TIME Study: Therapeutic Hypothermia for Infants With Mild Encephalopathy

Study Overview
=================
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.

Official Title
-----------------
The TIME STUDY: A Randomized Controlled Trial of Therapeutic Hypothermia for Infants With Mild Encephalopathy in California

Conditions
-----------------
Hypoxic-Ischemic Encephalopathy Mild, Neonatal Encephalopathy

Intervention / Treatment
-----------------
* Other: Therapeutic Hypothermia
* Other: Normothermia


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria (must meet all 3): Neonates born at ≥ 36 0/7 weeks Neonatal signs or contributing factors consistent with an acute peri-partum or intra-partum event (must meet a or b): pH ≤ 7.0 or Base deficit ≥ 16 in any umbilical cord or baby specimen at ≤ 1 hr of age OR 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) 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.

Ages Eligible for Study
-----------------
Maximum Age: 6 Hours

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapeutic Hypothermia<br>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. | Other: Therapeutic Hypothermia<br>* Therapeutic hypothermia involves use of a servo-controlled device and blanket to lower the core body temperature by 3°C for 72 hours followed by a period of re-warming in which the temperature is increased by 0.5°C per hour for 6 hours until normothermia is achieved.<br>|
| Active Comparator: Normothermia<br>Normothermia will be achieved using a servo-controlled temperature regulating blanket with the temperature goal of 36.5-37.3°C for 72 hours. | Other: Normothermia<br>* Normothermia will be achieved using the same servo-controlled device and blanket to assure normothermia of the control arm. The goal temperature for normothermia is 36.5-37.3°C for 72 hours.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) | Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) will be assessed at 12-14 months of age. The mean score for a 12 month old normally developing infant is 109 with a standard deviation of 16.5. Higher scores are associated with normal development. | Assessment takes up to 15 minutes and will be conducted at 12-14 months of age | 
| Alberta Infant Motors Scale (AIMS) | Alberta Infant Motors Scale (AIMS) will be assessed at 12-14 months of age. The AIMS score is determined by assessment of 4 positions and scoring the least and most mature position identified. The score is converted to a percentile for age with those in the 5th to 25th percentile identified as suspicious motor development and those with a score corresponding to < 5th percentile being identified as abnormal motor development. | Assessment takes up to 15 minutes and will be conducted at 12-14 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with sinus bradycardia | Investigators will determine the proportion of treated and control subjects who develop sinus bradycardia (HR < 80) during the intervention period (72 hours). | 72 hours | 
| Percentage of participants thrombocytopenia | Investigators will determine the proportion of treated and control subjects who develop thrombocytopenia (platelet count of < 150 x 109/L) during the intervention period | 72 hours | 
| Percentage of patients who require intubation and mechanical ventilation | Investigators will determine the proportion of treated and control subjects who require intubation and mechanical ventilation | 72 hours | 
| Percentage of patients with need for central line | Investigators will determine the proportion of treated and control subjects who have a central line (umbilical or PICC) | 72 hours | 
| Percentage of participants with Persistent Pulmonary Hypertension (PPHN) | Investigators will determine the proportion of treated and control subjects who have a clinical diagnosis of PPHN or who receive inhaled nitric oxide | 72 hours | 
| Percentage of participants exposed to sedating or analgesic medications | Investigators will determine the proportion of treated and control subjects who receive narcotics or benzodiazepines | 72 hours | 
| Percentage of participants exposed to inotropic agents | Investigators will determine the proportion of treated and control subjects who receive inotropic support | 76 hours | 
| Percentage of participants diagnosed with seizures | Investigators will determine the proportion of treated and control subjects who develop clinical and or electrographic seizures | During initial hospital stay up to 30 days | 
| Age at initiation of feeds | Investigators will determine the age at which enteral feeds are initiated in treated and control patients | During initial hospital stay up to 30 days from date of admission | 
| Age at full enteral feeds | Investigators will determine the age at which full enteral feeds or breastfeeding ad lib is achieved in treated and control patients | During initial hospital stay and up to 30 days from date of admission | 
| Percentage of participants who require feeding assistance at discharge | Investigators will determine the proportion of treated and control patients who require feeding support at discharge (NG tube or G-Tube feeds) | At time of discharge from hospital, up to 30 days from admission | 
| Percentage of participants with fat necrosis and hypercalcemia | Investigators will determine the proportion of treated and control patients who have a diagnosis of fat necrosis and hypercalcemia | From study entry to day of hospital discharge, up to 30 days from admission | 
| Percentage of participants discharged on anti-convulsant medications | Investigators will determine the proportion of treated and control patients who are discharged home on anti-convulsant medications | At time of discharge from hospital, up to 30 days from admission | 
| Count of participants with brain injury on MRI | Investigators will determine the number of treated and control patients who have brain injury on MRI | At time of discharge from hospital, up to 30 days from admission | 
| Length of Hospital Stay | Investigators will determine the length of hospital stay for treated and control patients | At time of discharge from hospital, up to 30 days from admission | 
| Percentage of participants breastfeeding at discharge | Investigators will determine the proportion of treated and control patients who are breastfeeding at discharge | At time of discharge from hospital, up to 30 days from admission | 
| Percentage of participants with death and/or hospice at discharge | Investigators will determine the proportion of treated and control patients who die or are discharged home on hospice | At time of discharge from hospital, up to 30 days from admission |