Safety and Efficacy of Topiramate in Neonates With Hypoxic Ischemic Encephalopathy Treated With Hypothermia

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the administration of topiramate to newborns with hypoxic-ischemic encephalopathy potentiates the neuroprotective effect of treatment with hypothermia.

Detailed Description
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Neonatal hypoxic-ischemic encephalopathy, due to perinatal asphyxia, is one of the leading causes of cerebral palsy, whose incidence, despite improvements in perinatal practice and neonatal care, has remained essentially unchanged over the recent past decades. It occurs approximately in 2-3 newborns every 1000 live births with a mortality rate of 10% for mild degrees and 60% for severe degrees. About 30% of survivors with mild hypoxic-ischemic encephalopathy and 100% with severe hypoxic-ischemic encephalopathy exhibit variable degrees of neurological disability. Several studies have demonstrated the therapeutic effects of whole-body or selective head cooling to treat neonates with hypoxic-ischemic encephalopathy. Mild hypothermia, (rectal or esophageal temperature 33-34°C), started within 6 h after birth and protracted for 48-72 h, can significantly improve primary outcome measures such as death or disability at 18 months or improve the neurological outcome in survivors. Consequently, mild hypothermia is at present recommended for the treatment of moderate degrees of encephalopathy. Topiramate an anticonvulsant agent widely used in adults and children, has been demonstrated to posses neuroprotective properties against hypoxic ischemic brain damage, both in vitro and in animal models and has been included in neuroprotective strategies for ischemic stroke and neonatal hypoxic-ischemic cerebral injury. Recently, topiramate treatment in asphyxiated newborns has been reported safe. Aim of the present study is to confirm the safety and to evaluate whether the association of topiramate enhances the neuroprotective properties of hypothermia for the treatment of neonatal hypoxic-ischemic encephalopathy.

Official Title
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Safety and Efficacy of Oral Topiramate in Neonates With Hypoxic Ischemic Encephalopathy Treated With Hypothermia: a Pilot Study of the Neonatal Neuroprotection of Asphyxiated Tuscan Infants (NeoNATI) Network

Conditions
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Hypoxic Ischemic Encephalopathy

Intervention / Treatment
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* Drug: Topiramate in newborns with hypoxic ischemic encephalopathy treated with therapeutic hypothermia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gestational age > 36 weeks and birth weigh > 1800 g with at least 1 of the following: a) Apgar score < 5 at 10 minutes; b) persisting need for resuscitation, including endotracheal intubation or mask ventilation 10 minutes after birth; c) acidosis (pH <7.0, base deficit >-16 mmol/L in umbilical cord blood or arterial, venous or capillary blood) within 60 minutes from birth; moderate to severe encephalopathy, consisting of altered state of consciousness (irritability, lethargy, stupor, or coma) and > 1 of the following sings: a) hypotonia, b) abnormal reflexes, including oculomotor or pupil abnormalities, c) absent or weak suck, d) clinical seizures. abnormal aEEG Exclusion Criteria: congenital abnormalities, congenital viral infections or evidence encephalopathy other than HIE. -

Ages Eligible for Study
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Minimum Age: 36 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topiramate<br>Newborns with hypoxic ischemic encephalopathy treated with mild hypothermia and topiramate | Drug: Topiramate in newborns with hypoxic ischemic encephalopathy treated with therapeutic hypothermia<br>* TPM 10 mg/kg once a day will be administered with an orogastric tube as enteric-coated granules mixed with water on arrival in the NICU, when the cooling will be begun (T0), once a day for the first 3 days of life, for a total of 3 doses per patient.<br>|
| No Intervention: Control<br>Newborns with hypoxic ischemic encephalopathy treated with mild hypothermia | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary aim is to evaluate the neurological outcome at 6, 12, 18 months of life |  | 18 months of life | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The secondary aim is to evaluate the efficacy of treatment with topiramate for improving neuroradiological outcome at 3 and 12 months of life |  | 12 months of life | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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asphyxia neonatorum, hypothermia, neuroprotection