Optimizing (Longer, Deeper) Cooling for Neonatal Hypoxic-Ischemic Encephalopathy(HIE)
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Infant, Newborn Hypoxia, Brain Hypoxia-Ischemia, Brain Encephalopathy, Hypoxic-Ischemic Hypoxic-Ischemic Encephalopathy Ischemic-Hypoxic Encephalopathy |
Procedure: Whole-body Cooling |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Factorial Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Optimizing Cooling Strategies at < 6 Hours of Age for Neonatal Hypoxic-Ischemic Encephalopathy |
- Death or Moderate to Severe Disability [ Time Frame: Birth to 22 months corrected age ] [ Designated as safety issue: Yes ]
- Death [ Time Frame: Birth to 22 months corrected age ] [ Designated as safety issue: Yes ]
- Mild, moderate, and severe disability [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]Number of infants with mild, moderate, and severe disability
- Withdrawal of care [ Time Frame: Birth to hospital discharge ] [ Designated as safety issue: Yes ]Number of infants for whom aggressive care is withdrawn
- Acute Adverse Events [ Time Frame: Until infant achieves normothermia ] [ Designated as safety issue: Yes ]Number of adverse events (severe bradycardia, acidosis, bleeding or ischemic CNS abnormalities)
- Clinical neonatal seizures [ Time Frame: Until death, discharge, or transfer ] [ Designated as safety issue: Yes ]
- Severe neonatal brain abnormalities [ Time Frame: 7-14 days of life ] [ Designated as safety issue: Yes ]MRIs taken between 7-14 days will be examined.
- Cognitive outcome [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
- Cerebral palsy [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
- Disability by stage of HIE [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
- Visual impairment [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
- Hearing impairment [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
- Multiple Disabilities [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
- Multiorgan Dysfunction [ Time Frame: Until death, discharge, or transfer ] [ Designated as safety issue: Yes ]
| Estimated Enrollment: | 726 |
| Study Start Date: | September 2010 |
| Estimated Study Completion Date: | March 2017 |
| Estimated Primary Completion Date: | August 2015 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: 33.5°C for 72 hours
Target Temp: 33.5°C Duration: 72 hrs
|
Procedure: Whole-body Cooling
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.
Other Names:
|
|
Experimental: 33.5°C for 120 hours
Target Temp: 33.5°C Duration: 120 hrs
|
Procedure: Whole-body Cooling
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.
Other Names:
|
|
Experimental: 32.0°C for 72 hours
Target Temp: 32.0°C Duration: 72 hrs
|
Procedure: Whole-body Cooling
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.
Other Names:
|
|
Experimental: 32.0°C for 120 hours
Target Temp: 32.0°C Duration:120 hrs
|
Procedure: Whole-body Cooling
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.
Other Names:
|
Detailed Description:
Hypoxic-ischemic encephalopathy (HIE) is a rare, but life-threatening condition characterized by brain injury due to asphyxia 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. Up to 80 percent of infants who survive stage 3 HIE develop significant long-term disabilities, including intellectual disabilities, epilepsy, and cerebral palsy with hemiplegia, paraplegia, or quadriplegia; 10-20 percent develop moderately serious disabilities; and up to 10 percent are normal.
Previous studies have shown treatment with hypothermia to be an effective therapy for HIE. Currently, infants diagnosed with HIE at less than six hours of age are given whole-body cooling, decreasing their core body temperature to 33.5°C (93.2° Fahrenheit) for a period 72 hours using a cooling blanket. This treatment appears to protect the brain, decreasing the rate of death and disability and improving the chances of survival and neurodevelopmental outcomes at 18 months correct age. But additional trials are needed to help define the most effective cooling strategies.
The Optimizing Cooling trial will examine whether cooling for a longer time period and/or to a lower temperature will improve the chance of survival and neurodevelopmental outcomes at 18-22 months corrected age. Eligible infants with HIE will be placed in one of four cooling groups: (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. Infants will be monitored closely and receive the care of the Neonatal Intensive Care Unit (NICU).
Infants enrolled in the study will be placed on a cooling blanket - the same type of blanket children's hospitals use in the NICU, in operating rooms during surgeries, and to cool children with high fevers. Each infant will be cooled according to the study group he or she is assigned to. During cooling, the infant's temperature will be very closely monitored by continuous esophageal (core)temperature readings. This will be done by placing a soft, narrow, flexible plastic tube into the infant's nose and down to just above the stomach. Skin temperatures will also be monitored closely. At the end of the assigned period of cooling, the infant will be slowly re-warmed until a normal core temperature of 36.5 to 37.0°C (97.7 to 98.6°C) is reached.
Infants will be examined at 18-22 months corrected age to assess their neurodevelopmental outcomes.
Secondary Studies include:
A. Using aEEG to 1)predict mortality or moderate to severe disability at 18-22 months in term infants with HIE treated with systemic hypothermia and 2) to record electrical seizure activity to compare rewarming initiated at 72 hours and later rewarming that is initiated at 120 hours.
B. Determine whether peri-cooling levels of circulating brain injury biomarkers predict adverse outcomes including 1) death or neurologic disability at 18-22 months and 2) MRI abnormalities at 7-14 days within and between the NRN primary trial whole body cooling treatment groups.
Eligibility| Ages Eligible for Study: | up to 6 Hours |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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.
Exclusion Criteria:
- 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.
Contacts and Locations| Contact: Seetha Shankaran, MD | (313) 745-1436 | sshankar@med.wayne.edu |
| Contact: Rosemary D. Higgins, MD | (301) 496-5575 | higginsr@mail.nih.gov |
| United States, Alabama | |
| University of Alabama at Birmingham | Recruiting |
| Birmingham, Alabama, United States, 35233 | |
| Contact: Waldemar A. Carlo, MD 205-934-4680 wcarlo@peds.uab.edu | |
| Contact: Monica V. Collins, RN BSN (205) 934-5771 mcollins@peds.uab.edu | |
| Principal Investigator: Waldemar A. Carlo, MD | |
| United States, California | |
| University of California - Los Angeles | Recruiting |
| Los Angeles, California, United States, 90025 | |
| Contact: Uday Devaskar, MD 310-825-9357 udevaskar@mednet.ucla.edu | |
| Contact: Teresa Chanlaw, BS (310) 794-4972 tchanlaw@mednet.ucla.edu | |
| Principal Investigator: Uday Devaskar, MD | |
| Sub-Investigator: James Dunn, MD, PhD | |
| Stanford University | Recruiting |
| Palo Alto, California, United States, 94304 | |
| Contact: Krisa P. Van Meurs, MD 650-723-5711 vanmeurs@leland.stanford.edu | |
| Contact: M. Bethany Ball, BS CCRC (650) 725-8342 mbball@stanford.edu | |
| Principal Investigator: Krisa P. Van Meurs, MD | |
| United States, Georgia | |
| Emory University | Recruiting |
| Atlanta, Georgia, United States, 30303 | |
| Contact: Barbara J. Stoll, MD 404-727-5740 barbara_stoll@oz.ped.emory.edu | |
| Contact: Ellen Hale, RN BS (404) 616-4218 ellen_hale@oz.ped.emory.edu | |
| Principal Investigator: Barbara J. Stoll, MD | |
| United States, Indiana | |
| Indiana University | Recruiting |
| Indianapolis, Indiana, United States, 46202 | |
| Contact: Brenda B. Poindexter, MD MS 317-274-3592 bpoindex@iupui.edu | |
| Contact: Leslie D. Wilson, RN BSN (317) 274-8255 ldw@iupui.edu | |
| Principal Investigator: Brenda B. Poindexter, MD MS | |
| United States, Iowa | |
| University of Iowa | Recruiting |
| Iowa City, Iowa, United States, 52242 | |
| Contact: Edward F. Bell, MD 319-356-4006 edward-bell@uiowa.edu | |
| Contact: Karen J. Johnson, RN BSN (319) 356-2924 karen-johnson@uiowa.edu | |
| Principal Investigator: Edward F. Bell, MD | |
| United States, Michigan | |
| Wayne State University | Recruiting |
| Detroit, Michigan, United States, 48201 | |
| Contact: Seetha Shankaran, MD 313-580-4452 sshankar@med.wayne.edu | |
| Contact: Rebecca Bara, RN BSN (313) 745-1436 rbara@med.wayne.edu | |
| Principal Investigator: Seetha Shankaran, MD | |
| United States, Missouri | |
| Children's Mercy Hospital | Recruiting |
| Kansas City, Missouri, United States, 64108 | |
| Contact: William Truog, MD 816-234-3592 wtruog@cmh.edu | |
| Contact: Cheri Gauldin, BSN (816) 234-3920 cagauldin@cmh.edu | |
| Principal Investigator: William Truog, MD | |
| Sub-Investigator: George Holcomb, MD | |
| United States, New Mexico | |
| University of New Mexico | Recruiting |
| Albuquerque, New Mexico, United States, 87131 | |
| Contact: Kristi L. Watterberg, MD 505-272-3967 kwatterberg@salud.unm.edu | |
| Contact: Conra Backstrom Lacy, RN (505) 272-0367 cbackstrom@salud.unm.edu | |
| Principal Investigator: Kristi L. Watterberg, MD | |
| United States, New York | |
| University of Rochester | Recruiting |
| Rochester, New York, United States, 14642 | |
| Contact: Carl T D'Angio, MD 585-273-4911 carl_dangio@urmc.rochester.edu | |
| Principal Investigator: Carl T D'Angio, MD | |
| Sub-Investigator: Walter Pegoli, MD | |
| United States, North Carolina | |
| Duke University | Recruiting |
| Durham, North Carolina, United States, 27710 | |
| Contact: Ronald N. Goldberg, MD 919-681-6025 goldb008@mc.duke.edu | |
| Contact: Joanne Finkle (919) 681-5859 j.finkle@duke.edu | |
| Principal Investigator: Ronald N. Goldberg, MD | |
| Sub-Investigator: C. Michael Cotten, MD MHS | |
| RTI International | Active, not recruiting |
| Durham, North Carolina, United States, 27705 | |
| United States, Ohio | |
| Cincinnati Children's Medical Center | Recruiting |
| Cincinnati, Ohio, United States, 45267 | |
| Contact: Kurt Schibler, MD 513-636-3972 kurt.schibler@cchmc.org | |
| Contact: Cathy Grisby, BSN CCRC (513) 558-4953 grisbyca@email.uc.edu | |
| Principal Investigator: Kurt Schibler, MD | |
| Case Western Reserve University, Rainbow Babies and Children's Hospital | Recruiting |
| Cleveland, Ohio, United States, 44106 | |
| Contact: Michele C. Walsh, MD MS 216-844-3759 mcw3@cwru.edu | |
| Contact: Nancy S. Newman, BA RN (216) 368-3084 nxs5@cwru.edu | |
| Principal Investigator: Michele C. Walsh, MD MS | |
| Research Institute at Nationwide Children's Hospital | Recruiting |
| Columbus, Ohio, United States, 43205 | |
| Contact: Leif Nelin, MD 614-722-3030 Leif.Nelin@nationwidechildrens.org | |
| Contact: Christine Fortney, MS, RN 614-722-6489 christine.fortney@nationwidechildrens.org | |
| Principal Investigator: Leif Nelin, MD | |
| Sub-Investigator: Gail E Besner, MD | |
| United States, Pennsylvania | |
| Univeristy of Pennsylvania | Recruiting |
| Philadelphia, Pennsylvania, United States, 19104 | |
| Contact: Barbara Schmidt, MD 215-662-3228 barbara.schmidt@uphs.upenn.edu | |
| Contact: Aasma Chaudhary, BS 215-615-5442 aasma.chaudhary@uphs.upenn.edu | |
| Principal Investigator: Barbara Schmidt, MD | |
| Sub-Investigator: Alan Flake, MD | |
| United States, Rhode Island | |
| Brown University, Women & Infants Hospital of Rhode Island | Recruiting |
| Providence, Rhode Island, United States, 02905 | |
| Contact: Abbot R. Laptook, MD 401-274-1122 alaptook@WIHRI.org | |
| Contact: Angelita Hensman (401) 274-1122 ahensman@wihri.org | |
| Principal Investigator: Abbot R. Laptook, MD | |
| United States, Texas | |
| University of Texas Southwestern Medical Center at Dallas | Recruiting |
| Dallas, Texas, United States, 75235 | |
| Contact: Pablo J. Sanchez, MD 214-648-3753 Pablo.Sanchez@UTSouthwestern.edu | |
| Contact: Diana M. Vasil, RNC-NIC (214) 648-3789 Diana.Vasil@utsouthwestern.edu | |
| Principal Investigator: Pablo J. Sanchez, MD | |
| University of Texas Health Science Center at Houston | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Kathleen A. Kennedy, MD MPH 713-500-6708 Kathleen.A.Kennedy@uth.tmc.edu | |
| Contact: Georgia E. McDavid, RN (713) 500-5734 Georgia.E.McDavid@uth.tmc.edu | |
| Principal Investigator: Kathleen A. Kennedy, MD MPH | |
| Sub-Investigator: Jon E. Tyson, MD MPH | |
| Study Chair: | Seetha Shankaran, MD | Wayne State University |
| 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: | 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: | 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, MD | Research Institute at Nationwide Children's Hospital |
More Information
Additional Information:
No publications provided
| Responsible Party: | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) |
| ClinicalTrials.gov Identifier: | NCT01192776 History of Changes |
| Other Study ID Numbers: | NICHD-NRN-0043, U10HD021364, U10HD021373, U10HD021385, U10HD027851, U10HD027853, U10HD027856, U10HD027871, U10HD027880, U10HD027904, U10HD034216, U10HD036790, U10HD040492, U10HD040689, U10HD053089, U10HD053109, U10HD053119, U10HD053124, UL1RR024139, UL1RR024979, UL1RR025008, UL1RR025744, UL1RR025747, UL1RR025761, UL1RR025764, U10HD068284, U10HD068278, U10HD068270, U10HD068263, U10HD068244 |
| Study First Received: | August 31, 2010 |
| Last Updated: | February 13, 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 Fetal acidosis |
Additional relevant MeSH terms:
|
Hypoxia, Brain Brain Ischemia 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 Pathologic Processes Confusion Neurobehavioral Manifestations Neurologic Manifestations Signs and Symptoms Delirium, Dementia, Amnestic, Cognitive Disorders Mental Disorders Central Nervous System Viral Diseases Virus Diseases Central Nervous System Infections Liver Failure Hepatic Insufficiency Liver Diseases Digestive System Diseases |
ClinicalTrials.gov processed this record on May 16, 2013