Clinical trial NCT00614744: Late Hypothermia for Hypoxic-Ischemic Encephalopathy
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Infant, Newborn
Hypoxia, Brain
Hypoxia-Ischemia, Brain
Encephalopathy, Hypoxic-Ischemic
Hypoxic-Ischemic Encephalopathy
Ischemic-Hypoxic Encephalopathy
Keywords: NICHD Neonatal Research Network
Hypoxic-ischemic encephalopathy (HIE)
Hypothermia
Neonatal depression
Perinatal asphyxia
Lead sponsor: NICHD Neonatal Research Network
Sponsor class: NETWORK
Collaborators: name: National Center for Research Resources (NCRR)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2008-02-13
Enrollment: 168
Sex: ALL
Minimum age (years): 6
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

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

Eligibility criteria: 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

Primary outcomes:
measure: Death or Moderate or Severe Disability
timeFrame: Birth to 18-22 months corrected gestational age
Secondary outcomes:
measure: Number of Deaths in the NICU and Following Discharge
timeFrame: Birth to 18-22 months corrected gestational age
measure: Number of Infants With Moderate and Severe Disability
timeFrame: Birth to 18-22 months corrected gestational age
measure: Number of Infants With Mild, Moderate and Severe Disability
timeFrame: Birth to 18-22 months corrected gestational age
measure: Number of Infants With Any Disability Based on Level of Encephalopathy at Randomization
timeFrame: Birth to 18-22 months corrected gestational age
measure: Number of Infants With Non-CNS Organ System Dysfunction
timeFrame: Birth to 18-22 months corrected gestational age
measure: Number of Infants With a DNR Order
timeFrame: Birth to 18-22 months corrected gestational age
measure: Number of Infants With a DNR Order and Support is Withdrawn
timeFrame: Birth to 18-22 months corrected gestational age
measure: Number of Infants With a DNR Order That Died
timeFrame: Birth to 18-22 months corrected gestational age
measure: Number of Infants With Neonatal Seizures, With and Without EEG Abnormalities
timeFrame: Birth to 18-22 months corrected gestational age
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: University of California - Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Durham
country: United States
facility: RTI International
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University, Rainbow Babies and Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Research Institute at Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Univeristy of Pennsylvania
state: Pennsylvania
city: Providence
country: United States
facility: Brown University, Women & Infants Hospital of Rhode Island
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: Brown University, Women & Infants Hospital of Rhode Island
name: Abbot R. Laptook, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Case Western Reserve University, Rainbow Babies and Children's Hospital
name: Michele C. Walsh, MD MS
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: Ronald N. Goldberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Barbara J. Stoll, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Indiana University
name: Brenda B. Poindexter, MD MS
role: PRINCIPAL_INVESTIGATOR
affiliation: RTI International
name: Abhik Das, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Krisa P. Van Meurs, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Tufts Medical Center
name: Ivan D. Frantz III, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Kurt Schibler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Waldemar A. Carlo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Iowa
name: Edward F. Bell, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of New Mexico
name: Kristi L. Watterberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas, Southwestern Medical Center at Dallas
name: Myra Wyckoff, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Texas Health Science Center, Houston
name: Kathleen A. Kennedy, MD MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Utah
name: Roger G. Faix, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wayne State University
name: Seetha Shankaran, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale University
name: Richard A. Ehrenkranz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Mercy Hospital Kansas City
name: William Truog, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Barbara Schmidt, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Carl D'Angio, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Uday Devaskar, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ohio State University
name: Pablo Sanchez, M.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.