Open Access Highly Accessed Study protocol

Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI)

Luca Filippi1*, Patrizio Fiorini1, Marta Daniotti1, Serena Catarzi1, Sara Savelli2, Claudio Fonda2, Laura Bartalena3, Antonio Boldrini3, Matteo Giampietri3, Rosa Scaramuzzo4, Paola Papoff5, Francesca Del Balzo5, Alberto Spalice6, Giancarlo la Marca78, Sabrina Malvagia8, Maria Luisa Della Bona8, Gianpaolo Donzelli9, Francesca Tinelli10, Giovanni Cioni10, Tiziana Pisano11, Melania Falchi11 and Renzo Guerrini11

Author Affiliations

1 Neonatal Intensive Care Unit, Medical Surgical Feto-Neonatal Department, “A. Meyer” University Children’s Hospital, Viale Pieraccini, 24, I-50139, Florence, Italy

2 Department of Radiological Sciences, “A. Meyer” University Children's Hospital, Viale Pieraccini, 24, I-50139, Florence, Italy

3 Neonatal Unit, University of Pisa, Via Roma, 67, I-56126, Pisa, Italy

4 Istituto di Scienze della Vita, Scuola Superiore Sant’Anna, Piazza Martiri della Libertà, 33, I-56127, Pisa, Italy

5 Pediatric Emergency and Intensive Care, Department of Pediatrics, La Sapienza University of Rome, Viale del Policlinico, 155, I-00186, Rome, Italy

6 Division of Child Neurology, Department of Pediatrics, La Sapienza University of Rome, Viale del Policlinico, 155, I-00186, Rome, Italy

7 Department of Pharmacology, University of Florence, Viale Pieraccini, 6, I-50139, Florence, Italy

8 Laboratory for diseases of the nervous system and metabolism, “A. Meyer” University Children’s Hospital, Viale Pieraccini, 24, I-50139, Florence, Italy

9 Department of Sciences for Woman and Child's Health, University of Florence, “A. Meyer” Children's Hospital, Viale Pieraccini, 24, I-50139, Florence, Italy

10 Department of Developmental Neuroscience, Stella Maris Scientific Institute, Viale del Tirreno, 331, I-56128, Calambrone, Pisa, Italy

11 Paediatric Neurology Unit and Laboratories, “A. Meyer” Children’s Hospital, University of Florence, Viale Pieraccini, 24, I-50139, Florence, Italy

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BMC Pediatrics 2012, 12:144  doi:10.1186/1471-2431-12-144

Published: 5 September 2012

Abstract

Background

Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2–3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment.

Methods/Design

Term newborns (gestational age ≥ 36 weeks and birth weight ≥ 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests.

Discussion

This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns.

Trial registration

Current Controlled Trials ISRCTN62175998; ClinicalTrials.gov Identifier NCT01241019; EudraCT Number 2010-018627-25

Keywords:
Neonatal hypoxic-ischemic encephalopathy; Therapeutic hypothermia; Topiramate