Clinical trial NCT04176471: TIME Study: Therapeutic Hypothermia for Infants With Mild Encephalopathy
Official title: The TIME STUDY: A Randomized Controlled Trial of Therapeutic Hypothermia for Infants With Mild Encephalopathy in California
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Hypoxic-Ischemic Encephalopathy Mild
Neonatal Encephalopathy
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: Thrasher Research Fund
First posted: 2019-11-25
Enrollment: 68
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A total of 68 neonates with mild HIE will be enrolled and randomized to therapeutic hypothermia (33.5°C ± 0.5°C for 72 hours plus 6 hours of rewarming) or normothermia (36.5-37.3°C for 72 hours ) with targeted temperature management. Each treatment group will have 34 patients. Participants randomized to normothermia who develop signs of moderate-severe HIE in the first 24 hours after birth will be crossed over to the treatment arm, as therapeutic hypothermia is the standard of care treatment for neonates with moderate-severe HIE.
Primary purpose: TREATMENT

Brief summary: The TIME study is a randomized, controlled trial to evaluate impact on early measures of neurodevelopment and the safety profile of therapeutic hypothermia in term neonates with Mild Hypoxic-Ischemic Encephalopathy who are \< 6 hours of age. Neurodevelopmental outcome will be assessed at 12-14 months of age. The study will enroll 68 neonates randomized to therapeutic hypothermia or normothermia across 5 centers in California.

Detailed description: The TIME study is a multi-center randomized, controlled trial of Therapeutic Hypothermia (TH) (33.5°C ± 0.5° for 72 hours) versus normothermia using targeted temperature management, initiated within 6 hours after birth in term neonates with Mild Hypoxic-Ischemic Encephalopathy (HIE). Mild encephalopathy will be identified using the 6 component modified Sarnat exam as in the Neonatal Research Network of the National Institute of Child Health and Human Development trials of TH for moderate-severe encephalopathy and will be expanded to include features of mild encephalopathy. Eligible subjects must demonstrate ≥ 2 exam abnormalities (mild, moderate, severe) but without evidence of moderate-severe encephalopathy (≥ 3 moderate or severe features). The primary outcome is neurodevelopmental outcome at 12-14 months of age. Secondary outcomes include evaluating the safety profile of therapeutic hypothermia in patients with Mild HIE. Therapeutic hypothermia is well tolerated and did not demonstrate serious safety concerns when evaluated in multiple large studies of neonates with moderate-severe HIE. It is now being applied by some practitioners to neonates with Mild HIE without systematic evidence of benefit or potential harm. This data will be necessary in order to develop and larger trial of efficacy to be determined at 2 years of age.

Eligibility criteria: Inclusion Criteria (must meet all 3):

1. Neonates born at ≥ 36 0/7 weeks
2. Neonatal signs or contributing factors consistent with an acute peri-partum or intra-partum event (must meet a or b):

   1. pH ≤ 7.0 or Base deficit ≥ 16 in any umbilical cord or baby specimen at ≤ 1 hr of age OR
   2. No umbilical cord or baby blood gas at ≤ 1 hr of age OR pH 7.01-7.15 or Base deficit 10-15.9 in any cord or baby specimen at ≤ 1 hr of age AND at least one of the following

      * Apgar score at 10 min ≤ 5
      * Continued need for resuscitation at 10 min (chest compressions, bag mask ventilation, intubation with positive pressure ventilation)
      * Acute Perinatal Event: uterine rupture, placental abruption, cord accident (prolapse, rupture, knot or tight nuchal cord), maternal trauma, maternal hemorrhage or cardiorespiratory arrest, fetal exsanguination from either vasa previa or feto-maternal hemorrhage
      * Fetal heart rate monitor pattern consistent with acute peripartum or intrapartum event (category III trace: no heart rate variability, presence of recurrent late or variable decelerations, bradycardia, or sinusoidal pattern)
3. Evidence of Mild Encephalopathy on Modified Sarnat Exam.

   * Presence of at least 2 signs of mild, moderate or severe encephalopathy with no more than 2 moderate or severe findings in the 6 tested categories (level of consciousness, spontaneous activity, posture, tone, neonatal reflexes (suck and moro), and autonomic nervous system

Exclusion Criteria:

* Patients \< 36 0/7 weeks birthweight \< 1800gm; congenital or chromosomal anomaly associated with abnormal neurodevelopment or death; patients with moderate or severe HIE (by Sarnat exam or presence of clinical or electrographic seizures) identified within 6 hours after birth; core body temperature \< 34°C for more than 1 hour prior to randomization.

Primary outcomes:
measure: Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS)
timeFrame: Assessment takes up to 15 minutes and will be conducted at 12-14 months of age
measure: Alberta Infant Motors Scale (AIMS)
timeFrame: Assessment takes up to 15 minutes and will be conducted at 12-14 months of age
Secondary outcomes:
measure: Percentage of participants with sinus bradycardia
timeFrame: 72 hours
measure: Percentage of participants thrombocytopenia
timeFrame: 72 hours
measure: Percentage of patients who require intubation and mechanical ventilation
timeFrame: 72 hours
measure: Percentage of patients with need for central line
timeFrame: 72 hours
measure: Percentage of participants with Persistent Pulmonary Hypertension (PPHN)
timeFrame: 72 hours
measure: Percentage of participants exposed to sedating or analgesic medications
timeFrame: 72 hours
measure: Percentage of participants exposed to inotropic agents
timeFrame: 76 hours
measure: Percentage of participants diagnosed with seizures
timeFrame: During initial hospital stay up to 30 days
measure: Age at initiation of feeds
timeFrame: During initial hospital stay up to 30 days from date of admission
measure: Age at full enteral feeds
timeFrame: During initial hospital stay and up to 30 days from date of admission
measure: Percentage of participants who require feeding assistance at discharge
timeFrame: At time of discharge from hospital, up to 30 days from admission
measure: Percentage of participants with fat necrosis and hypercalcemia
timeFrame: From study entry to day of hospital discharge, up to 30 days from admission
measure: Percentage of participants discharged on anti-convulsant medications
timeFrame: At time of discharge from hospital, up to 30 days from admission
measure: Count of participants with brain injury on MRI
timeFrame: At time of discharge from hospital, up to 30 days from admission
measure: Length of Hospital Stay
timeFrame: At time of discharge from hospital, up to 30 days from admission
measure: Percentage of participants breastfeeding at discharge
timeFrame: At time of discharge from hospital, up to 30 days from admission
measure: Percentage of participants with death and/or hospice at discharge
timeFrame: At time of discharge from hospital, up to 30 days from admission
Other outcomes:
measure: Age at Randomization
timeFrame: First 24 hours of life
measure: Age at Initiation of Treatment
timeFrame: First 24 hours of life
measure: Percentage of participants with disability at 2 years of age
timeFrame: 2 years
Locations:
city: Loma Linda
country: United States
facility: Loma Linda Children's Hospital
state: California
city: Oakland
country: United States
facility: Benioff Children's Hospital Oakland
state: California
city: Orange
country: United States
facility: Children's Hospital Orange County
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital
state: California
Study officials:
affiliation: Stanford University
name: Sonia Bonifacio, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Blecharczyk E, Lee L, Birnie K, Gupta A, Davis A, Van Meurs K, Bonifacio S, Frymoyer A. Standardized Evaluation of Cord Gases in Neonates at Risk for Hypoxic Ischemic Encephalopathy. Hosp Pediatr. 2022 Jan 1;12(1):29-37. doi: 10.1542/hpeds.2021-006135.