Late Hypothermia for Hypoxic-Ischemic Encephalopathy
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Purpose
This study is a randomized, placebo-controlled, clinical trial to evaluate whether induced whole-body hypothermia initiated between 6-24 hours of age and continued for 96 hours in infants ≥ 36 weeks gestational age with hypoxic-ischemic encephalopathy will reduce the incidence of death or disability at 18-24 months of age. The study will enroll 168 infants with signs of hypoxic-ischemic encephalopathy at 16 NICHD Neonatal Research Network sites, and randomly assign them to either receive hypothermia or participate in a non-cooled control group.
| Condition | Intervention | Phase |
|---|---|---|
|
Infant, Newborn Hypoxia, Brain Hypoxia-Ischemia, Brain Encephalopathy, Hypoxic-Ischemic Hypoxic-Ischemic Encephalopathy Ischemic-Hypoxic Encephalopathy |
Procedure: Hypothermia Procedure: Normothermic Control |
Phase 2 Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: 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 |
- Death or moderate or severe disability [ Time Frame: Birth to 18-24 months corrected gestational age ] [ Designated as safety issue: Yes ]
- Number of deaths in the NICU and following discharge [ Time Frame: Birth to 18-24 months corrected gestational age ] [ Designated as safety issue: Yes ]
- Number of infants with moderate and severe disability [ Time Frame: Birth to 18-24 months corrected gestational age ] [ Designated as safety issue: Yes ]
- Number of infants with mild, moderate and severe disability [ Time Frame: Birth to 18-24 months corrected gestational age ] [ Designated as safety issue: Yes ]
- Number of infants with any disability based on level of encephalopathy at randomization [ Time Frame: Birth to 18-24 months corrected gestational age ] [ Designated as safety issue: Yes ]
- Number of infants with non-CNS organ system dysfunction [ Time Frame: Birth to 18-24 months corrected gestational age ] [ Designated as safety issue: Yes ]
- Number of infants with a DNR order [ Time Frame: Birth to 18-24 months corrected gestational age ] [ Designated as safety issue: Yes ]
- Number of infants with a DNR order and support is withdrawn [ Time Frame: Birth to 18-24 months corrected gestational age ] [ Designated as safety issue: Yes ]
- Number of infants with a DNR order and either die or survive [ Time Frame: Birth to 18-24 months corrected gestational age ] [ Designated as safety issue: Yes ]
- Number of infants with neonatal seizures, with and without EEG abnormalities [ Time Frame: Birth to 18-24 months corrected gestational age ] [ Designated as safety issue: Yes ]
| Estimated Enrollment: | 168 |
| Study Start Date: | April 2008 |
| Estimated Study Completion Date: | March 2014 |
| Estimated Primary Completion Date: | March 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Whole-body Hypothermia
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
|
Procedure: Hypothermia
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
|
|
Active Comparator: Normothermia
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
|
Procedure: Normothermic Control
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
|
Detailed Description:
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.
Eligibility| Ages Eligible for Study: | up to 24 Hours |
| Genders Eligible for Study: | Both |
| 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
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
Contacts and Locations| Contact: Abbot R. Laptook, MD | (401) 274-1122 | alaptook@WIHRI.org |
| Contact: Rosemary D. Higgins, MD | (301) 496-5575 | higginsr@mail.nih.gov |
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 | Cincinnati Children's Medical Center |
| 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: | 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, MO |
| 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 | Ohio State University |
More Information
Additional Information:
No publications provided
| Responsible Party: | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) |
| ClinicalTrials.gov Identifier: | NCT00614744 History of Changes |
| Other Study ID Numbers: | NICHD-NRN-0038, U10HD036790, U10HD021364, U10HD021373, U10HD021385, U10HD027851, U10HD027853, U10HD027856, U10HD027871, U10HD027880, U10HD027904, U10HD034216, U10HD040492, U10HD040689, U10HD053089, U10HD053109, U10HD053119, U10HD053124, UL1RR024139, UL1RR025744, UL1RR024979, U10HD068244, 1U10HD068263-01, U10HD068270, U10HD068278, U10HD068284 |
| Study First Received: | February 11, 2008 |
| Last Updated: | January 17, 2013 |
| Health Authority: | United States: Federal Government United States: Institutional Review Board |
Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):
|
NICHD Neonatal Research Network Hypoxic-ischemic encephalopathy (HIE) Hypothermia Neonatal depression Perinatal asphyxia |
Additional relevant MeSH terms:
|
Hypoxia, Brain Brain Ischemia Hypothermia Ischemia Brain Damage, Chronic Delirium Encephalitis Hepatic Encephalopathy Neurotoxicity Syndromes Anoxia Hypoxia-Ischemia, Brain Brain Diseases Central Nervous System Diseases Nervous System Diseases Cerebrovascular Disorders |
Vascular Diseases Cardiovascular Diseases Body Temperature Changes Signs and Symptoms Pathologic Processes Confusion Neurobehavioral Manifestations Neurologic Manifestations Delirium, Dementia, Amnestic, Cognitive Disorders Mental Disorders Central Nervous System Viral Diseases Virus Diseases Central Nervous System Infections Liver Failure Hepatic Insufficiency |
ClinicalTrials.gov processed this record on May 16, 2013