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TIME Study: Therapeutic Hypothermia for Infants With Mild Encephalopathy (TIME)

Primary Purpose

Hypoxic-Ischemic Encephalopathy Mild, Neonatal Encephalopathy

Status
Not yet recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Therapeutic Hypothermia
Normothermia
Sponsored by
Stanford University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypoxic-Ischemic Encephalopathy Mild

Eligibility Criteria

undefined - 6 Hours (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Loma Linda Children's Hospital
  • Benioff Children's Hospital Oakland
  • Children's Hospital Orange County
  • Stanford University
  • Rady Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Therapeutic Hypothermia

Normothermia

Arm Description

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 will be achieved using a servo-controlled temperature regulating blanket with the temperature goal of 36.5-37.3°C for 72 hours.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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).
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
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
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)
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
Percentage of participants exposed to sedating or analgesic medications
Investigators will determine the proportion of treated and control subjects who receive narcotics or benzodiazepines
Percentage of participants exposed to inotropic agents
Investigators will determine the proportion of treated and control subjects who receive inotropic support
Percentage of participants diagnosed with seizures
Investigators will determine the proportion of treated and control subjects who develop clinical and or electrographic seizures
Age at initiation of feeds
Investigators will determine the age at which enteral feeds are initiated in treated and control patients
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
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)
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
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
Count of participants with brain injury on MRI
Investigators will determine the number of treated and control patients who have brain injury on MRI
Length of Hospital Stay
Investigators will determine the length of hospital stay for treated and control patients
Percentage of participants breastfeeding at discharge
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
Investigators will determine the proportion of treated and control patients who die or are discharged home on hospice

Full Information

First Posted
November 14, 2019
Last Updated
March 16, 2020
Sponsor
Stanford University
Collaborators
Thrasher Research Fund
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1. Study Identification

Unique Protocol Identification Number
NCT04176471
Brief Title
TIME Study: Therapeutic Hypothermia for Infants With Mild Encephalopathy
Acronym
TIME
Official Title
The TIME STUDY: A Randomized Controlled Trial of Therapeutic Hypothermia for Infants With Mild Encephalopathy in California
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Not yet recruiting
Study Start Date
May 1, 2020 (Anticipated)
Primary Completion Date
January 31, 2023 (Anticipated)
Study Completion Date
January 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Stanford University
Collaborators
Thrasher Research Fund

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoxic-Ischemic Encephalopathy Mild, Neonatal Encephalopathy

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
A total of 68 neonates with mild HIE will be enrolled and randomized to therapeutic hypothermia (33.5°C ± 0.5°C for 72 hours plus 6 hours of rewarming) or normothermia (36.5-37.3°C for 72 hours ) with targeted temperature management. Each treatment group will have 34 patients. Participants randomized to normothermia who develop signs of moderate-severe HIE in the first 24 hours after birth will be crossed over to the treatment arm, as therapeutic hypothermia is the standard of care treatment for neonates with moderate-severe HIE.
Masking
Outcomes Assessor
Masking Description
Assessors of neurodevelopmental outcome at 12-14 months of age will be blinded to the allotted treatment group
Allocation
Randomized
Enrollment
68 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Therapeutic Hypothermia
Arm Type
Experimental
Arm Description
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.
Arm Title
Normothermia
Arm Type
Active Comparator
Arm Description
Normothermia will be achieved using a servo-controlled temperature regulating blanket with the temperature goal of 36.5-37.3°C for 72 hours.
Intervention Type
Other
Intervention Name(s)
Therapeutic Hypothermia
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Normothermia
Intervention Description
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.
Primary Outcome Measure Information:
Title
Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS)
Description
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.
Time Frame
Assessment takes up to 15 minutes and will be conducted at 12-14 months of age
Title
Alberta Infant Motors Scale (AIMS)
Description
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.
Time Frame
Assessment takes up to 15 minutes and will be conducted at 12-14 months of age
Secondary Outcome Measure Information:
Title
Percentage of participants with sinus bradycardia
Description
Investigators will determine the proportion of treated and control subjects who develop sinus bradycardia (HR < 80) during the intervention period (72 hours).
Time Frame
72 hours
Title
Percentage of participants thrombocytopenia
Description
Investigators will determine the proportion of treated and control subjects who develop thrombocytopenia (platelet count of < 150 x 109/L) during the intervention period
Time Frame
72 hours
Title
Percentage of patients who require intubation and mechanical ventilation
Description
Investigators will determine the proportion of treated and control subjects who require intubation and mechanical ventilation
Time Frame
72 hours
Title
Percentage of patients with need for central line
Description
Investigators will determine the proportion of treated and control subjects who have a central line (umbilical or PICC)
Time Frame
72 hours
Title
Percentage of participants with Persistent Pulmonary Hypertension (PPHN)
Description
Investigators will determine the proportion of treated and control subjects who have a clinical diagnosis of PPHN or who receive inhaled nitric oxide
Time Frame
72 hours
Title
Percentage of participants exposed to sedating or analgesic medications
Description
Investigators will determine the proportion of treated and control subjects who receive narcotics or benzodiazepines
Time Frame
72 hours
Title
Percentage of participants exposed to inotropic agents
Description
Investigators will determine the proportion of treated and control subjects who receive inotropic support
Time Frame
76 hours
Title
Percentage of participants diagnosed with seizures
Description
Investigators will determine the proportion of treated and control subjects who develop clinical and or electrographic seizures
Time Frame
During initial hospital stay up to 30 days
Title
Age at initiation of feeds
Description
Investigators will determine the age at which enteral feeds are initiated in treated and control patients
Time Frame
During initial hospital stay up to 30 days from date of admission
Title
Age at full enteral feeds
Description
Investigators will determine the age at which full enteral feeds or breastfeeding ad lib is achieved in treated and control patients
Time Frame
During initial hospital stay and up to 30 days from date of admission
Title
Percentage of participants who require feeding assistance at discharge
Description
Investigators will determine the proportion of treated and control patients who require feeding support at discharge (NG tube or G-Tube feeds)
Time Frame
At time of discharge from hospital, up to 30 days from admission
Title
Percentage of participants with fat necrosis and hypercalcemia
Description
Investigators will determine the proportion of treated and control patients who have a diagnosis of fat necrosis and hypercalcemia
Time Frame
From study entry to day of hospital discharge, up to 30 days from admission
Title
Percentage of participants discharged on anti-convulsant medications
Description
Investigators will determine the proportion of treated and control patients who are discharged home on anti-convulsant medications
Time Frame
At time of discharge from hospital, up to 30 days from admission
Title
Count of participants with brain injury on MRI
Description
Investigators will determine the number of treated and control patients who have brain injury on MRI
Time Frame
At time of discharge from hospital, up to 30 days from admission
Title
Length of Hospital Stay
Description
Investigators will determine the length of hospital stay for treated and control patients
Time Frame
At time of discharge from hospital, up to 30 days from admission
Title
Percentage of participants breastfeeding at discharge
Description
Investigators will determine the proportion of treated and control patients who are breastfeeding at discharge
Time Frame
At time of discharge from hospital, up to 30 days from admission
Title
Percentage of participants with death and/or hospice at discharge
Description
Investigators will determine the proportion of treated and control patients who die or are discharged home on hospice
Time Frame
At time of discharge from hospital, up to 30 days from admission
Other Pre-specified Outcome Measures:
Title
Age at Randomization
Description
Age in hours and minutes after birth at randomization
Time Frame
First 24 hours of life
Title
Age at Initiation of Treatment
Description
Age in hours and minutes after birth at which normothermia or therapeutic hypothermia are initiated
Time Frame
First 24 hours of life
Title
Percentage of participants with disability at 2 years of age
Description
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
Time Frame
2 years

10. Eligibility

Sex
All
Maximum Age & Unit of Time
6 Hours
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria (must meet all 3): Neonates born at ≥ 36 0/7 weeks Neonatal signs or contributing factors consistent with an acute peri-partum or intra-partum event (must meet a or b): pH ≤ 7.0 or Base deficit ≥ 16 in any umbilical cord or baby specimen at ≤ 1 hr of age OR 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) 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sonia L Bonifacio, MD
Phone
650-723-5711
Email
soniab1@stanford.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Krisa Van Meurs, MD
Phone
650-723-5711
Email
vanmeurs@stanford.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sonia Bonifacio, MD
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Loma Linda Children's Hospital
City
Loma Linda
State/Province
California
ZIP/Postal Code
92354
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Andrew Hopper, MD
Facility Name
Benioff Children's Hospital Oakland
City
Oakland
State/Province
California
ZIP/Postal Code
94606
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Priscilla Joe, MD
Facility Name
Children's Hospital Orange County
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
John Tran, MD
Facility Name
Stanford University
City
Palo Alto
State/Province
California
ZIP/Postal Code
94034
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sonia Bonifacio, MD
Facility Name
Rady Children's Hospital
City
San Diego
State/Province
California
ZIP/Postal Code
92123
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jose Honald, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34854918
Citation
Blecharczyk E, Lee L, Birnie K, Gupta A, Davis A, Van Meurs K, Bonifacio S, Frymoyer A. Standardized Evaluation of Cord Gases in Neonates at Risk for Hypoxic Ischemic Encephalopathy. Hosp Pediatr. 2022 Jan 1;12(1):29-37. doi: 10.1542/hpeds.2021-006135.
Results Reference
derived

Learn more about this trial

TIME Study: Therapeutic Hypothermia for Infants With Mild Encephalopathy

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