TIME Study: Therapeutic Hypothermia for Infants With Mild Encephalopathy

Neonatal Encephalopathy Clinical Trial

— TIME  

Official title:

The TIME STUDY: A Randomized Controlled Trial of Therapeutic Hypothermia for Infants With Mild Encephalopathy in California

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04176471
• Other study ID #: 53274
• Status: Not yet recruiting
• Phase: N/A
• Start date: May 1, 2020
• Est. completion date: January 31, 2025

Study information

• Verified date: March 2020
• Source: Stanford University
• Contact: Sonia L Bonifacio, MD
• Phone: 650-723-5711
• Email: soniab1[@]stanford.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 68
• Est. completion date: January 31, 2025
• Est. primary completion date: January 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 6 Hours

Eligibility

Inclusion Criteria (must meet all 3):

1. Neonates born at = 36 0/7 weeks

2. Neonatal signs or contributing factors consistent with an acute peri-partum or intra-partum event (must meet a or b):

1. pH = 7.0 or Base deficit = 16 in any umbilical cord or baby specimen at = 1 hr of age OR

2. No umbilical cord or baby blood gas at = 1 hr of age OR pH 7.01-7.15 or Base deficit 10-15.9 in any cord or baby specimen at = 1 hr of age AND at least one of the following

• Apgar score at 10 min = 5

• Continued need for resuscitation at 10 min (chest compressions, bag mask ventilation, intubation with positive pressure ventilation)

• Acute Perinatal Event: uterine rupture, placental abruption, cord accident (prolapse, rupture, knot or tight nuchal cord), maternal trauma, maternal hemorrhage or cardiorespiratory arrest, fetal exsanguination from either vasa previa or feto-maternal hemorrhage

• Fetal heart rate monitor pattern consistent with acute peripartum or intrapartum event (category III trace: no heart rate variability, presence of recurrent late or variable decelerations, bradycardia, or sinusoidal pattern)

3. Evidence of Mild Encephalopathy on Modified Sarnat Exam.

• Presence of at least 2 signs of mild, moderate or severe encephalopathy with no more than 2 moderate or severe findings in the 6 tested categories (level of consciousness, spontaneous activity, posture, tone, neonatal reflexes (suck and moro), and autonomic nervous system

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.

Related Conditions & MeSH terms

• Brain Diseases
• Brain Ischemia
• Hypothermia
• Hypoxia-Ischemia, Brain
• Hypoxic-Ischemic Encephalopathy Mild
• Neonatal Encephalopathy

Intervention

Other:
• Therapeutic Hypothermia
Therapeutic hypothermia involves use of a servo-controlled device and blanket to lower the core body temperature by 3°C for 72 hours followed by a period of re-warming in which the temperature is increased by 0.5°C per hour for 6 hours until normothermia is achieved.
• Normothermia
Normothermia will be achieved using the same servo-controlled device and blanket to assure normothermia of the control arm. The goal temperature for normothermia is 36.5-37.3°C for 72 hours.

Locations

Country	Name	City	State
United States	Loma Linda Children's Hospital	Loma Linda	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	Rady Children's Hospital	San Diego	California

Sponsors (2)

Lead Sponsor	Collaborator
Stanford University	Thrasher Research Fund

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Age at Randomization	Age in hours and minutes after birth at randomization	First 24 hours of life
Other	Age at Initiation of Treatment	Age in hours and minutes after birth at which normothermia or therapeutic hypothermia are initiated	First 24 hours of life
Other	Percentage of participants with disability at 2 years of age	Most enrolled neonates will be followed in high-risk infant follow-up clinics. We will track developmental outcome at 2 years of age for all enrolled patients and determine the proportion of treated and control patients who abnormal measures of neurodevelopment	2 years
Primary	Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS)	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.	Assessment takes up to 15 minutes and will be conducted at 12-14 months of age
Primary	Alberta Infant Motors Scale (AIMS)	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.	Assessment takes up to 15 minutes and will be conducted at 12-14 months of age
Secondary	Percentage of participants with sinus bradycardia	Investigators will determine the proportion of treated and control subjects who develop sinus bradycardia (HR < 80) during the intervention period (72 hours).	72 hours
Secondary	Percentage of participants thrombocytopenia	Investigators will determine the proportion of treated and control subjects who develop thrombocytopenia (platelet count of < 150 x 109/L) during the intervention period	72 hours
Secondary	Percentage of patients who require intubation and mechanical ventilation	Investigators will determine the proportion of treated and control subjects who require intubation and mechanical ventilation	72 hours
Secondary	Percentage of patients with need for central line	Investigators will determine the proportion of treated and control subjects who have a central line (umbilical or PICC)	72 hours
Secondary	Percentage of participants with Persistent Pulmonary Hypertension (PPHN)	Investigators will determine the proportion of treated and control subjects who have a clinical diagnosis of PPHN or who receive inhaled nitric oxide	72 hours
Secondary	Percentage of participants exposed to sedating or analgesic medications	Investigators will determine the proportion of treated and control subjects who receive narcotics or benzodiazepines	72 hours
Secondary	Percentage of participants exposed to inotropic agents	Investigators will determine the proportion of treated and control subjects who receive inotropic support	76 hours
Secondary	Percentage of participants diagnosed with seizures	Investigators will determine the proportion of treated and control subjects who develop clinical and or electrographic seizures	During initial hospital stay up to 30 days
Secondary	Age at initiation of feeds	Investigators will determine the age at which enteral feeds are initiated in treated and control patients	During initial hospital stay up to 30 days from date of admission
Secondary	Age at full enteral feeds	Investigators will determine the age at which full enteral feeds or breastfeeding ad lib is achieved in treated and control patients	During initial hospital stay and up to 30 days from date of admission
Secondary	Percentage of participants who require feeding assistance at discharge	Investigators will determine the proportion of treated and control patients who require feeding support at discharge (NG tube or G-Tube feeds)	At time of discharge from hospital, up to 30 days from admission
Secondary	Percentage of participants with fat necrosis and hypercalcemia	Investigators will determine the proportion of treated and control patients who have a diagnosis of fat necrosis and hypercalcemia	From study entry to day of hospital discharge, up to 30 days from admission
Secondary	Percentage of participants discharged on anti-convulsant medications	Investigators will determine the proportion of treated and control patients who are discharged home on anti-convulsant medications	At time of discharge from hospital, up to 30 days from admission
Secondary	Count of participants with brain injury on MRI	Investigators will determine the number of treated and control patients who have brain injury on MRI	At time of discharge from hospital, up to 30 days from admission
Secondary	Length of Hospital Stay	Investigators will determine the length of hospital stay for treated and control patients	At time of discharge from hospital, up to 30 days from admission
Secondary	Percentage of participants breastfeeding at discharge	Investigators will determine the proportion of treated and control patients who are breastfeeding at discharge	At time of discharge from hospital, up to 30 days from admission
Secondary	Percentage of participants with death and/or hospice at discharge	Investigators will determine the proportion of treated and control patients who die or are discharged home on hospice	At time of discharge from hospital, up to 30 days from admission