Clinical trial NCT04621279: Cool Prime Comparative Effectiveness Study for Mild HIE
Official title: COOLPRIME: Comparative Effectiveness for Cooling Prospectively Infants With Mild Encephalopathy
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Mild Hypoxic Ischemic Encephalopathy of Newborn
Keywords: mild HIE (Hypoxic Ischemic Encephalopathy)
neonatal encephalopathy
brain ischemia
brain hypoxia
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
Collaborators: name: Nationwide Children's Hospital
name: University of California, San Francisco
name: Children's National Research Institute
name: Children's Hospital Los Angeles
name: St. Louis University
name: Stanford University
name: University of Utah
name: University of Pittsburgh Medical Center
name: Emory University
name: Children's Hospital Medical Center, Cincinnati
name: University College Cork
name: The Children's Hospital of San Antonio
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Harvard University
name: Washington University School of Medicine
name: Sharp HealthCare
First posted: 2020-11-09
Enrollment: 460
Sex: ALL
Minimum age (years): 35
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Term infants ≥ 35 weeks' gestation with evidence of both perinatal event fetal acidosis and encephalopathy on exam.

Brief summary: To determine effectiveness of therapy to improve neurodevelopmental outcomes in infants with mild HIE. To determine the adverse effects of Therapeutic Hypothermia (TH) in mild HIE on the neonate and his/her family. Determine heterogeneity of the treatment effect across key subgroups obtained in the first 6 hours after birth prior to the decision to initiate therapy.

Detailed description: This study leverages practice variation within and across 15 participating sites to compare the effectiveness of TH versus normothermia for mild HIE on neurodevelopmental outcomes at 2 years of age.After standardizing all aspects of clinical care for mild HIE (except for TH vs. normothermia)we will enroll 460 infants with mild HIE into the longitudinal, observational comparative effectiveness study.The central aim of the comparative longitudinal cohort of mild HIE is (1) to compare the effectiveness of hypothermia to normothermia on neurodevelopmental outcomes at 2 years, (2) determine the adverse effects of TH on the infant and his/her family; and (3) determine the heterogeneity of treatment effects (moderating effect) across mild HIE subgroups as determined by physiological biomarkers obtained during the 6 hours window to initiate hypothermia. The decision to apply TH or normothermia will be entirely determined by practice parameters at each site.

Eligibility criteria: Inclusion Criteria:

Infants must meet all 3 inclusion criteria

1. Neonates born at ≥ 35 0/7 weeks
2. Mild Encephalopathy on neonatal neurologic exam within 6 hours after birth: defined as presence of at least 2 signs of mild, moderate, or severe encephalopathy with no more than 2 signs in the moderate or severe category.
3. Perinatal Acidosis based on at least one of the following (A or B):

   1. pH ≤ 7.00 in any cord or first infant gas (arterial, venous, or capillary) within ≤ 60 min OR base deficit ≥ 16 in any cord or first infant gas (arterial, venous or capillary) within ≤ 60 min
   2. If pH is between 7.01 and 7.15, OR base deficit is between 10 and 15.9 mmol/liter, OR blood gas is not available, an acute perinatal event is an additional criteria required (see below definition)

An acute perinatal event is defined by at least one of the following:

1. Apgar score at 10 min ≤ 5
2. Continued need for resuscitation at 10 min (chest compressions, bag mask ventilation, or positive pressure ventilation)
3. Uterine rupture, placental abruption, cord accident (prolapse, rupture, knot or tight nuchal cord)
4. maternal trauma, maternal hemorrhage, or cardiorespiratory arrest
5. fetal exsanguination from either vasa previa or feto-maternal hemorrhage, shoulder dystocia
6. Any evidence suggestive of acute perinatal event.

Infants are still eligible for enrollment in the COOLPRIME study if the cord or infant's first blood gas (arterial, venous, or capillary) is obtained \>60 minutes of life.

Exclusion Criteria:

1. Gestational age at birth \< 35 0/7 weeks
2. Birth weight \< 1800gm
3. Head circumference \<30cm
4. Congenital or chromosomal anomaly associated with abnormal neurodevelopment or death
5. Moderate or Severe HIE of 3 or more moderate or severe abnormalities on COOLPRIME Sarnat exam within 6 hours of life
6. Any seizures within first six hours of life
7. Redirection of care is being considered

Primary outcomes:
measure: Effectiveness of normothermia in infants as measured by Composite Bayley IV score
timeFrame: 22-26 months of age.
Secondary outcomes:
measure: Adverse events SAE
timeFrame: Discharge (approximately 7 days)
measure: Parent-Infant stress and bonding as measured by MIBS
timeFrame: 3-4 months
measure: Parent-Infant stress and bonding as measured by IBQR
timeFrame: 3-4 months
measure: Parent-Infant stress and bonding as measured by PSI
timeFrame: 3-4 months
Other outcomes:
measure: Infant neurological integrity as measured with HNNE
timeFrame: Discharge
measure: Infant neurological integrity as measured with HINE
timeFrame: 3 - 4 months
measure: Infant neurological integrity as measured with HINE
timeFrame: 22-26 months
measure: Behavioral tendency CBCL
timeFrame: 22-26 months of age.
measure: Composite PARCA-R
timeFrame: 22-26 months of age.
measure: IFS-R
timeFrame: 9-12 months
measure: IBQ-R
timeFrame: 9-12months
Locations:
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
Study officials:
affiliation: University of Texas Southwestern Medical Center
name: Lina Chalak, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Prempunpong C, Chalak LF, Garfinkle J, Shah B, Kalra V, Rollins N, Boyle R, Nguyen KA, Mir I, Pappas A, Montaldo P, Thayyil S, Sanchez PJ, Shankaran S, Laptook AR, Sant'Anna G. Prospective research on infants with mild encephalopathy: the PRIME study. J Perinatol. 2018 Jan;38(1):80-85. doi: 10.1038/jp.2017.164. Epub 2017 Nov 2.
citation: Chalak LF, Nguyen KA, Prempunpong C, Heyne R, Thayyil S, Shankaran S, Laptook AR, Rollins N, Pappas A, Koclas L, Shah B, Montaldo P, Techasaensiri B, Sanchez PJ, Sant'Anna G. Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months. Pediatr Res. 2018 Dec;84(6):861-868. doi: 10.1038/s41390-018-0174-x. Epub 2018 Sep 13.
citation: Chalak LF, Adams-Huet B, Sant'Anna G. A Total Sarnat Score in Mild Hypoxic-ischemic Encephalopathy Can Detect Infants at Higher Risk of Disability. J Pediatr. 2019 Nov;214:217-221.e1. doi: 10.1016/j.jpeds.2019.06.026. Epub 2019 Jul 10.
citation: El-Dib M, Inder TE, Chalak LF, Massaro AN, Thoresen M, Gunn AJ. Should therapeutic hypothermia be offered to babies with mild neonatal encephalopathy in the first 6 h after birth? Pediatr Res. 2019 Mar;85(4):442-448. doi: 10.1038/s41390-019-0291-1. Epub 2019 Jan 16.