Late Hypothermia for Hypoxic-Ischemic Encephalopathy
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| ClinicalTrials.gov Identifier: NCT00614744 |
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Recruitment Status :
Completed
First Posted : February 13, 2008
Results First Posted : August 7, 2017
Last Update Posted : March 9, 2021
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Infant, Newborn Hypoxia, Brain Hypoxia-Ischemia, Brain Encephalopathy, Hypoxic-Ischemic Hypoxic-Ischemic Encephalopathy Ischemic-Hypoxic Encephalopathy | Procedure: Hypothermia Procedure: Normothermic Control | Not Applicable |
Hypoxic-ischemic encephalopathy (HIE) is a rare, but life-threatening condition characterized by acute or subacute brain injury due to asphyxia. In most cases the underlying cause and timing of injury are unknown, but many cases are 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.
The incidence of long-term complications depends on the severity of HIE. Up to 80 percent of infants who survive stage 3 HIE develop significant long-term neurological disabilities - mental retardation, epilepsy, and cerebral palsy with hemiplegia, paraplegia, or quadriplegia; 10-20 percent develop moderately serious disabilities; and up to 10 percent are normal.
Because animal data suggests that brain injury from HIE evolves over several hours to days after the initial asphyxic insult, induced hypothermia holds promise as a neuroprotective therapy. Additional trials are needed to help define the most effective cooling strategies.
With this in mind, and knowing that many babies with HIE arrive at neonatal intensive care units several hours after birth, this study will evaluate the safety and efficacy of initiating hypothermia 6-24 hours after birth.
Study subjects: Infants born at 36 0/7ths weeks or greater gestational age that have been diagnosed with neonatal depression, perinatal asphyxia, or encephalopathy. The goal is to enroll 168 subjects.
Stratification: After informed consent is obtained, infants will be randomized to either a hypothermia arm (with a target esophageal temperature of 33.5°C) or a control arm (37.0°C) for 96 hours. Enrolled infants will be stratified by age of enrollment (≤ 12 and > 12 hours) and stage of encephalopathy (moderate or severe).
Informed Consent: Parents of eligible infants will be approached for consent to enroll in the study if the infant has a high probability of acute hemodynamic compromise, as defined above. Subsequent screening will determine whether the infant meets all inclusion criteria.
Randomization: eligible and consented infants will be randomly assigned to either a hypothermia intervention group, or a non-cooled (control) group.
Study Intervention: Induced whole-body hypothermia (with a target esophageal temperature of 33.5°C) or a control group (37.0°C) for 96 hours.
Interim Study Interruptions: None to date.
Secondary Study includes determining an association between MRI detectable injury and neurodevelopment at 18-22 months.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 168 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Evaluation of Systemic Hypothermia Initiated After 6 Hours of Age in Infants ≥36 Weeks Gestation With Hypoxic-Ischemic Encephalopathy: A Bayesian Evaluation. A Protocol for the NICHD Neonatal Research Network |
| Study Start Date : | April 2008 |
| Actual Primary Completion Date : | June 2016 |
| Actual Study Completion Date : | June 2016 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Whole-body Hypothermia
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
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Procedure: Hypothermia
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours |
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Active Comparator: Normothermia
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
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Procedure: Normothermic Control
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours |
- Death or Moderate or Severe Disability [ Time Frame: Birth to 18-22 months corrected gestational age ]Severe disability was defined by any of the following: a Bayley III cognitive score < 70 or Gross Motor Functional (GMF) Level of 3-5 blindness or profound hearing loss requiring amplification but still unable to follow 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.
- Number of Deaths in the NICU and Following Discharge [ Time Frame: Birth to 18-22 months corrected gestational age ]
- Number of Infants With Moderate and Severe Disability [ Time Frame: Birth to 18-22 months corrected gestational age ]Moderate disability will be 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. Severe disability will be defined by any of the following: a Bayley III cognitive score < 70 or Gross Motor Functional (GMF) Level of 3-5 or blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate.
- Number of Infants With Mild, Moderate and Severe Disability [ Time Frame: Birth to 18-22 months corrected gestational age ]Mild disability will be defined by either a Bayley III cognitive score of 70-84 alone or a Bayley III cognitive score >= 85 and any of the following: presence of a GMF level 1 or 2 OR seizure disorder or hearing loss. 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. Severe disability will be defined by any of the following: a Bayley III cognitive score < 70 OR Gross Motor Functional (GMF) Level of 3-5 OR blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate.
- Number of Infants With Any Disability Based on Level of Encephalopathy at Randomization [ Time Frame: Birth to 18-22 months corrected gestational age ]Mild disability will be defined by either a Bayley III cognitive score of 70-84 alone or a Bayley III cognitive score >= 85 and any of the following: presence of a GMF level 1 or 2OR seizure disorder or hearing loss. 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. Severe disability will be defined by any of the following: a Bayley III cognitive score < 70 OR Gross Motor Functional (GMF) Level of 3-5 OR blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate.
- Number of Infants With Non-CNS Organ System Dysfunction [ Time Frame: Birth to 18-22 months corrected gestational age ]Based on observing presence of organ dysfunction on at least one of the following: Pulmonary (Meconium aspiration syndrome, PPHN, Pulmonary hemorrhage, Pneumonia, Chronic lung disease, ECMO, INO), Cardiovascular (Cardiomegaly, Cardiac failure, Cardiac dysfunction (by echo), Cardiac ischemia (by EKG and/or increased enzymes), Hypotension, Arrhythmia), Renal (Oliguria, Anuria, Dialysis), Gastrointestinal (NEC, Hepatic dysfunction), Hematologic (DIC) and Metabolic (Hypoglycemia, Hypocalcemia, Hypomagnesemia)
- Number of Infants With a DNR Order [ Time Frame: Birth to 18-22 months corrected gestational age ]
- Number of Infants With a DNR Order and Support is Withdrawn [ Time Frame: Birth to 18-22 months corrected gestational age ]
- Number of Infants With a DNR Order That Died [ Time Frame: Birth to 18-22 months corrected gestational age ]
- Number of Infants With Neonatal Seizures, With and Without EEG Abnormalities [ Time Frame: Birth to 18-22 months corrected gestational age ]
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| Ages Eligible for Study: | 6 Hours to 24 Hours (Child) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Infants born at 36 0/7ths weeks gestational age or greater (by best obstetrical estimate)
- Postnatal age between 6 and 24 hours following birth
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Infants with a high probability of acute hemodynamic compromise, such as those with:
- An acute perinatal event (abruptio placenta, cord prolapse, severe FHR abnormality)
- An Apgar score ≤ 5 at 10 minutes
- Continued need for ventilation initiated at birth for at least 10 minutes
- Cord pH or first postnatal blood gas pH at ≤ 1 hour of ≤ 7.0
- Base deficit on cord gas or first postnatal blood gas at ≤ 1 hour of ≥ 16 mEq/L
- Infants matching the above criteria who also have an abnormal neurological exam showing the presence of moderate or severe encephalopathy
- Infants whose parents/legal guardians have provided consent for enrollment.
NOTE: These inclusion criteria are identical to the NICHD Neonatal Research Network's 2005 Hypothermia study (see links below), except for the time of entry (6-24 hours vs. < 6 hours of age).
Exclusion Criteria:
- Any infant with a core body temperature (axilla, rectal) less than 34.0°C for greater than 1 hour
- Presence of a known anomaly or chromosomal aberration
- Birth weight < 1,800 grams
- Infant in extremis
- Infants whose parents/legal guardians or attending physician refuse consent
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00614744
Show 22 study locations
| 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: | Ivan D. Frantz III, MD | Tufts Medical Center | |
| 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: | Myra Wyckoff, 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: | Roger G. Faix, MD | University of Utah | |
| Principal Investigator: | Seetha Shankaran, MD | Wayne State University | |
| Principal Investigator: | Richard A. Ehrenkranz, MD | Yale University | |
| 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: | Pablo Sanchez, M.D | Ohio State University |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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NICHD Neonatal Research Network Hypoxic-ischemic encephalopathy (HIE) Hypothermia Neonatal depression Perinatal asphyxia |
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Brain Diseases Brain Ischemia Hypoxia-Ischemia, Brain Hypoxia, Brain Ischemia Hypoxia Hypothermia Pathologic Processes |
Signs and Symptoms, Respiratory Central Nervous System Diseases Nervous System Diseases Body Temperature Changes Cerebrovascular Disorders Vascular Diseases Cardiovascular Diseases |