TIME Study: Therapeutic Hypothermia for Infants With Mild Encephalopathy (TIME)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Hypoxic-Ischemic Encephalopathy Mild; Neonatal Encephalopathy
• Intervention / Treatment: Other: Therapeutic Hypothermia; Other: Normothermia

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.

• Study Type: Interventional
• Enrollment (Anticipated): 68
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sonia L Bonifacio, MD; Phone Number: 650-723-5711; Email: soniab1@stanford.edu
• Study Contact Backup: Name: Krisa Van Meurs, MD; Phone Number: 650-723-5711; Email: vanmeurs@stanford.edu

Study Locations

• United States
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda Children's Hospital
      • Contact: Andrew Hopper, MD
    • Oakland, California, United States, 94606
      • Benioff Children's Hospital Oakland
      • Contact: Priscilla Joe, MD
    • Orange, California, United States, 92868
      • Children's Hospital Orange County
      • Contact: John Tran, MD
    • Palo Alto, California, United States, 94034
      • Stanford University
      • Contact: Sonia Bonifacio, MD
    • San Diego, California, United States, 92123
      • Rady Children's Hospital
      • Contact: Jose Honald, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 6 hours (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Therapeutic Hypothermia; 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; 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.
Active Comparator: Normothermia; 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; 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.

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age at Randomization	Age in hours and minutes after birth at randomization	First 24 hours of life
Age at Initiation of Treatment	Age in hours and minutes after birth at which normothermia or therapeutic hypothermia are initiated	First 24 hours of life
Percentage of participants with disability at 2 years of age	Most enrolled neonates will be followed in high-risk infant follow-up clinics. We will track developmental outcome at 2 years of age for all enrolled patients and determine the proportion of treated and control patients who abnormal measures of neurodevelopment	2 years

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: Thrasher Research Fund
• Investigators: Principal Investigator: Sonia Bonifacio, MD, Stanford University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2020
• Primary Completion (Anticipated): January 31, 2023
• Study Completion (Anticipated): January 31, 2025

Study Registration Dates

• First Submitted: November 14, 2019
• First Submitted That Met QC Criteria: November 22, 2019
• First Posted (Actual): November 25, 2019

Study Record Updates

• Last Update Posted (Actual): March 18, 2020
• Last Update Submitted That Met QC Criteria: March 16, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Respiratory; Body Temperature Changes; Hypoxia; Hypoxia, Brain; Brain Ischemia; Brain Diseases; Hypothermia; Hypoxia-Ischemia, Brain
• Other Study ID Numbers: 53274

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No