Preemie Hypothermia for Neonatal Encephalopathy

A Randomized Trial of Targeted Temperature Management With Whole Body Hypothermia For Moderate And Severe Hypoxic-Ischemic Encephalopathy In Premature Infants 33-35 Weeks Gestational Age.

This study is a randomized, controlled trial to assess safety and effectiveness of whole body hypothermia for 72 hours in preterm infants 33-35 weeks gestational age (GA) who present at <6 hours postnatal age with moderate to severe neonatal encephalopathy (NE). The study will enroll infants with signs of NE at 18 NICHD Neonatal Research Network sites, and randomly assign them to either receive hypothermia or participate in a non-cooled control group.

Study Overview

• Status: Completed
• Conditions: Hypoxia, Brain; Hypoxia-Ischemia, Brain; Hypoxic-Ischemic Encephalopathy; Infant, Newborn; Ischemic-Hypoxic Encephalopathy; Encephalopathy, Hypoxic-Ischemic
• Intervention / Treatment: Procedure: Normothermic Control; Device: Hypothermia

Detailed Description

Most clinical studies of neonatal encephalopathy (NE) and potential interventions have focused on infants ≥36 weeks GA. Although many interventions have been suggested and assessed for prevention or palliation of NE, the only one currently supported by rigorous clinical evidence to improve outcome in human newborns has been hypothermia implemented at <6 hours of postnatal age and maintained for 72 hrs. Data about diagnosis, frequency, severity, and outcome of NE in infants 33-35 weeks GA are sparse.

This trial will assess safety and effectiveness of whole body hypothermia for 72 hours in preterm infants 33-35 weeks gestational age (GA) who present at <6 hrs postnatal age with moderate to severe neonatal encephalopathy. Infants 33 0/7 to 35 6/7 weeks GA (best obstetrical estimate) and greater than or equal to 1500 grams birth weight (selected to minimize potential difficulties placing esophageal probe) who meet clinical, biochemical and neurologic criteria for moderate to severe NE will be randomized to either whole body hypothermia or participate in a non-cooled control group. The primary outcome will be death or moderate to severe disability at 18-22 months corrected age. The presence or absence of disability will be determined by the standard NRN interdisciplinary follow-up exam.

Secondary Study includes determining an association between MRI detectable injury and neurodevelopment at 18-22 months.

• Study Type: Interventional
• Enrollment (Actual): 168
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Durham, North Carolina, United States, 27705
      • RTI International
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Cincinnati Children's Medical Center
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University, Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Research Institute at Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Univeristy of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University, Women & Infants Hospital of Rhode Island
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center at Dallas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 months to 8 months (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Infants 33 0/7 to 35 6/7 weeks GA (best obstetrical estimate)
• Infants weight greater than or equal to 1500 grams at birth
• Postnatal age less than 6 hours
• Infants who meet clinical, biochemical and neurologic criteria for moderate to severe NE:

Biochemical: Cord gas or blood gas within first hour of life with pH ≤7.00 or base deficit (BD) ≥16 mEq/L OR

Acute perinatal event (e.g., abruptio placenta, cord prolapse, uterine rupture, severe FHR abnormality such as variable or late decelerations) AND Requirement for positive pressure ventilation for apnea or poor respiratory effort since birth for at least 10 minutes OR 10 minute Apgar score ≤5

AND

Neurologic:

Seizures OR modified Sarnat score with abnormalities in at least 3 of the 6 categories; at least one must be altered level of consciousness (lethargy or stupor/coma) as determined by a certified examiner (All infants who meet criteria for potential inclusion will undergo standard neurologic exam as for infants ≥36 wks GA being considered for hypothermia, with findings recorded)

Exclusion Criteria:

• Receipt of sedative, analgesic or paralytic agent that may confound the qualifying neurologic exam
• Etiology of NE not likely to be hypoxic-ischemic in origin
• Major congenital anomaly that may confound outcome
• Considered to be moribund and will not be receiving full intensive care
• Equipment and/or appropriate staff not available
• Core temperature < 33.5oC for more than one hour at time of screening
• Unable to randomize by 6 hours of age
• Infant needs ECMO
• All blood gases (cord and postnatal at < 1hr of age) have a pH > 7.15 AND a base deficit < 10mEq/L

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Whole-body Hypothermia; Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 72 hours	Device: Hypothermia; Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 72 hours
Placebo Comparator: Normothermia; Control group (with esophageal temperature at or near 37.0°C) for 72 hours	Procedure: Normothermic Control; Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death or Moderate or Severe Disability	Severe disability was defined by any of the following: a Bayley III cognitive score < 70 or Gross Motor Function (GMF) Level of 3-5 blindness or profound hearing loss requiring amplification but still unable to following commands/communicate. Moderate disability was defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit.	Birth to 18-22 months corrected age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Deaths in the NICU and Following Discharge	Number of deaths in the NICU and following discharge among infants with a primary outcome.	Birth to 18-22 months corrected age
Number of Infants With Abnormal MRIs During Post-intervention Period	An MRI was considered abnormal if any abnormal findings were indicated on the CRF form.	Post-intervention to through discharge, death, or transfer (whichever comes first), average of 29 days
Number of Infants With Moderate or Severe Disability	Number of infants with moderate or severe disability among survivors through 18-22 months corrected age.	Birth to 18-22 months corrrected age
Causes of Death	Causes of any deaths that occurred through 18-22 months corrected age.	Birth to 18-22 months corrrected age
Neurological Injury by Cranial Ultrasound During Intervention	Infants with recorded events of intraventricular hemorrhage grade I, II, III, or IV, posterior fossa hemorrhage with/without shift of midline structures, intraparenchymal hemorrhage.	Within 6 hours of life to 72 hours after start of intervention

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Brenda Poindexter, MD, Children's Hospital Medical Center, Cincinnati; Principal Investigator: David P Carlton, MD, Emory University; Principal Investigator: Greg Sokol, MD, MS, Indiana University; Principal Investigator: Wally A Carlo, MD, University of Alabama at Birmingham; Principal Investigator: Myra Wyckoff, MD, University of Texas Southwestern Medical Center at Dalla; Principal Investigator: Bradley Yoder, MD, University of Utah; Principal Investigator: Seetha Shankaran, MD, Wayne State University; Principal Investigator: Abhik Das, PhD, RTI International; Principal Investigator: Jon E Tyson, MD, MPH, The University of Texas Health Science Center, Houston; Principal Investigator: Carl T D'Angio, MD, University of Rochester; Principal Investigator: Abbot R Laptook, MD, Brown University, Women & Infants Hospital of Rhode Island; Principal Investigator: C. Michael Cotten, MD, Duke University; Principal Investigator: Krisa P Van Meurs, MD, Stanford University; Principal Investigator: Kristi L Watterberg, MD, University of New Mexico; Principal Investigator: Pablo Sanchez, MD, Research Institute at Nationwide Children's Hospital; Principal Investigator: Michele C Walsh, MD, Case Western Reserve University, Rainbow Babies and Children's Hospital; Principal Investigator: Edward F Bell, MD, University of Iowa; Principal Investigator: Eric Eichenwald, MD, University of Pennsylvania

Publications and helpful links

Helpful Links

• Neonatal Research Network website

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): December 9, 2022
• Study Completion (Actual): December 9, 2022

Study Registration Dates

• First Submitted: February 13, 2013
• First Submitted That Met QC Criteria: February 13, 2013
• First Posted (Estimated): February 15, 2013

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Hypothermia; Perinatal asphyxia; NICHD Neonatal Research Network; Hypoxic-ischemic encephalopathy (HIE); Neonatal depression
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Respiratory; Body Temperature Changes; Brain Ischemia; Ischemia; Brain Diseases; Hypoxia; Hypothermia; Hypoxia, Brain; Hypoxia-Ischemia, Brain
• Other Study ID Numbers: NICHD-NRN-0051; UG1HD087226 (U.S. NIH Grant/Contract); U10HD036790 (U.S. NIH Grant/Contract); U10HD021364 (U.S. NIH Grant/Contract); U10HD021373 (U.S. NIH Grant/Contract); U10HD021385 (U.S. NIH Grant/Contract); U10HD027851 (U.S. NIH Grant/Contract); U10HD027853 (U.S. NIH Grant/Contract); U10HD027856 (U.S. NIH Grant/Contract); U10HD027880 (U.S. NIH Grant/Contract); U10HD027904 (U.S. NIH Grant/Contract); U10HD034216 (U.S. NIH Grant/Contract); U10HD040492 (U.S. NIH Grant/Contract); U10HD040689 (U.S. NIH Grant/Contract); U10HD053109 (U.S. NIH Grant/Contract); U10HD040461 (U.S. NIH Grant/Contract); U10HD068244 (U.S. NIH Grant/Contract); U10HD068263 (U.S. NIH Grant/Contract); U10HD068270 (U.S. NIH Grant/Contract); U10HD068278 (U.S. NIH Grant/Contract); U10HD068284 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NIH has had a long-standing policy to share and make available to the public the results and accomplishments of the activities that it funds. The NRN plans to share de-identified data after final publication in an NIH supported data repository such as the NICHD Data and Specimen Hub (https://dash.nichd.nih.gov)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes