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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: July 17, 2017
Last verified: July 2017
August 31, 2010
July 17, 2017
September 2010
March 2016   (Final data collection date for primary outcome measure)
Death or Moderate to Severe Disability [ Time Frame: Birth to 22 months corrected age ]
Death includes any mortality prior to follow up at 18-22 months. Severe disability was defined by any of the following: a Bayley III cognitive score <70, a GMFCS level of 3-5, blindness or profound hearing loss (inability to understand commands despite amplification). Moderate disability was defined as a Bayley cognitive score of 70-84 and either a GMFCS level of 2, seizure disorder, or a hearing deficit requiring amplification to understand commands.
Death or Moderate to Severe Disability [ Time Frame: Birth to 22 months corrected age ]
Complete list of historical versions of study NCT01192776 on ClinicalTrials.gov Archive Site
  • Death [ Time Frame: Birth to 22 months corrected age ]
    Death includes any mortality prior to follow up at 18-22 months.
  • Level of Disability Among Survivors [ Time Frame: Follow up at 18-22 months corrected age ]

    Among survivors number of normal infants and infants with mild, moderate, and severe disability

    Severe disability was defined by any of the following: a Bayley III cognitive score <70, a GMFCS level of 3-5, blindness or profound hearing loss (inability to understand commands despite amplification). Moderate disability was defined as a Bayley cognitive score of 70-84 and either a GMFCS level of 2, seizure disorder, or a hearing deficit requiring amplification to understand commands. Mild impairment was defined by a cognitive score 70-84, or a cognitive score ≥ 85 and any of the following: presence of a GMFCS level 1 or 2, seizure disorder or hearing loss not requiring amplification. Normal was defined by a cognitive score ≥ 85 in the absence of any neurosensory deficits or seizures after NICU discharge.

  • Withdrawal of Care [ Time Frame: Through hospital discharge ]
    Number of infants for whom aggressive care is withdrawn
  • Clinical Neonatal Seizures [ Time Frame: Through death, discharge, or transfer ]
    Documented seizures during hospital course
  • Bayley Cognitive Score [ Time Frame: Follow up at 18-22 months corrected age ]
    Bayley Scale of Infant Development Composite Cognitive Score. The total composite score is reported, ranging from the lowest score of 55 to the highest score of 145. Lower values specify worse outcome.
  • Cerebral Palsy [ Time Frame: Follow up at 18-22 months corrected age ]
  • Level of Disability Among Survivors, by Level of HIE [ Time Frame: Follow up at 18-22 months corrected age ]
    Among survivors, number of normal infants and infants with mild, moderate and severe disability Severe disability was defined by any of the following: a Bayley III cognitive score <70, a GMFCS level of 3-5, blindness or profound hearing loss (inability to understand commands despite amplification). Moderate disability was defined as a Bayley cognitive score of 70-84 and either a GMFCS level of 2, seizure disorder, or a hearing deficit requiring amplification to understand commands. Mild impairment was defined by a cognitive score 70-84, or a cognitive score ≥ 85 and any of the following: presence of a GMFCS level 1 or 2, seizure disorder or hearing loss not requiring amplification. Normal was defined by a cognitive score ≥ 85 in the absence of any neurosensory deficits or seizures after NICU discharge.
  • Visual Impairment [ Time Frame: Follow up at 18-22 months corrected age ]
    Visual impairment is defined as bilateral blindness with some/no useful vision
  • Hearing Impairment [ Time Frame: Follow up at 18-22 months corrected age ]
    Hearing impairment is defined as hearing impairment despite amplification
  • Multiple Disabilities [ Time Frame: Follow up at 18-22 months corrected age ]
    Multiple disabilities is defined as two or more of the following 5 components: disabling CP, GMFCS level 3-5, Bayley cognitive score < 70, blindness, or deafness.
  • Multiorgan Dysfunction [ Time Frame: Until death, discharge, or transfer ]
    The data needed for this analysis are not collected directly, and needs to be coded based on the available information. This is a complex undertaking and will take additional time to create. Once created, we will promptly report the results and anticipate reporting by March 2018.
  • Death [ Time Frame: Birth to 22 months corrected age ]
  • Mild, moderate, and severe disability [ Time Frame: 18-22 months corrected age ]
    Number of infants with mild, moderate, and severe disability
  • Withdrawal of Care [ Time Frame: Birth to hospital discharge ]
    Number of infants for whom aggressive care is withdrawn
  • Acute Adverse Events [ Time Frame: Until infant achieves normothermia ]
    Number of adverse events (severe bradycardia, acidosis, bleeding or ischemic CNS abnormalities)
  • Clinical Neonatal Seizures [ Time Frame: Until death, discharge, or transfer ]
  • Severe neonatal brain abnormalities [ Time Frame: 7-14 days of life ]
    MRIs taken between 7-14 days will be examined.
  • Cognitive outcome [ Time Frame: 18-22 months corrected age ]
  • Cerebral Palsy [ Time Frame: 18-22 months corrected age ]
  • Disability by stage of HIE [ Time Frame: 18-22 months corrected age ]
  • Visual Impairment [ Time Frame: 18-22 months corrected age ]
  • Hearing Impairment [ Time Frame: 18-22 months corrected age ]
  • Multiple Disabilities [ Time Frame: 18-22 months corrected age ]
  • Multiorgan Dysfunction [ Time Frame: Until death, discharge, or transfer ]
Severe Neonatal Brain Abnormalities [ Time Frame: 7-14 days of life ]

The data for this analysis have not yet been collected.

MRIs taken between 7-14 days will be examined.

Not Provided
 
Optimizing (Longer, Deeper) Cooling for Neonatal Hypoxic-Ischemic Encephalopathy(HIE)
Optimizing Cooling Strategies at < 6 Hours of Age for Neonatal Hypoxic-Ischemic Encephalopathy
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.

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.

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

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Infant, Newborn
  • Hypoxia, Brain
  • Hypoxia-Ischemia, Brain
  • Encephalopathy, Hypoxic-Ischemic
  • Hypoxic-Ischemic Encephalopathy
  • Ischemic-Hypoxic Encephalopathy
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)
  • Active Comparator: 33.5°C for 72 hours
    Target Temp: 33.5°C Duration: 72 hrs
    Intervention: Procedure: Whole-body Cooling
  • Experimental: 33.5°C for 120 hours
    Target Temp: 33.5°C Duration: 120 hrs
    Intervention: Procedure: Whole-body Cooling
  • Experimental: 32.0°C for 72 hours
    Target Temp: 32.0°C Duration: 72 hrs
    Intervention: Procedure: Whole-body Cooling
  • Experimental: 32.0°C for 120 hours
    Target Temp: 32.0°C Duration:120 hrs
    Intervention: Procedure: Whole-body Cooling

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
364
March 2016
March 2016   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
up to 6 Hours   (Child)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01192776
NICHD-NRN-0043
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 )
U10HD027871 ( U.S. NIH Grant/Contract )
U10HD027880 ( U.S. NIH Grant/Contract )
U10HD027904 ( U.S. NIH Grant/Contract )
U10HD034216 ( U.S. NIH Grant/Contract )
U10HD036790 ( U.S. NIH Grant/Contract )
U10HD040492 ( U.S. NIH Grant/Contract )
U10HD040689 ( U.S. NIH Grant/Contract )
U10HD053089 ( U.S. NIH Grant/Contract )
U10HD053109 ( U.S. NIH Grant/Contract )
U10HD053119 ( U.S. NIH Grant/Contract )
U10HD053124 ( U.S. NIH Grant/Contract )
UL1RR024139 ( U.S. NIH Grant/Contract )
UL1RR024979 ( U.S. NIH Grant/Contract )
UL1RR025008 ( U.S. NIH Grant/Contract )
UL1RR025744 ( U.S. NIH Grant/Contract )
UL1RR025747 ( U.S. NIH Grant/Contract )
UL1RR025761 ( U.S. NIH Grant/Contract )
UL1RR025764 ( U.S. NIH Grant/Contract )
U10HD068284 ( U.S. NIH Grant/Contract )
U10HD068278 ( U.S. NIH Grant/Contract )
U10HD068270 ( U.S. NIH Grant/Contract )
U10HD068263 ( U.S. NIH Grant/Contract )
U10HD068244 ( U.S. NIH Grant/Contract )
Yes
Not Provided
Not Provided
NICHD Neonatal Research Network
NICHD Neonatal Research Network
  • National Center for Research Resources (NCRR)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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
NICHD Neonatal Research Network
July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP