Topiramate in Neonates Receiving Whole Body Cooling for Hypoxic Ischemic Encephalopathy

Topiramate as an Adjuvant to Therapeutic Hypothermia for Infants With Hypoxic Ischemic Encephalopathy

The goal is to see whether topiramate (an anti-epileptic agent) improves the outcome of babies with neonatal hypoxic encephalopathy who are receiving whole body cooling.

Study Overview

• Status: Terminated
• Conditions: Hypoxic Ischemic Encephalopathy
• Intervention / Treatment: Drug: Placebo; Drug: Topiramate

Detailed Description

Hypoxic ischemic encephalopathy (HIE) is a devastating and unexpected disease in newborns that affects 1.5-2.6 per 1000 live births. Hypoxic ischemic encephalopathy has a mortality rate of up to 30% and survivors are at significant risk for adverse long-term outcomes, including seizures, cerebral palsy, and developmental delay. The investigators propose a randomized controlled study comparing therapeutic hypothermia alone, or therapeutic hypothermia combined with topiramate. The investigators hypothesize that adjuvant therapy with topiramate will reduce short term severity of HIE including seizures (the primary outcome), a composite HIE severity score, and reduce the time of normalization of the amplitude integrated EEG (aEEG). The investigators further hypothesize, that it will improve longer term outcomes such as developmental outcome. The primary hypothesis is that seizures before hospital discharge (or before 4 weeks post-natal age (which ever is earlier)) will be significantly reduced in the topiramate group compared to the control group

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95822
      • UC Davis Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 6 hours (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

In order to be eligible for cooling the baby must meet all three of the following sets of criteria

1. Be near term (typically ≥34wks gestation) and be aged < 6h old
2. Have signs of early perinatal depression (EITHER 10 minute Apgar score < 5, OR pH < 7.00 within 60mins of age, OR Base Excess < -12 within 60mins of age, OR need respiratory support at 10min of age due to respiratory depression)
3. Have signs of moderate or severe encephalopathy based on either clinical examination or on amplitude integrated aEEG assessment

Exclusion Criteria:

1. Known congenital myopathy
2. Known congenital neuropathy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Subjects will receive the standard of care intervention for HIE at our institution (whole body cooling for 72h followed by gradual rewarming)	Drug: Placebo; A placebo identical in appearance to the active agent (topiramate)
Active Comparator: Topiramate; In addition to whole body cooling, infants assigned to the topiramate group will receive 5mg/kg of topiramate daily enterally for a total of 5 doses. The first dose will be administered as soon as possible on admission.	Drug: Topiramate; Infants assigned to the topiramate group will receive 5mg/kg of topiramate daily enterally for a total of 5 doses. The first dose will be administered as soon as possible on admission.; Other Names: Topamax; Topiragen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Seizures	Clinical or electrical seizures occuring before hospital discharge or before 4w post-natal age (which ever is earlier) will be compared between the topiramate and control groups.	At 4 weeks post-natal age or the time of hospital discharge (whichever is earlier)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIE score	Differences in daily HIE score between the two groups will be compared from birth to day-5, and from birth to the time of discharge from hospital	At 4 weeks post-natal age or the time of hospital discharge (whichever is earlier)
Normalization of aEEG	The time for normalization of aEEG voltages will be compared in the two groups.	At 4 weeks post-natal age or the time of hospital discharge (whichever is earlier)
S100-beta levels	Serum and urine S100beta levels (a marker of neuronal injury) will be compared in the two groups at three time points (on day of life 1, 3, and 7)	Day of life 1, 3 and 7
MRI score	The MRI score on day 5 to 7 of life will be compared in the two groups.	On day 5-7 of life
Developmental Outcome	Bayley scales of infant development III will be compared in the two groups at 9, 18 and 27m of age	At 9, 18 and 27 months

Collaborators and Investigators

• Sponsor: Kristin R Hoffman
• Investigators: Principal Investigator: Kristin R Hoffman, MD, UC Davis

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2013
• Primary Completion (Actual): January 27, 2022
• Study Completion (Actual): January 27, 2022

Study Registration Dates

• First Submitted: January 7, 2013
• First Submitted That Met QC Criteria: January 8, 2013
• First Posted (Estimated): January 10, 2013

Study Record Updates

• Last Update Posted (Actual): June 11, 2024
• Last Update Submitted That Met QC Criteria: May 15, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Therapeutic hypothermia; HIE; Perinatal depression; Hypoxic ischemic encephalopathy; Whole body cooling
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Respiratory; Hypoxia, Brain; Brain Ischemia; Ischemia; Brain Diseases; Hypoxia; Hypoxia-Ischemia, Brain; Hypoglycemic Agents; Physiological Effects of Drugs; Anticonvulsants; Topiramate
• Other Study ID Numbers: 1182678