Optimizing (Longer, Deeper) Cooling for Neonatal Hypoxic-Ischemic Encephalopathy(HIE)

This study has been terminated.
(The trial closed for emerging safety profile and futility analysis and will not resume.)
Sponsor:
Collaborators:
National Center for Research Resources (NCRR)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
NICHD Neonatal Research Network
ClinicalTrials.gov Identifier:
NCT01192776
First received: August 31, 2010
Last updated: August 23, 2016
Last verified: February 2016
  Purpose
The Optimizing Cooling trial will compare four whole-body cooling treatments for infants born at 36 weeks gestational age or later with hypoxic-ischemic encephalopathy: (1) cooling for 72 hours to 33.5°C; (2) cooling for 120 hours to 33.5°C; (3) cooling for 72 hours to 32.0°C; and (4) cooling for 120 hours to 32.0°C. The objective of this study is to evaluate whether whole-body cooling initiated at less than 6 hours of age and continued for 120 hours and/or a depth at 32.0°C in will reduce death and disability at 18-22 months corrected age.

Condition Intervention Phase
Infant, Newborn
Hypoxia, Brain
Hypoxia-Ischemia, Brain
Encephalopathy, Hypoxic-Ischemic
Hypoxic-Ischemic Encephalopathy
Ischemic-Hypoxic Encephalopathy
Procedure: Whole-body Cooling
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Optimizing Cooling Strategies at < 6 Hours of Age for Neonatal Hypoxic-Ischemic Encephalopathy

Resource links provided by NLM:


Further study details as provided by NICHD Neonatal Research Network:

Primary Outcome Measures:
  • Death or Moderate to Severe Disability [ Time Frame: Birth to 22 months corrected age ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Death [ Time Frame: Birth to 22 months corrected age ] [ Designated as safety issue: Yes ]
  • Mild, moderate, and severe disability [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
    Number of infants with mild, moderate, and severe disability

  • Withdrawal of care [ Time Frame: Birth to hospital discharge ] [ Designated as safety issue: Yes ]
    Number of infants for whom aggressive care is withdrawn

  • Acute Adverse Events [ Time Frame: Until infant achieves normothermia ] [ Designated as safety issue: Yes ]
    Number of adverse events (severe bradycardia, acidosis, bleeding or ischemic CNS abnormalities)

  • Clinical neonatal seizures [ Time Frame: Until death, discharge, or transfer ] [ Designated as safety issue: Yes ]
  • Severe neonatal brain abnormalities [ Time Frame: 7-14 days of life ] [ Designated as safety issue: Yes ]
    MRIs taken between 7-14 days will be examined.

  • Cognitive outcome [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
  • Cerebral palsy [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
  • Disability by stage of HIE [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
  • Visual impairment [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
  • Hearing impairment [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
  • Multiple Disabilities [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
  • Multiorgan Dysfunction [ Time Frame: Until death, discharge, or transfer ] [ Designated as safety issue: Yes ]

Enrollment: 364
Study Start Date: September 2010
Study Completion Date: March 2016
Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 33.5°C for 72 hours
Target Temp: 33.5°C Duration: 72 hrs
Procedure: Whole-body Cooling
Whole-body cooling using a Blanketrol II or III to reach either a target core temperature of 33.5°C or 32.0°C for a duration of either 72 hours or 120 hours.
Other Names:
  • Blanketrol II Model 222R
  • Blanketrol III Model 233 (used in the II mode)
Experimental: 33.5°C for 120 hours
Target Temp: 33.5°C Duration: 120 hrs
Procedure: Whole-body Cooling
Whole-body cooling using a Blanketrol II or III to reach either a target core temperature of 33.5°C or 32.0°C for a duration of either 72 hours or 120 hours.
Other Names:
  • Blanketrol II Model 222R
  • Blanketrol III Model 233 (used in the II mode)
Experimental: 32.0°C for 72 hours
Target Temp: 32.0°C Duration: 72 hrs
Procedure: Whole-body Cooling
Whole-body cooling using a Blanketrol II or III to reach either a target core temperature of 33.5°C or 32.0°C for a duration of either 72 hours or 120 hours.
Other Names:
  • Blanketrol II Model 222R
  • Blanketrol III Model 233 (used in the II mode)
Experimental: 32.0°C for 120 hours
Target Temp: 32.0°C Duration:120 hrs
Procedure: Whole-body Cooling
Whole-body cooling using a Blanketrol II or III to reach either a target core temperature of 33.5°C or 32.0°C for a duration of either 72 hours or 120 hours.
Other Names:
  • Blanketrol II Model 222R
  • Blanketrol III Model 233 (used in the II mode)

Detailed Description:

Hypoxic-ischemic encephalopathy (HIE) is a rare, but life-threatening condition characterized by brain injury due to asphyxia diagnosed at or shortly after birth. According to the World Health Organization, more than 722,000 children died from birth asphyxia and birth trauma worldwide in 2004. An estimated 50-75 percent of infants with severe (stage 3) HIE will die, with 55 percent of these deaths occurring in the first month. Up to 80 percent of infants who survive stage 3 HIE develop significant long-term disabilities, including intellectual disabilities, epilepsy, and cerebral palsy with hemiplegia, paraplegia, or quadriplegia; 10-20 percent develop moderately serious disabilities; and up to 10 percent are normal.

Previous studies have shown treatment with hypothermia to be an effective therapy for HIE. Currently, infants diagnosed with HIE at less than six hours of age are given whole-body cooling, decreasing their core body temperature to 33.5°C (93.2° Fahrenheit) for a period 72 hours using a cooling blanket. This treatment appears to protect the brain, decreasing the rate of death and disability and improving the chances of survival and neurodevelopmental outcomes at 18 months correct age. But additional trials are needed to help define the most effective cooling strategies.

The Optimizing Cooling trial will examine whether cooling for a longer time period and/or to a lower temperature will improve the chance of survival and neurodevelopmental outcomes at 18-22 months corrected age. Eligible infants with HIE will be placed in one of four cooling groups: (1) cooling for 72 hours to 33.5°C; (2) cooling for 120 hours to 33.5°C; (3) cooling for 72 hours to 32.0°C; and (4) cooling for 120 hours to 32.0°C. Infants will be monitored closely and receive the care of the Neonatal Intensive Care Unit (NICU).

Infants enrolled in the study will be placed on a cooling blanket - the same type of blanket children's hospitals use in the NICU, in operating rooms during surgeries, and to cool children with high fevers. Each infant will be cooled according to the study group he or she is assigned to. During cooling, the infant's temperature will be very closely monitored by continuous esophageal (core)temperature readings. This will be done by placing a soft, narrow, flexible plastic tube into the infant's nose and down to just above the stomach. Skin temperatures will also be monitored closely. At the end of the assigned period of cooling, the infant will be slowly re-warmed until a normal core temperature of 36.5 to 37.0°C (97.7 to 98.6°C) is reached.

Infants will be examined at 18-22 months corrected age to assess their neurodevelopmental outcomes.

Secondary Studies include:

A. Using aEEG to 1)predict mortality or moderate to severe disability at 18-22 months in term infants with HIE treated with systemic hypothermia and 2) to record electrical seizure activity to compare rewarming initiated at 72 hours and later rewarming that is initiated at 120 hours.

  Eligibility

Ages Eligible for Study:   up to 6 Hours   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Eligibility will be determined in a stepped process:

  1. All infants with a gestational age ≥ 36 weeks will be screened for study entry if they are admitted to the NICU with a diagnosis of fetal acidosis, perinatal asphyxia, neonatal depression or encephalopathy.
  2. Infants will be eligible if:

    • They have a pH ≤ 7.0 or a base deficit ≥ 16m mEq/ L on umbilical cord or any postnatal sample within 1 hour of age.
    • If, during this interval, they have a pH between 7.01 and 7.15, a base deficit is between 10 and 15.9 mEq/L, or a blood gas is not available, AND they have an acute perinatal event AND either a 10-minute Apgar score ≤ 5 or assisted ventilation initiated at birth and continued for at least 10 minutes.
  3. Once these criteria are met, eligible infants will have a standardized neurological examination performed by a certified physician examiner. Infants will be candidates for the study when encephalopathy or seizures are present. For this study, encephalopathy is defined as the presence of 1 or more signs in 3 of the following 6 categories:

    • Level of consciousness: lethargy, stupor or coma;
    • Spontaneous activity: decreased, absent;
    • Posture: distal flexion, decerebrate;
    • tone: hypotonia, flaccid or hypertonia, rigid;
    • Primitive reflexes: a) suck, weak, absent; b) Moro, incomplete, flaccid;
    • Autonomic nervous system: a) pupils: constricted, unequal, skew deviation or non reactive to light; b) heart rate: bradycardia, variable heart rate or c) respiration: periodic breathing, apnea.

Eligible infants from multiple births will be enrolled in the same arm of the study.

Exclusion Criteria:

  • Inability to randomize by 6 hours of age
  • Major congenital abnormality
  • Major chromosomal abnormality (including Trisomy 21),
  • Severe growth restriction (≤ 1800gm birth weight),
  • Infant is moribund and will not receive any further aggressive treatment,
  • Refusal of consent by parent
  • Refusal of consent by attending neonatologist
  • Infants with a core temperature < 33.5°C for > 1 hour at the time of screening by the research team would not be eligible for the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01192776

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
United States, California
University of California - Los Angeles
Los Angeles, California, United States, 90025
Stanford University
Palo Alto, California, United States, 94304
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30303
United States, Indiana
Indiana University
Indianapolis, Indiana, United States, 46202
United States, Iowa
University of Iowa
Iowa City, Iowa, United States, 52242
United States, Michigan
Wayne State University
Detroit, Michigan, United States, 48201
United States, Missouri
Children's Mercy Hospital
Kansas City, Missouri, United States, 64108
United States, New Mexico
University of New Mexico
Albuquerque, New Mexico, United States, 87131
United States, New York
University of Rochester
Rochester, New York, United States, 14642
United States, North Carolina
RTI International
Durham, North Carolina, United States, 27705
Duke University
Durham, North Carolina, United States, 27710
United States, Ohio
Cincinnati Children's Medical Center
Cincinnati, Ohio, United States, 45267
Case Western Reserve University, Rainbow Babies and Children's Hospital
Cleveland, Ohio, United States, 44106
Research Institute at Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Pennsylvania
Univeristy of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Rhode Island
Brown University, Women & Infants Hospital of Rhode Island
Providence, Rhode Island, United States, 02905
United States, Texas
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas, United States, 75235
University of Texas Health Science Center at Houston
Houston, Texas, United States, 77030
Sponsors and Collaborators
NICHD Neonatal Research Network
National Center for Research Resources (NCRR)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
Study Chair: Seetha Shankaran, MD Wayne State University
Principal Investigator: Abbot R Laptook, MD Brown University, Women & Infants Hospital of Rhode Island
Principal Investigator: Michele C Walsh, MD MS Case Western Reserve University, Rainbow Babies and Children's Hospital
Principal Investigator: Ronald N. Goldberg, MD Duke University
Principal Investigator: Barbara J. Stoll, MD Emory University
Principal Investigator: Brenda B. Poindexter, MD MS Indiana University
Principal Investigator: Abhik Das, PhD RTI International
Principal Investigator: Krisa P. Van Meurs, MD Stanford University
Principal Investigator: Kurt Schibler, MD Children's Hospital Medical Center, Cincinnati
Principal Investigator: Waldemar A. Carlo, MD University of Alabama at Birmingham
Principal Investigator: Edward F. Bell, MD University of Iowa
Principal Investigator: Kristi L. Watterberg, MD University of New Mexico
Principal Investigator: Pablo J. Sanchez, MD University of Texas, Southwestern Medical Center at Dallas
Principal Investigator: Kathleen A. Kennedy, MD MPH The University of Texas Health Science Center, Houston
Principal Investigator: William Truog, MD Children's Mercy Hospital Kansas City
Principal Investigator: Barbara Schmidt, MD, MSc University of Pennsylvania
Principal Investigator: Carl D'Angio, MD University of Rochester
Principal Investigator: Uday Devaskar, MD University of California, Los Angeles
Principal Investigator: Leif Nelin, MD Research Institute at Nationwide Children's Hospital
  More Information

Additional Information:
Study Data/Documents: Publication  This link exits the ClinicalTrials.gov site

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: NICHD Neonatal Research Network
ClinicalTrials.gov Identifier: NCT01192776     History of Changes
Other Study ID Numbers: NICHD-NRN-0043  U10HD021364  U10HD021373  U10HD021385  U10HD027851  U10HD027853  U10HD027856  U10HD027871  U10HD027880  U10HD027904  U10HD034216  U10HD036790  U10HD040492  U10HD040689  U10HD053089  U10HD053109  U10HD053119  U10HD053124  UL1RR024139  UL1RR024979  UL1RR025008  UL1RR025744  UL1RR025747  UL1RR025761  UL1RR025764  U10HD068284  U10HD068278  U10HD068270  U10HD068263  U10HD068244 
Study First Received: August 31, 2010
Last Updated: August 23, 2016
Health Authority: United States: Federal Government
United States: Institutional Review Board

Keywords provided by NICHD Neonatal Research Network:
NICHD Neonatal Research Network
Hypoxic-ischemic encephalopathy (HIE)
Hypothermia
Neonatal depression
Perinatal asphyxia
Fetal acidosis

Additional relevant MeSH terms:
Ischemia
Anoxia
Brain Diseases
Brain Ischemia
Hypoxia-Ischemia, Brain
Hypoxia, Brain
Pathologic Processes
Signs and Symptoms, Respiratory
Signs and Symptoms
Central Nervous System Diseases
Nervous System Diseases
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases

ClinicalTrials.gov processed this record on August 23, 2016