Late Hypothermia for Hypoxic-Ischemic Encephalopathy

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

168 participants

Study Classification

INTERVENTIONAL

Study Start Date

2008-04-30

Study Completion Date

2016-06-30

Brief Summary

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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 18-22 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.

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Detailed Description

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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.

Conditions

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Infant, Newborn Hypoxia, Brain Hypoxia-Ischemia, Brain Encephalopathy, Hypoxic-Ischemic Hypoxic-Ischemic Encephalopathy Ischemic-Hypoxic Encephalopathy

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Whole-body Hypothermia

Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours

Group Type EXPERIMENTAL

Hypothermia

Intervention Type PROCEDURE

Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours

Normothermia

Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours

Group Type ACTIVE_COMPARATOR

Normothermic Control

Intervention Type PROCEDURE

Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours

Interventions

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Hypothermia

Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours

Intervention Type PROCEDURE

Normothermic Control

Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours

Intervention Type PROCEDURE

Eligibility Criteria

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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.

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

Minimum Eligible Age

6 Hours

Maximum Eligible Age

24 Hours

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Abbot R. Laptook, MD

Role: PRINCIPAL_INVESTIGATOR

Brown University, Women & Infants Hospital of Rhode Island

Michele C. Walsh, MD MS

Role: PRINCIPAL_INVESTIGATOR

Case Western Reserve University, Rainbow Babies and Children's Hospital

Ronald N. Goldberg, MD

Role: PRINCIPAL_INVESTIGATOR

Duke University

Barbara J. Stoll, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Brenda B. Poindexter, MD MS

Role: PRINCIPAL_INVESTIGATOR

Indiana University

Abhik Das, PhD

Role: PRINCIPAL_INVESTIGATOR

RTI International

Krisa P. Van Meurs, MD

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Ivan D. Frantz III, MD

Role: PRINCIPAL_INVESTIGATOR

Tufts Medical Center

Kurt Schibler, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Medical Center, Cincinnati

Waldemar A. Carlo, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Edward F. Bell, MD

Role: PRINCIPAL_INVESTIGATOR

University of Iowa

Kristi L. Watterberg, MD

Role: PRINCIPAL_INVESTIGATOR

University of New Mexico

Myra Wyckoff, MD

Role: PRINCIPAL_INVESTIGATOR

University of Texas, Southwestern Medical Center at Dallas

Kathleen A. Kennedy, MD MPH

Role: PRINCIPAL_INVESTIGATOR

The University of Texas Health Science Center, Houston

Roger G. Faix, MD

Role: PRINCIPAL_INVESTIGATOR

University of Utah

Seetha Shankaran, MD

Role: PRINCIPAL_INVESTIGATOR

Wayne State University

Richard A. Ehrenkranz, MD

Role: PRINCIPAL_INVESTIGATOR

Yale University

William Truog, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Mercy Hospital Kansas City

Barbara Schmidt, MD, MSc

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Carl D'Angio, MD

Role: PRINCIPAL_INVESTIGATOR

University of Rochester

Uday Devaskar, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, Los Angeles

Pablo Sanchez, M.D

Role: PRINCIPAL_INVESTIGATOR

Ohio State University

Locations

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University of Alabama at Birmingham

Birmingham, Alabama, United States

Site Status

University of California - Los Angeles

Los Angeles, California, United States

Site Status

Stanford University

Palo Alto, California, United States

Site Status

Yale University

New Haven, Connecticut, United States

Site Status

Emory University

Atlanta, Georgia, United States

Site Status

Indiana University

Indianapolis, Indiana, United States

Site Status

University of Iowa

Iowa City, Iowa, United States

Site Status

Tufts Medical Center

Boston, Massachusetts, United States

Site Status

Wayne State University

Detroit, Michigan, United States

Site Status

Children's Mercy Hospital

Kansas City, Missouri, United States

Site Status

University of New Mexico

Albuquerque, New Mexico, United States

Site Status

University of Rochester

Rochester, New York, United States

Site Status

RTI International

Durham, North Carolina, United States

Site Status

Duke University

Durham, North Carolina, United States

Site Status

Cincinnati Children's Medical Center

Cincinnati, Ohio, United States

Site Status

Case Western Reserve University, Rainbow Babies and Children's Hospital

Cleveland, Ohio, United States

Site Status

Research Institute at Nationwide Children's Hospital

Columbus, Ohio, United States

Site Status

Univeristy of Pennsylvania

Philadelphia, Pennsylvania, United States

Site Status

Brown University, Women & Infants Hospital of Rhode Island

Providence, Rhode Island, United States

Site Status

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States

Site Status

University of Texas Health Science Center at Houston

Houston, Texas, United States

Site Status

University of Utah

Salt Lake City, Utah, United States

Site Status

Countries

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United States

References

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Bonifacio SL, Chalak LF, Van Meurs KP, Laptook AR, Shankaran S. Neuroprotection for hypoxic-ischemic encephalopathy: Contributions from the neonatal research network. Semin Perinatol. 2022 Nov;46(7):151639. doi: 10.1016/j.semperi.2022.151639. Epub 2022 Jun 10.

Reference Type DERIVED

PMID: 35835616 (View on PubMed)

Laptook AR, Shankaran S, Barnes P, Rollins N, Do BT, Parikh NA, Hamrick S, Hintz SR, Tyson JE, Bell EF, Ambalavanan N, Goldberg RN, Pappas A, Huitema C, Pedroza C, Chaudhary AS, Hensman AM, Das A, Wyckoff M, Khan A, Walsh MC, Watterberg KL, Faix R, Truog W, Guillet R, Sokol GM, Poindexter BB, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Limitations of Conventional Magnetic Resonance Imaging as a Predictor of Death or Disability Following Neonatal Hypoxic-Ischemic Encephalopathy in the Late Hypothermia Trial. J Pediatr. 2021 Mar;230:106-111.e6. doi: 10.1016/j.jpeds.2020.11.015. Epub 2020 Nov 13.

Reference Type DERIVED

PMID: 33189747 (View on PubMed)

Laptook AR, Shankaran S, Tyson JE, Munoz B, Bell EF, Goldberg RN, Parikh NA, Ambalavanan N, Pedroza C, Pappas A, Das A, Chaudhary AS, Ehrenkranz RA, Hensman AM, Van Meurs KP, Chalak LF, Khan AM, Hamrick SEG, Sokol GM, Walsh MC, Poindexter BB, Faix RG, Watterberg KL, Frantz ID 3rd, Guillet R, Devaskar U, Truog WE, Chock VY, Wyckoff MH, McGowan EC, Carlton DP, Harmon HM, Brumbaugh JE, Cotten CM, Sanchez PJ, Hibbs AM, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA. 2017 Oct 24;318(16):1550-1560. doi: 10.1001/jama.2017.14972.

Reference Type DERIVED

PMID: 29067428 (View on PubMed)