TIME Study: Therapeutic Hypothermia for Infants With Mild Encephalopathy

Stanford University

Status: Not yet enrolling

Conditions: Neonatal Encephalopathy; Hypoxic-Ischemic Encephalopathy Mild

Treatments: Other: Therapeutic Hypothermia; Other: Normothermia

Study type: Interventional

Funder types: Other

Identifiers

NCT04176471

53274

Details and patient eligibility

About

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.

Full 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.

Enrollment: 68 estimated patients

Sex: All

Ages: Under 6 hours old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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68 participants in 2 patient groups

Therapeutic Hypothermia

Experimental group

Description:

Therapeutic hypothermia will be achieved using a servo-controlled temperature regulating blanket that is approved for use in neonates and is currently used for the treatment of neonates with moderate-severe HIE. The goal target temperature is 33.5°C ± 0.5°C for 72 hours and the subject will then be rewarmed at a rate of 0.5°C per hour to a goal of 36.5°C.

Treatment:

Other: Therapeutic Hypothermia

Normothermia

Active Comparator group

Description:

Normothermia will be achieved using a servo-controlled temperature regulating blanket with the temperature goal of 36.5-37.3°C for 72 hours.

Treatment:

Other: Normothermia