Optimizing (Longer, Deeper) Cooling for Neonatal Hypoxic-Ischemic Encephalopathy(HIE)
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| ClinicalTrials.gov Identifier: NCT01192776 |
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Recruitment Status :
Terminated
(The trial closed for emerging safety profile and futility analysis and will not resume.)
First Posted : September 1, 2010
Results First Posted : August 15, 2017
Last Update Posted : April 11, 2022
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Infant, Newborn Hypoxia, Brain Hypoxia-Ischemia, Brain Encephalopathy, Hypoxic-Ischemic Hypoxic-Ischemic Encephalopathy Ischemic-Hypoxic Encephalopathy | Procedure: Whole-body Cooling | Not Applicable |
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. Secondary Study includes determining an association between MRI detectable injury and neurodevelopment at 18-22 months.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 364 participants |
| Allocation: | Randomized |
| Intervention Model: | Factorial Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Optimizing Cooling Strategies at < 6 Hours of Age for Neonatal Hypoxic-Ischemic Encephalopathy |
| Study Start Date : | September 2010 |
| Actual Primary Completion Date : | March 2016 |
| Actual Study Completion Date : | March 2016 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: 33.5°C for 72 hours
Target Temp: 33.5°C Duration: 72 hrs
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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:
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Experimental: 33.5°C for 120 hours
Target Temp: 33.5°C Duration: 120 hrs
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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:
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Experimental: 32.0°C for 72 hours
Target Temp: 32.0°C Duration: 72 hrs
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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:
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Experimental: 32.0°C for 120 hours
Target Temp: 32.0°C Duration:120 hrs
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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:
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- Death or Moderate to Severe Disability [ Time Frame: Birth to 22 months corrected age ]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.
- Death [ Time Frame: Birth to 22 months corrected age ]Death includes any mortality prior to follow up at 18-22 months.
- Level of Disability Among Survivors [ Time Frame: Follow up at 18-22 months corrected age ]
Among survivors number of normal infants and infants with mild, moderate, and severe disability
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. Mild impairment was defined by a cognitive score 70-84, or a cognitive score ≥ 85 and any of the following: presence of a GMFCS level 1 or 2, seizure disorder or hearing loss not requiring amplification. Normal was defined by a cognitive score ≥ 85 in the absence of any neurosensory deficits or seizures after NICU discharge.
- Withdrawal of Care [ Time Frame: Birth through hospital discharge, average 22 days. ]Number of infants for whom aggressive care is withdrawn
- Clinical Neonatal Seizures [ Time Frame: Through death, discharge, or transfer ]Documented seizures during hospital course
- Bayley Cognitive Score [ Time Frame: Follow up at 18-22 months corrected age ]Bayley Scale of Infant Development Composite Cognitive Score. The total composite score is reported, ranging from the lowest score of 55 to the highest score of 145. Lower values specify worse outcome.
- Cerebral Palsy [ Time Frame: Follow up at 18-22 months corrected age ]
- Level of Disability Among Survivors, by Level of HIE [ Time Frame: Follow up at 18-22 months corrected age ]Among survivors, number of normal infants and infants with mild, moderate and severe disability 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. Mild impairment was defined by a cognitive score 70-84, or a cognitive score ≥ 85 and any of the following: presence of a GMFCS level 1 or 2, seizure disorder or hearing loss not requiring amplification. Normal was defined by a cognitive score ≥ 85 in the absence of any neurosensory deficits or seizures after NICU discharge.
- Visual Impairment [ Time Frame: Follow up at 18-22 months corrected age ]Visual impairment is defined as bilateral blindness with some/no useful vision
- Hearing Impairment [ Time Frame: Follow up at 18-22 months corrected age ]Hearing impairment is defined as hearing impairment despite amplification
- Multiple Disabilities [ Time Frame: Follow up at 18-22 months corrected age ]Multiple disabilities is defined as two or more of the following 5 components: disabling CP, GMFCS level 3-5, Bayley cognitive score < 70, blindness, or deafness.
- Multiorgan Dysfunction [ Time Frame: Until death, discharge, or transfer ]The data needed for this analysis are not collected directly, and will not be analyzed as the study was terminated early and no funds available to complete this complex analysis. The data for this study will be stored at the NICHD-DASH for investigators.
- Severe Neonatal Brain Abnormalities [ Time Frame: 7-14 days of life ]
The data for this analysis have not yet been collected.
MRIs taken between 7-14 days will be examined.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | up to 6 Hours (Child) |
| Sexes Eligible for Study: | All |
| 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.
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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.
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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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01192776
Show 19 study locations
| 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 | 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 |
Study Data/Documents: Publication
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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NICHD Neonatal Research Network Hypoxic-ischemic encephalopathy (HIE) Hypothermia |
Neonatal depression Perinatal asphyxia Fetal acidosis |
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Brain Diseases Brain Ischemia Hypoxia-Ischemia, Brain Hypoxia, Brain Ischemia Hypoxia Pathologic Processes |
Signs and Symptoms, Respiratory Central Nervous System Diseases Nervous System Diseases Cerebrovascular Disorders Vascular Diseases Cardiovascular Diseases |