TIME Study: Therapeutic Hypothermia for Infants With Mild Encephalopathy

NCT ID: NCT04176471

Last Updated: 2020-03-18

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 68 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-05-01
• Study Completion Date: 2025-01-31

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.

Conditions

Hypoxic-Ischemic Encephalopathy Mild; Neonatal Encephalopathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: EXPERIMENTAL

Therapeutic Hypothermia

Intervention Type: 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.

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.

Group Type: ACTIVE_COMPARATOR

Normothermia

Intervention Type: 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.

Interventions

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.

Intervention Type: OTHER

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.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

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.

• Maximum Eligible Age: 6 Hours
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Thrasher Research Fund

OTHER

Sponsor Role: collaborator

Stanford University

OTHER

Sponsor Role: lead

Responsible Party

Sonia Bonifacio

Clinical Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Sonia Bonifacio, MD

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Locations

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, United States

Countries

United States

Central Contacts

Sonia L Bonifacio, MD

Role: CONTACT

soniab1@stanford.edu

650-723-5711

Krisa Van Meurs, MD

Role: CONTACT

vanmeurs@stanford.edu

650-723-5711

Facility Contacts

Andrew Hopper, MD

Role: primary

Priscilla Joe, MD

Role: primary

John Tran, MD

Role: primary

Sonia Bonifacio, MD

Role: primary

Jose Honald, MD

Role: primary

References

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.

Reference Type: DERIVED

PMID: 35999380 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34854918 (View on PubMed)

Other Identifiers

53274

Identifier Type: -

Identifier Source: org_study_id