Topiramate in Neonates Receiving Whole Body Cooling for Hypoxic Ischemic Encephalopathy

Study Overview
=================
Brief Summary
-----------------
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.

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

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

Conditions
-----------------
Hypoxic Ischemic Encephalopathy

Intervention / Treatment
-----------------
* Drug: Topiramate
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: In order to be eligible for cooling the baby must meet all three of the following sets of criteria Be near term (typically ≥34wks gestation) and be aged < 6h old 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) Have signs of moderate or severe encephalopathy based on either clinical examination or on amplitude integrated aEEG assessment Exclusion Criteria: Known congenital myopathy Known congenital neuropathy

Ages Eligible for Study
-----------------
Maximum Age: 6 Hours

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects will receive the standard of care intervention for HIE at our institution (whole body cooling for 72h followed by gradual rewarming) | Drug: Placebo<br>* A placebo identical in appearance to the active agent (topiramate)<br>|
| Active Comparator: Topiramate<br>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<br>* 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.<br>* Other names: Topiragen;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIE, Hypoxic ischemic encephalopathy, Perinatal depression, Whole body cooling, Therapeutic hypothermia