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

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

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.

Study Overview

• Status: Completed
• Conditions: Hypoxic Ischemic Encephalopathy
• Intervention / Treatment: Drug: Topiramate in newborns with hypoxic ischemic encephalopathy treated with therapeutic hypothermia

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Florence, Italy, I-50139
    • Neonatal Intensive Care Unit - Azienda Ospedaliero-Universitaria Meyer
  • Pisa, Italy, I-56100
    • Neonatal Intensive Care Unit - Azienda Ospedaliero-Universitaria Pisana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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;
2. 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.
3. abnormal aEEG

Exclusion Criteria:

congenital abnormalities, congenital viral infections or evidence encephalopathy other than HIE.

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Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Topiramate; Newborns with hypoxic ischemic encephalopathy treated with mild hypothermia and topiramate	Drug: Topiramate in newborns with hypoxic ischemic encephalopathy treated with therapeutic hypothermia; 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.
No Intervention: Control; Newborns with hypoxic ischemic encephalopathy treated with mild hypothermia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Azienda Ospedaliero, Universitaria Meyer
• Collaborators: Azienda Ospedaliero, Universitaria Pisana
• Investigators: Principal Investigator: Luca Filippi, MD, Azienda Ospedaliero-Universitaria A. Meyer, Firenze, Italy

Publications and helpful links

General Publications

• Shankaran S. Outcomes of hypoxic-ischemic encephalopathy in neonates treated with hypothermia. Clin Perinatol. 2014 Mar;41(1):149-59. doi: 10.1016/j.clp.2013.10.008.
• Filippi L, la Marca G, Fiorini P, Poggi C, Cavallaro G, Malvagia S, Pellegrini-Giampietro DE, Guerrini R. Topiramate concentrations in neonates treated with prolonged whole body hypothermia for hypoxic ischemic encephalopathy. Epilepsia. 2009 Nov;50(11):2355-61. doi: 10.1111/j.1528-1167.2009.02302.x. Epub 2009 Sep 10.
• Filippi L, Poggi C, la Marca G, Furlanetto S, Fiorini P, Cavallaro G, Plantulli A, Donzelli G, Guerrini R. Oral topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia: a safety study. J Pediatr. 2010 Sep;157(3):361-6. doi: 10.1016/j.jpeds.2010.04.019. Epub 2010 May 31.
• Filippi L, Fiorini P, Daniotti M, Catarzi S, Savelli S, Fonda C, Bartalena L, Boldrini A, Giampietri M, Scaramuzzo R, Papoff P, Del Balzo F, Spalice A, la Marca G, Malvagia S, Della Bona ML, Donzelli G, Tinelli F, Cioni G, Pisano T, Falchi M, Guerrini R. Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI). BMC Pediatr. 2012 Sep 5;12:144. doi: 10.1186/1471-2431-12-144.

Helpful Links

• Drug information

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: November 10, 2010
• First Submitted That Met QC Criteria: November 15, 2010
• First Posted (Estimate): November 16, 2010

Study Record Updates

• Last Update Posted (Estimate): December 13, 2013
• Last Update Submitted That Met QC Criteria: December 12, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: asphyxia neonatorum, hypothermia, neuroprotection
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Respiratory; Body Temperature Changes; Hypoxia, Brain; Brain Ischemia; Ischemia; Brain Diseases; Hypoxia; Hypothermia; Hypoxia-Ischemia, Brain; Hypoglycemic Agents; Physiological Effects of Drugs; Anticonvulsants; Topiramate
• Other Study ID Numbers: EudraCT: 2010-018627-25