Caffeine for Hypoxic Ischemic Encephalopathy

Official title

Caffeine for Hypoxic Ischemic Encephalopathy (CHIME Trial)

Overview

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.

Interventions

• 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

Primary outcome measures

• Composite outcome, defined by the occurrence of any of the following: [Time frame: 18-22 months]

Secondary outcome measures (12)

• Secondary composite outcome, defined by the occurrence of any of the following: [Time frame: 18-22 months]
• All-cause neonatal mortality [Time frame: 28 days after delivery]
• All-cause infant mortality [Time frame: 12 months]
• All-cause mortality [Time frame: 18 months]
• Time to all-cause mortality [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 [Time frame: 18-22 months]
• Hammersmith Infant Neurological Exam score [Time frame: 6 months]
• Global Scale for Early Development D-score and DAZ [Time frame: 12 months]
• Global Scale for Early Development Short Form D-score and DAZ [Time frame: 18-22 months]
• Acute kidney injury within the first postnatal week [Time frame: Postnatal days 2-4]

Eligibility criteria

Participant Inclusion Criteria:

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

• Liveborn infants ≥36 weeks
• Birth weight ≥1800 grams
• 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:

• pH <7.0; or
• Base Deficit ≥16 mmol/L; or
• Lactate >8 mmol/L.
• 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
• 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:

• 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
• 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:

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

India · 2 centers

• KLE University's J N Medical College — Belagavi
• Lata Medical Research Foundation — Nagpur

Bangladesh · 1 center

• ICDDR,B — Saidpur

Democratic Republic of the Congo · 1 center

• Kinshasa School of Public Health — Kinshasa

Guatemala · 1 center

• Institute of Nutrition of Central America And Panama (INCAP) — Chimaltenango

Pakistan · 1 center

• Aga Khan University — Karachi

Zambia · 1 center

• University Teaching Hospital — Lusaka

Identifiers

NCT: NCT06855108 · CP CHIME · INV-068776

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗