an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Studies of the drug tested here: Caffeine
NICHD Global Network for Women's and Children's Health