Caffeine for Hypoxic Ischemic Encephalopathy (CHIME Trial)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 830
- 试验地点
- 14
- 主要终点
- Composite outcome, defined by the occurrence of any of the following:
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The protocol study team, international principal investigator (iPI), site staff and participants will be masked to the assigned treatment arm. Lab personnel will be masked to the assigned treatment arm until assays for samples collected after randomization are complete.
入排标准
- 年龄范围
- — 至 6 Hours（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Oral placebo solution (Drug)
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.
干预措施: Caffeine citrate oral solution (Drug)
结局指标
主要结局
Composite outcome, defined by the occurrence of any of the following:
时间窗: 18-22 months
All-cause infant mortality or moderate to severe neurodevelopmental impairment
次要结局
- Secondary composite outcome, defined by the occurrence of any of the following:(18-22 months)
- All-cause neonatal mortality(28 days after delivery)
- All-cause infant mortality(12 months)
- All-cause mortality(18 months)
- Time to all-cause mortality(18-22 months)
- Severe neurodevelopmental impairment(18-22 months)
- Moderate neurodevelopmental impairment(18-22 months)
- Hammersmith Infant Neurological Exam score(6 months)
- Global Scale for Early Development D-score and DAZ(12 months)
- Global Scale for Early Development Short Form D-score and DAZ(18-22 months)
- Acute kidney injury within the first postnatal week(Postnatal days 2-4)
- Manual blood pressure (systolic and diastolic)(18-22 months)
- Hypertension(18-22 months)
- Serum creatinine(18-22 months)
- Serious adverse events (SAEs)(Discharge or 7 days after administration of the last study drug (whichever occurs first))
- Adverse events of special interest (AESIs)(Discharge or 7 days after administration of the last study drug (whichever occurs first))
- 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(Birth, 1 month, 6 months, 12 months, and 18-22 months)
- Head circumference and Head circumference-for-age z-score(Birth, 1 month, 6 months, 12 months, and 18-22 months)
- Composite cognitive, language, and motor scores on the Bayley Scales of Infant and Toddler Development-Fourth Edition(18-22 months)