Encephalopathy, Hypoxic-Ischemic, Hypoxia, Brain, Hypoxia-Ischemia, Brain, Hypoxic-Ischemic Encephalopathy, Infant, Newborn, Ischemic-Hypoxic Encephalopathy
Conditions
Keywords
NICHD Neonatal Research Network, Hypoxic-ischemic encephalopathy (HIE), Hypothermia, Neonatal depression, Perinatal asphyxia
Brief summary
This study is a randomized, controlled trial to assess safety and effectiveness of whole body hypothermia for 72 hours in preterm infants 33-35 weeks gestational age (GA) who present at \<6 hours postnatal age with moderate to severe neonatal encephalopathy (NE). The study will enroll infants with signs of NE at 18 NICHD Neonatal Research Network sites, and randomly assign them to either receive hypothermia or participate in a non-cooled control group.
Detailed description
Most clinical studies of neonatal encephalopathy (NE) and potential interventions have focused on infants ≥36 weeks GA. Although many interventions have been suggested and assessed for prevention or palliation of NE, the only one currently supported by rigorous clinical evidence to improve outcome in human newborns has been hypothermia implemented at \<6 hours of postnatal age and maintained for 72 hrs. Data about diagnosis, frequency, severity, and outcome of NE in infants 33-35 weeks GA are sparse. This trial will assess safety and effectiveness of whole body hypothermia for 72 hours in preterm infants 33-35 weeks gestational age (GA) who present at \<6 hrs postnatal age with moderate to severe neonatal encephalopathy. Infants 33 0/7 to 35 6/7 weeks GA (best obstetrical estimate) and greater than or equal to 1500 grams birth weight (selected to minimize potential difficulties placing esophageal probe) who meet clinical, biochemical and neurologic criteria for moderate to severe NE will be randomized to either whole body hypothermia or participate in a non-cooled control group. The primary outcome will be death or moderate to severe disability at 18-22 months corrected age. The presence or absence of disability will be determined by the standard NRN interdisciplinary follow-up exam. Secondary Study includes determining an association between MRI detectable injury and neurodevelopment at 18-22 months.
Interventions
DEVICEHypothermia
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 72 hours
PROCEDURENormothermic Control
Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NICHD Neonatal Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
33 Weeks to 35 Weeks
Healthy volunteers
No
Inclusion criteria
* Infants 33 0/7 to 35 6/7 weeks GA (best obstetrical estimate) * Infants weight greater than or equal to 1500 grams at birth * Postnatal age less than 6 hours * Infants who meet clinical, biochemical and neurologic criteria for moderate to severe NE: Biochemical: Cord gas or blood gas within first hour of life with pH ≤7.00 or base deficit (BD) ≥16 mEq/L OR Acute perinatal event (e.g., abruptio placenta, cord prolapse, uterine rupture, severe FHR abnormality such as variable or late decelerations) AND Requirement for positive pressure ventilation for apnea or poor respiratory effort since birth for at least 10 minutes OR 10 minute Apgar score ≤5 AND Neurologic: Seizures OR modified Sarnat score with abnormalities in at least 3 of the 6 categories; at least one must be altered level of consciousness (lethargy or stupor/coma) as determined by a certified examiner (All infants who meet criteria for potential inclusion will undergo standard neurologic exam as for infants ≥36 wks GA being considered for hypothermia, with findings recorded)
Exclusion criteria
* Receipt of sedative, analgesic or paralytic agent that may confound the qualifying neurologic exam * Etiology of NE not likely to be hypoxic-ischemic in origin * Major congenital anomaly that may confound outcome * Considered to be moribund and will not be receiving full intensive care * Equipment and/or appropriate staff not available * Core temperature \< 33.5oC for more than one hour at time of screening * Unable to randomize by 6 hours of age * Infant needs ECMO * All blood gases (cord and postnatal at \< 1hr of age) have a pH \> 7.15 AND a base deficit \< 10mEq/L
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Death or Moderate or Severe Disability | Birth to 18-22 months corrected age | Severe disability was defined by any of the following: a Bayley III cognitive score \< 70 or Gross Motor Function (GMF) Level of 3-5 blindness or profound hearing loss requiring amplification but still unable to following commands/communicate. Moderate disability was defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Deaths in the NICU and Following Discharge | Birth to 18-22 months corrected age | Number of deaths in the NICU and following discharge among infants with a primary outcome. |
| Number of Infants With Abnormal MRIs During Post-intervention Period | Post-intervention to through discharge, death, or transfer (whichever comes first), average of 29 days | An MRI was considered abnormal if any abnormal findings were indicated on the CRF form. |
| Number of Infants With Moderate or Severe Disability | Birth to 18-22 months corrrected age | Number of infants with moderate or severe disability among survivors through 18-22 months corrected age. |
| Causes of Death | Birth to 18-22 months corrrected age | Causes of any deaths that occurred through 18-22 months corrected age. |
| Neurological Injury by Cranial Ultrasound During Intervention | Within 6 hours of life to 72 hours after start of intervention | Infants with recorded events of intraventricular hemorrhage grade I, II, III, or IV, posterior fossa hemorrhage with/without shift of midline structures, intraparenchymal hemorrhage. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Whole-body Hypothermia Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 72 hours
Hypothermia: Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 72 hours | 88 |
| Normothermia Control group (with esophageal temperature at or near 37.0°C) for 72 hours
Normothermic Control: Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours | 80 |
| Total | 168 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 7 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Normothermia | Total | Whole-body Hypothermia |
|---|---|---|---|
| Age, Continuous | 4.5 Hours STANDARD_DEVIATION 1.3 | 4.5 Hours STANDARD_DEVIATION 1.3 | 4.5 Hours STANDARD_DEVIATION 1.2 |
| Birthweight | 2371.4 grams STANDARD_DEVIATION 607.9 | 2419.6 grams STANDARD_DEVIATION 621.7 | 2463.5 grams STANDARD_DEVIATION 634.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 25 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 67 Participants | 138 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 2 Participants |
| Gestational Age | 34.1 Weeks STANDARD_DEVIATION 0.8 | 34 Weeks STANDARD_DEVIATION 0.8 | 34.0 Weeks STANDARD_DEVIATION 0.8 |
| Length | 45.1 cm STANDARD_DEVIATION 2.8 | 45.6 cm STANDARD_DEVIATION 3.1 | 46.0 cm STANDARD_DEVIATION 3.2 |
| Level of Encephalopathy Moderate | 57 Participants | 118 Participants | 61 Participants |
| Level of Encephalopathy Severe | 23 Participants | 50 Participants | 27 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 9 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 31 Participants | 58 Participants | 27 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) White | 42 Participants | 94 Participants | 52 Participants |
| Region of Enrollment United States | 80 participants | 168 participants | 88 participants |
| Sex: Female, Male Female | 35 Participants | 77 Participants | 42 Participants |
| Sex: Female, Male Male | 45 Participants | 91 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 18 / 88 | 9 / 80 |
| other Total, other adverse events | 22 / 88 | 12 / 78 |
| serious Total, serious adverse events | 29 / 88 | 17 / 78 |
Outcome results
Primary
Death or Moderate or Severe Disability
Severe disability was defined by any of the following: a Bayley III cognitive score \< 70 or Gross Motor Function (GMF) Level of 3-5 blindness or profound hearing loss requiring amplification but still unable to following commands/communicate. Moderate disability was defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit.
Time frame: Birth to 18-22 months corrected age
Population: Includes all infants with primary outcome. Does not include 10 lost to follow up, 4 infants without outcome because the Bayley test was not completed, and 2 infants who withdrew from the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Whole-body Hypothermia | Death or Moderate or Severe Disability | 29 Participants |
| Normothermia | Death or Moderate or Severe Disability | 20 Participants |
Comparison: Whole-body Hypothermia vs. Normothermia (Normothermia is the comparison group)95% CI: [0.74, 2]
Secondary
Causes of Death
Causes of any deaths that occurred through 18-22 months corrected age.
Time frame: Birth to 18-22 months corrrected age
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Whole-body Hypothermia | Causes of Death | Multi-organ Failure | 2 Participants |
| Whole-body Hypothermia | Causes of Death | Complications of HIE | 1 Participants |
| Whole-body Hypothermia | Causes of Death | Asphyxial Brain Injury | 14 Participants |
| Whole-body Hypothermia | Causes of Death | Secondary to severe HIE | 0 Participants |
| Whole-body Hypothermia | Causes of Death | Cardiomyopathy | 1 Participants |
| Whole-body Hypothermia | Causes of Death | Pulmonary Hypoplasia | 0 Participants |
| Whole-body Hypothermia | Causes of Death | BPD/CLD | 0 Participants |
| Normothermia | Causes of Death | Pulmonary Hypoplasia | 1 Participants |
| Normothermia | Causes of Death | BPD/CLD | 1 Participants |
| Normothermia | Causes of Death | Asphyxial Brain Injury | 4 Participants |
| Normothermia | Causes of Death | Multi-organ Failure | 2 Participants |
| Normothermia | Causes of Death | Cardiomyopathy | 0 Participants |
| Normothermia | Causes of Death | Complications of HIE | 0 Participants |
| Normothermia | Causes of Death | Secondary to severe HIE | 1 Participants |
Secondary
Neurological Injury by Cranial Ultrasound During Intervention
Infants with recorded events of intraventricular hemorrhage grade I, II, III, or IV, posterior fossa hemorrhage with/without shift of midline structures, intraparenchymal hemorrhage.
Time frame: Within 6 hours of life to 72 hours after start of intervention
Population: Infants who had at least one cranial ultrasound during intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Whole-body Hypothermia | Neurological Injury by Cranial Ultrasound During Intervention | 2 Participants |
| Normothermia | Neurological Injury by Cranial Ultrasound During Intervention | 3 Participants |
Secondary
Number of Deaths in the NICU and Following Discharge
Number of deaths in the NICU and following discharge among infants with a primary outcome.
Time frame: Birth to 18-22 months corrected age
Population: Includes all infants with primary outcome. Does not include 10 lost to follow up and 2 infants who withdrew from the study. Also excluded 4 infants without primary outcome because the Bayley test was not completed, so results can be compared with primary outcome which includes death. These 4 infants without primary outcome because the Bayley test was not completed are in the all-cause mortality summary in the Adverse Events module.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Whole-body Hypothermia | Number of Deaths in the NICU and Following Discharge | 18 Participants |
| Normothermia | Number of Deaths in the NICU and Following Discharge | 9 Participants |
Secondary
Number of Infants With Abnormal MRIs During Post-intervention Period
An MRI was considered abnormal if any abnormal findings were indicated on the CRF form.
Time frame: Post-intervention to through discharge, death, or transfer (whichever comes first), average of 29 days
Population: Infants who had at least one MRI post-intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Whole-body Hypothermia | Number of Infants With Abnormal MRIs During Post-intervention Period | 48 Participants |
| Normothermia | Number of Infants With Abnormal MRIs During Post-intervention Period | 50 Participants |
Secondary
Number of Infants With Moderate or Severe Disability
Number of infants with moderate or severe disability among survivors through 18-22 months corrected age.
Time frame: Birth to 18-22 months corrrected age
Population: infants who were alive at 18-22 months corrected age.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Whole-body Hypothermia | Number of Infants With Moderate or Severe Disability | 11 Participants |
| Normothermia | Number of Infants With Moderate or Severe Disability | 11 Participants |