Caffeine for Hypoxic Ischemic Encephalopathy (CHIME)

Caffeine for Hypoxic Ischemic Encephalopathy (CHIME Trial)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Hypoxic Ischemic Encephalopathy (HIE)
• Intervention / Treatment: Drug: Caffeine citrate oral solution; Drug: Oral placebo solution

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.

• Study Type: Interventional
• Enrollment (Estimated): 830
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Laura Danielle Wagner, MPH; Phone Number: +1-919-541-6000; Email: wagner@rti.org
• Study Contact Backup: Name: Jennifer J Hemingway-Foday, MPH, MSW; Email: hemingway@rti.org

Study Locations

• Bangladesh
  • Saidpur, Bangladesh
    • Icddr,b
    • Contact: Rashidul Haque, MD; Email: rhaque@icddrb.org
    • Contact: Rashidul Haque, MD
    • Contact: SK Masum Billah
    • Contact: William A Petri, MD
• Congo, The Democratic Republic of the
  • Kinshasa, Congo, The Democratic Republic of the
    • Kinshasa School of Public Health
    • Contact: Antoinette Tshefu, MD, PhD, MPH; Email: antotshe@yahoo.com
    • Contact: Antoinette Tshefu, MD, PhD, MPH
    • Contact: Adrien Lokangaka, MD, MPH; Email: adrinloks@gmail.com
    • Contact: Melissa Bauserman, MD, MPH
    • Contact: Jackie Patterson, MD, MPH
    • Contact: Adrien Lokangaka, MD, MPH
    • Contact: Keia Sanderson, MD, MSCR
• Guatemala
  • Chimaltenango, Guatemala
    • Institute of Nutrition of Central America and Panama (INCAP)
    • Contact: Manolo Mazariegos, MD, MPH; Email: mmaziergos@incap.org
    • Contact: Manolo Mazariegos, MD, MPH
    • Contact: Nancy F Krebs, MD
    • Contact: Edwin J Asturias, MD
• India
  • Belgaum, India
    • KLE University's J N Medical College
    • Contact: Shivaprasad S. Goudar, MD, MHPE; Email: sgoudar@jnmc.edu
    • Contact: Shivaprasad S Goudar, MD, MHPE
    • Contact: Richard J Derman, MD, MPH
  • Nagpur, India
    • Lata Medical Research Foundation
    • Contact: Archana Patel, MD, DNB, MSCE, PhD; Email: Dr_apatel@yahoo.com
    • Contact: Archana Patel, MD, DNB, MSCE, PhD
• Pakistan
  • Karachi, Pakistan
    • Aga Khan University
    • Contact: Sarah Saleem, MD; Email: sarah.saleem@aku.edu
    • Contact: Sarah Saleem, MD
    • Contact: Robert L Goldenberg, MD
    • Contact: Blair Wylie, MD
• Zambia
  • Lusaka, Zambia
    • University Teaching Hospital
    • Contact: Elwyn Chomba, MBChB, DCH, MRCP
    • Contact: Elwyn Chomba, MBChB, DCH, MRCP; Email: echomba@zamnet.zm
    • Contact: Wally A. Carlo, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Participant Inclusion Criteria:

Infants who meet all the following criteria are eligible for enrollment as study participants:

1. Liveborn infants ≥36 weeks
2. Birth weight ≥1800 grams

3. Meets physiologic criteria for moderate to severe HIE, defined as meeting either of the following two criteria:

   1. Criterion #1: Severe acidosis, defined as an umbilical cord sample or neonatal serum sample within one hour after birth demonstrating any of following criteria:

      • pH <7.0; or
      • Base Deficit ≥16 mmol/L; or
      • Lactate >8 mmol/L.
   2. Criterion #2: Participant must meet all of the following three criteria:

   i. Moderate acidosis, defined as an umbilical cord sample or neonatal serum sample within one hour after birth demonstrating any of following criteria:

   • POC pH 7.0-7.15; or
   • Base Deficit 10.0-15.9 mmol/L; or
   • Lactate 6-8 mmol/L.

   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:

   • 10-minute Apgar <5; or
   • Need for assisted ventilation initiated at birth and continued for ≥10 minutes

4. 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:

   1. Moderate to severe encephalopathy in at least three out of six modified Sarnat categories (level of consciousness, spontaneous activity, muscle tone, posture, primitive reflexes, autonomic function); or
   2. A clinical diagnosis of seizure in the first six hours after birth.

Participant Exclusion Criteria:

Infants who meet any of the following criteria are not eligible for enrollment as study participants:

1. Home births
2. Infants who cannot be enrolled, randomized and receive study medication within 6 hours post-delivery
3. Infants with a recognized major congenital anomaly or genetic syndrome that would affect their neurodevelopment.
4. Infants for whom medical care will not be provided based on the severity of their condition or any other condition that would preclude participation per clinical judgement.
5. Infant has received therapeutic hypothermia or there is a clinical plan to initiate active or passive hypothermia for the infant.
6. Infants who will be unavailable to complete follow-up visits.
7. Infants who have received caffeine after delivery.
8. Infants whom the health care team deem ineligible for the study based on likelihood to receive caffeine outside of the study protocol.
9. Enrollment in another trial that will impact participation in this trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Caffeine citrate oral solution; 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; 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.
Placebo Comparator: Oral placebo; 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; Identical placebo oral solution; Other Names: Oral placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite outcome, defined by the occurrence of any of the following:	All-cause infant mortality or moderate to severe neurodevelopmental impairment	18-22 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary composite outcome, defined by the occurrence of any of the following:	All-cause infant mortality or severe neurodevelopmental impairment	18-22 months
All-cause neonatal mortality	Death from any cause to 28 days after delivery	28 days after delivery
All-cause infant mortality	Death from any cause before first birthday	12 months
All-cause mortality	Death from any cause	18 months
Time to all-cause mortality	Timespan from randomization to death from any cause	18-22 months
Severe neurodevelopmental impairment		18-22 months
Moderate neurodevelopmental impairment		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.	18-22 months
Hammersmith Infant Neurological Exam score	Ranges from 0 to 78 where higher scores indicate a better neurological outcome.	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.	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.	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	Postnatal days 2-4
Manual blood pressure (systolic and diastolic)	Systolic and diastolic blood pressure taken using manual measurement	18-22 months
Hypertension	Based on the systolic blood pressure at the ≥95% for age related normative values	18-22 months
Serum creatinine	Measured using serum creatinine testing.	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.	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	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	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	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	Birth, 1 month, 6 months, 12 months, and 18-22 months

Collaborators and Investigators

• Sponsor: NICHD Global Network for Women's and Children's Health
• Collaborators: University of Colorado, Denver; University of Alabama at Birmingham; Columbia University; University of North Carolina, Chapel Hill; Aga Khan University; University of Virginia; International Centre for Diarrhoeal Disease Research, Bangladesh; Thomas Jefferson University; RTI International; University Teaching Hospital, Lusaka, Zambia; Kinshasa School of Public Health; Lata Medical Research Foundation, Nagpur; KLE Academy of Higher Education and Research (Deemed- to- be-University), Jawaharlal Nehru Medical College (JNMC), Belagavi, India; Gates Foundation; Institute of Nutrition of Central America and Panama (INCAP)
• Investigators: Principal Investigator: Melissa Bauserman, MD, MPH, University of North Carolina, Chapel Hill; Principal Investigator: Elizabeth M McClure, PhD, RTI International; Principal Investigator: Denise C Babineau, PhD, RTI International

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2025
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): July 1, 2030

Study Registration Dates

• First Submitted: January 27, 2025
• First Submitted That Met QC Criteria: February 26, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 26, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Hypoxic Ischemic Encephalopathy; HIE; Caffeine; AKI
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Signs and Symptoms, Respiratory; Hypoxia, Brain; Ischemia; Hypoxia; Brain Diseases; Brain Ischemia; Hypoxia-Ischemia, Brain; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Neurotransmitter Agents; Purinergic Antagonists; Purinergic Agents; Central Nervous System Stimulants; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Pharmaceutical Solutions; Caffeine; Caffeine citrate
• Other Study ID Numbers: CP CHIME; INV-068776 (Other Grant/Funding Number: Gates Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Only aggregate and deidentified data will be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No