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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

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):

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):
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)
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

NCT ID

NCT04176471

First Posted

November 14, 2019

Last Updated

March 16, 2020

Sponsor

Stanford University

Collaborators

Thrasher Research Fund

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

Studies a U.S. FDA-regulated Device Product

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

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

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

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

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

soniab1@stanford.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Krisa Van Meurs, MD

Phone

650-723-5711

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

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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