Optimizing (Longer, Deeper) Cooling for Neonatal Hypoxic-Ischemic Encephalopathy(HIE)

NCT01192776 | Terminated Results DMC

• 30 other identifiers: NICHD-NRN-0043U10HD021364U10HD021373U10HD021385U10HD027851U10HD027853U10HD027856U10HD027871U10HD027880U10HD027904U10HD034216U10HD036790U10HD040492U10HD040689U10HD053089U10HD053109U10HD053119U10HD053124UL1RR024139UL1RR024979UL1RR025008UL1RR025744UL1RR025747UL1RR025761UL1RR025764U10HD068284U10HD068278U10HD068270U10HD068263U10HD068244
• Study Type: interventional
• Target: 364
• Locations: 1 country
• Sites: 19

Brief Summary

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.

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; Fetal acidosis

Outcome Measures

Primary Outcomes (1)

• Death or Moderate to Severe Disability

  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.

  Birth to 22 months corrected age

Secondary Outcomes (11)

• Death

  Birth to 22 months corrected age

• Level of Disability Among Survivors

  Follow up at 18-22 months corrected age

• Withdrawal of Care

  Birth through hospital discharge, average 22 days.

• Clinical Neonatal Seizures

  Through death, discharge, or transfer

• Bayley Cognitive Score

  Follow up at 18-22 months corrected age

Other Outcomes (1)

• Severe Neonatal Brain Abnormalities

  7-14 days of life

Study Arms (4)

33.5°C for 72 hours

ACTIVE COMPARATOR

Target Temp: 33.5°C Duration: 72 hrs

Procedure: Whole-body Cooling

33.5°C for 120 hours

EXPERIMENTAL

Target Temp: 33.5°C Duration: 120 hrs

Procedure: Whole-body Cooling

32.0°C for 72 hours

EXPERIMENTAL

Target Temp: 32.0°C Duration: 72 hrs

Procedure: Whole-body Cooling

32.0°C for 120 hours

EXPERIMENTAL

Target Temp: 32.0°C Duration:120 hrs

Procedure: Whole-body Cooling

Interventions

Whole-body Cooling PROCEDURE

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.

Also known as: Blanketrol II Model 222R, Blanketrol III Model 233 (used in the II mode)

32.0°C for 120 hours; 32.0°C for 72 hours; 33.5°C for 120 hours; 33.5°C for 72 hours

Eligibility Criteria

• Age: Up to 6 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Eligibility will be determined in a stepped process:
• 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.
• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• NICHD Neonatal Research Network: lead
• National Center for Research Resources (NCRR): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (19)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

University of California - Los Angeles

Los Angeles, California, 90025, United States

Location

Stanford University

Palo Alto, California, 94304, United States

Location

Emory University

Atlanta, Georgia, 30303, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Wayne State University

Detroit, Michigan, 48201, United States

Location

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

University of New Mexico

Albuquerque, New Mexico, 87131, United States

Location

University of Rochester

Rochester, New York, 14642, United States

Location

RTI International

Durham, North Carolina, 27705, United States

Location

Duke University

Durham, North Carolina, 27710, United States

Location

Cincinnati Children's Medical Center

Cincinnati, Ohio, 45267, United States

Location

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

Cleveland, Ohio, 44106, United States

Location

Research Institute at Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Univeristy of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Brown University, Women & Infants Hospital of Rhode Island

Providence, Rhode Island, 02905, United States

Location

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, 75235, United States

Location

University of Texas Health Science Center at Houston

Houston, Texas, 77030, United States

Location

Related Publications (9)

• Shankaran S, Laptook AR, Guimaraes C, Murnick J, McDonald SA, Das A, Petrie Huitema CM, Pappas A, Higgins RD, Hintz SR, Zaterka-Baxter KM, Van Meurs KP, Sokol GM, Chalak LF, Colaizy TT, Devaskar U, Tyson JE, Reynolds AM, DeMauro SB, Sanchez PJ, Laughon MM, Carlo WA, Watterberg K, Puopolo KM, Hibbs AM, Hamrick SEG, Cotten CM, Barks J, Poindexter BB, Truog WE, D'Angio CT; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. NICHD Magnetic Resonance Brain Imaging Score in Term Infants With Hypoxic-Ischemic Encephalopathy: A Secondary Analysis of a Randomized Clinical Trial. JAMA Pediatr. 2025 Apr 1;179(4):383-395. doi: 10.1001/jamapediatrics.2024.6209.

  PMID: 39960680 DERIVED

• 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.

  PMID: 35835616 DERIVED

• Shukla VV, Bann CM, Ramani M, Ambalavanan N, Peralta-Carcelen M, Hintz SR, Higgins RD, Natarajan G, Laptook AR, Shankaran S, Carlo WA. Predictive Ability of 10-Minute Apgar Scores for Mortality and Neurodevelopmental Disability. Pediatrics. 2022 Apr 1;149(4):e2021054992. doi: 10.1542/peds.2021-054992.

  PMID: 35296895 DERIVED

• Chalak LF, Pappas A, Tan S, Das A, Sanchez PJ, Laptook AR, Van Meurs KP, Shankaran S, Bell EF, Davis AS, Heyne RJ, Pedroza C, Poindexter BB, Schibler K, Tyson JE, Ball MB, Bara R, Grisby C, Sokol GM, D'Angio CT, Hamrick SEG, Dysart KC, Cotten CM, Truog WE, Watterberg KL, Timan CJ, Garg M, Carlo WA, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study. JAMA Neurol. 2021 Dec 1;78(12):1484-1493. doi: 10.1001/jamaneurol.2021.3723.

  PMID: 34882200 DERIVED

• Ambalavanan N, Shankaran S, Laptook AR, Carper BA, Das A, Carlo WA, Cotten CM, Duncan AF, Higgins RD; EUNICE KENNEDY SHRIVER NICHD NEONATAL RESEARCH NETWORK. Early Determination of Prognosis in Neonatal Moderate or Severe Hypoxic-Ischemic Encephalopathy. Pediatrics. 2021 Jun;147(6):e2020048678. doi: 10.1542/peds.2020-048678. Epub 2021 May 13.

  PMID: 33986149 DERIVED

• Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, Poindexter BB, Schibler K, Bell EF, Heyne RJ, Pedroza C, Bara R, Van Meurs KP, Huitema CMP, Grisby C, Devaskar U, Ehrenkranz RA, Harmon HM, Chalak LF, DeMauro SB, Garg M, Hartley-McAndrew ME, Khan AM, Walsh MC, Ambalavanan N, Brumbaugh JE, Watterberg KL, Shepherd EG, Hamrick SEG, Barks J, Cotten CM, Kilbride HW, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA. 2017 Jul 4;318(1):57-67. doi: 10.1001/jama.2017.7218.

  PMID: 28672318 DERIVED

• Pedroza C, Tyson JE, Das A, Laptook A, Bell EF, Shankaran S; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Advantages of Bayesian monitoring methods in deciding whether and when to stop a clinical trial: an example of a neonatal cooling trial. Trials. 2016 Jul 22;17(1):335. doi: 10.1186/s13063-016-1480-4.

  PMID: 27450203 DERIVED

• Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, Poindexter BB, Schibler K, Bell EF, Heyne RJ, Pedroza C, Bara R, Van Meurs KP, Grisby C, Huitema CM, Garg M, Ehrenkranz RA, Shepherd EG, Chalak LF, Hamrick SE, Khan AM, Reynolds AM, Laughon MM, Truog WE, Dysart KC, Carlo WA, Walsh MC, Watterberg KL, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA. 2014 Dec 24-31;312(24):2629-39. doi: 10.1001/jama.2014.16058.

  PMID: 25536254 DERIVED

• Shankaran S. Outcomes of hypoxic-ischemic encephalopathy in neonates treated with hypothermia. Clin Perinatol. 2014 Mar;41(1):149-59. doi: 10.1016/j.clp.2013.10.008.

  PMID: 24524452 DERIVED

Related Links

• Neonatal Research Network website

MeSH Terms

Conditions

Hypoxia, Brain; Hypoxia-Ischemia, Brain; Hypothermia

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Brain Ischemia; Cerebrovascular Disorders; Vascular Diseases; Cardiovascular Diseases; Body Temperature Changes

Limitations and Caveats

This RCT was stopped for safety and futility reasons by the Data Safety and Monitoring Committee so did not enroll the target number of participants needed to achieve target power and statistically reliable results.

Results Point of Contact

• Title: Seetha Shankaran
• Organization: Wayne State University

sshankar@med.wayne.edu

(313) 745-1436

Study Officials

• Seetha Shankaran, MD

  Wayne State University

  STUDY CHAIR

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 31, 2010
• First Posted: September 1, 2010
• Study Start: September 1, 2010
• Primary Completion: March 1, 2016
• Study Completion: March 1, 2016
• Last Updated: November 28, 2025
• Results First Posted: August 15, 2017

Record last verified: 2024-06

Locations

US (19)