TIME Study: Therapeutic Hypothermia for Infants With Mild Encephalopathy

Not Applicable

Not yet recruiting

• Conditions: Hypoxic-Ischemic Encephalopathy Mild; Neonatal Encephalopathy
• Interventions: Other: Therapeutic Hypothermia; Other: Normothermia

• Registration Number: NCT04176471
• Lead Sponsor: Stanford University

Brief Summary

The TIME study is a randomized, controlled trial to evaluate impact on early measures of neurodevelopment and the safety profile of therapeutic hypothermia in term neonates with Mild Hypoxic-Ischemic Encephalopathy who are \< 6 hours of age. Neurodevelopmental outcome will be assessed at 12-14 months of age. The study will enroll 68 neonates randomized to therapeutic hypothermia or normothermia across 5 centers in California.

Detailed Description

The TIME study is a multi-center randomized, controlled trial of Therapeutic Hypothermia (TH) (33.5°C ± 0.5° for 72 hours) versus normothermia using targeted temperature management, initiated within 6 hours after birth in term neonates with Mild Hypoxic-Ischemic Encephalopathy (HIE). Mild encephalopathy will be identified using the 6 component modified Sarnat exam as in the Neonatal Research Network of the National Institute of Child Health and Human Development trials of TH for moderate-severe encephalopathy and will be expanded to include features of mild encephalopathy. Eligible subjects must demonstrate ≥ 2 exam abnormalities (mild, moderate, severe) but without evidence of moderate-severe encephalopathy (≥ 3 moderate or severe features). The primary outcome is neurodevelopmental outcome at 12-14 months of age. Secondary outcomes include evaluating the safety profile of therapeutic hypothermia in patients with Mild HIE. Therapeutic hypothermia is well tolerated and did not demonstrate serious safety concerns when evaluated in multiple large studies of neonates with moderate-severe HIE. It is now being applied by some practitioners to neonates with Mild HIE without systematic evidence of benefit or potential harm. This data will be necessary in order to develop and larger trial of efficacy to be determined at 2 years of age.

Study Timeline

• Study First Submitted: 2019-11-14
• Study First Submitted QC: 2019-11-22
• Study First Posted: 2019-11-25
• Status Verified: 2020-03
• Last Update Submitted: 2020-03-16
• Last Update Posted: 2020-03-18
• Study Start: 2020-05-01
• Primary Completion: 2023-01-31
• Study Completion: 2025-01-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 68

Inclusion Criteria

Not provided

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Exclusion Criteria

• Patients < 36 0/7 weeks birthweight < 1800gm; congenital or chromosomal anomaly associated with abnormal neurodevelopment or death; patients with moderate or severe HIE (by Sarnat exam or presence of clinical or electrographic seizures) identified within 6 hours after birth; core body temperature < 34°C for more than 1 hour prior to randomization.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Therapeutic Hypothermia	Therapeutic Hypothermia	Therapeutic hypothermia will be achieved using a servo-controlled temperature regulating blanket that is approved for use in neonates and is currently used for the treatment of neonates with moderate-severe HIE. The goal target temperature is 33.5°C ± 0.5°C for 72 hours and the subject will then be rewarmed at a rate of 0.5°C per hour to a goal of 36.5°C.
Normothermia	Normothermia	Normothermia will be achieved using a servo-controlled temperature regulating blanket with the temperature goal of 36.5-37.3°C for 72 hours.

Primary Outcome Measures

Name	Time	Method
Alberta Infant Motors Scale (AIMS)	Assessment takes up to 15 minutes and will be conducted at 12-14 months of age	Alberta Infant Motors Scale (AIMS) will be assessed at 12-14 months of age. The AIMS score is determined by assessment of 4 positions and scoring the least and most mature position identified. The score is converted to a percentile for age with those in the 5th to 25th percentile identified as suspicious motor development and those with a score corresponding to \< 5th percentile being identified as abnormal motor development.
Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS)	Assessment takes up to 15 minutes and will be conducted at 12-14 months of age	Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) will be assessed at 12-14 months of age. The mean score for a 12 month old normally developing infant is 109 with a standard deviation of 16.5. Higher scores are associated with normal development.

Secondary Outcome Measures

Name	Time	Method
Percentage of participants with sinus bradycardia	72 hours	Investigators will determine the proportion of treated and control subjects who develop sinus bradycardia (HR \< 80) during the intervention period (72 hours).
Percentage of participants thrombocytopenia	72 hours	Investigators will determine the proportion of treated and control subjects who develop thrombocytopenia (platelet count of \< 150 x 109/L) during the intervention period
Percentage of patients who require intubation and mechanical ventilation	72 hours	Investigators will determine the proportion of treated and control subjects who require intubation and mechanical ventilation
Percentage of participants diagnosed with seizures	During initial hospital stay up to 30 days	Investigators will determine the proportion of treated and control subjects who develop clinical and or electrographic seizures
Age at initiation of feeds	During initial hospital stay up to 30 days from date of admission	Investigators will determine the age at which enteral feeds are initiated in treated and control patients
Age at full enteral feeds	During initial hospital stay and up to 30 days from date of admission	Investigators will determine the age at which full enteral feeds or breastfeeding ad lib is achieved in treated and control patients
Percentage of participants who require feeding assistance at discharge	At time of discharge from hospital, up to 30 days from admission	Investigators will determine the proportion of treated and control patients who require feeding support at discharge (NG tube or G-Tube feeds)
Percentage of patients with need for central line	72 hours	Investigators will determine the proportion of treated and control subjects who have a central line (umbilical or PICC)
Percentage of participants with Persistent Pulmonary Hypertension (PPHN)	72 hours	Investigators will determine the proportion of treated and control subjects who have a clinical diagnosis of PPHN or who receive inhaled nitric oxide
Percentage of participants exposed to sedating or analgesic medications	72 hours	Investigators will determine the proportion of treated and control subjects who receive narcotics or benzodiazepines
Percentage of participants exposed to inotropic agents	76 hours	Investigators will determine the proportion of treated and control subjects who receive inotropic support
Percentage of participants with fat necrosis and hypercalcemia	From study entry to day of hospital discharge, up to 30 days from admission	Investigators will determine the proportion of treated and control patients who have a diagnosis of fat necrosis and hypercalcemia
Percentage of participants discharged on anti-convulsant medications	At time of discharge from hospital, up to 30 days from admission	Investigators will determine the proportion of treated and control patients who are discharged home on anti-convulsant medications
Count of participants with brain injury on MRI	At time of discharge from hospital, up to 30 days from admission	Investigators will determine the number of treated and control patients who have brain injury on MRI
Length of Hospital Stay	At time of discharge from hospital, up to 30 days from admission	Investigators will determine the length of hospital stay for treated and control patients
Percentage of participants breastfeeding at discharge	At time of discharge from hospital, up to 30 days from admission	Investigators will determine the proportion of treated and control patients who are breastfeeding at discharge
Percentage of participants with death and/or hospice at discharge	At time of discharge from hospital, up to 30 days from admission	Investigators will determine the proportion of treated and control patients who die or are discharged home on hospice

Trial Locations

Locations (5)

Loma Linda Children's Hospital; 🇺🇸 Loma Linda, California, United States

Rady Children's Hospital; 🇺🇸 San Diego, California, United States

Benioff Children's Hospital Oakland; 🇺🇸 Oakland, California, United States

Children's Hospital Orange County; 🇺🇸 Orange, California, United States

Stanford University; 🇺🇸 Palo Alto, California, United States