TIME Study: Therapeutic Hypothermia for Infants With Mild Encephalopathy

NCT04176471 | Unknown DMC

• 1 other identifier: 53274
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 5

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.

Conditions

Hypoxic-Ischemic Encephalopathy Mild; Neonatal Encephalopathy

Outcome Measures

Primary Outcomes (2)

• 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

• 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 Outcomes (17)

• Percentage of participants with sinus bradycardia

  72 hours

• Percentage of participants thrombocytopenia

  72 hours

• Percentage of patients who require intubation and mechanical ventilation

  72 hours

• Percentage of patients with need for central line

  72 hours

• Percentage of participants with Persistent Pulmonary Hypertension (PPHN)

  72 hours

Other Outcomes (3)

• Age at Randomization

  First 24 hours of life

• Age at Initiation of Treatment

  First 24 hours of life

• Percentage of participants with disability at 2 years of age

  2 years

Study Arms (2)

Therapeutic Hypothermia

EXPERIMENTAL

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.

Other: Therapeutic Hypothermia

Normothermia

ACTIVE COMPARATOR

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

Other: Normothermia

Interventions

Therapeutic Hypothermia OTHER

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.

Therapeutic Hypothermia

Normothermia OTHER

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.

Normothermia

Eligibility Criteria

• Age: Up to 6 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Stanford University: lead
• Thrasher Research Fund: collaborator

Study Sites (5)

Loma Linda Children's Hospital

Loma Linda, California, 92354, United States

Location

Benioff Children's Hospital Oakland

Oakland, California, 94606, United States

Location

Children's Hospital Orange County

Orange, California, 92868, United States

Location

Stanford University

Palo Alto, California, 94034, United States

Location

Rady Children's Hospital

San Diego, California, 92123, United States

Location

Related Publications (2)

• Akula VP, Sriram A, Xu S, Walsh E, Van Meurs K, Cranshaw M, Kuzniewicz MW. Adverse short- and long-term outcomes among infants with mild neonatal encephalopathy. Pediatr Res. 2023 Sep;94(3):1003-1010. doi: 10.1038/s41390-022-02249-8. Epub 2022 Aug 23.

  PMID: 35999380 DERIVED

• 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.

  PMID: 34854918 DERIVED

MeSH Terms

Interventions

Hypothermia, Induced

Intervention Hierarchy (Ancestors)

Cryotherapy; Therapeutics

Study Officials

• Sonia Bonifacio, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sonia L Bonifacio, MD

CONTACT

650-723-5711; soniab1@stanford.edu

Krisa Van Meurs, MD

CONTACT

650-723-5711; vanmeurs@stanford.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Assessors of neurodevelopmental outcome at 12-14 months of age will be blinded to the allotted treatment group
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Associate Professor

Model Details: 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.

Study Record Dates

• First Submitted: November 14, 2019
• First Posted: November 25, 2019
• Study Start: May 1, 2020
• Primary Completion: January 31, 2023
• Study Completion: January 31, 2025
• Last Updated: March 18, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)