title: Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI).
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
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neonatal Intensive Care Unit, Medical Surgical Feto-Neonatal Department, A. Meyer University Children's Hospital, Viale Pieraccini, 24, I-50139, Florence, Italy. l.filippi@meyer.it
authors.forename: Luca
authors.initials: L
authors.lastname: Filippi
authors.forename: Patrizio
authors.initials: P
authors.lastname: Fiorini
authors.forename: Marta
authors.initials: M
authors.lastname: Daniotti
authors.forename: Serena
authors.initials: S
authors.lastname: Catarzi
authors.forename: Sara
authors.initials: S
authors.lastname: Savelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Fonda
authors.forename: Laura
authors.initials: L
authors.lastname: Bartalena
authors.forename: Antonio
authors.initials: A
authors.lastname: Boldrini
authors.forename: Matteo
authors.initials: M
authors.lastname: Giampietri
authors.forename: Rosa
authors.initials: R
authors.lastname: Scaramuzzo
authors.forename: Paola
authors.initials: P
authors.lastname: Papoff
authors.forename: Francesca
authors.initials: F
authors.lastname: Del Balzo
authors.forename: Alberto
authors.initials: A
authors.lastname: Spalice
authors.forename: Giancarlo
authors.initials: G
authors.lastname: la Marca
authors.forename: Sabrina
authors.initials: S
authors.lastname: Malvagia
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Della Bona
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Donzelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Tinelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cioni
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pisano
authors.forename: Melania
authors.initials: M
authors.lastname: Falchi
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
mesh_terms: D003131:Combined Modality Therapy; D005632:Fructose / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000628:therapy*; D007231:Infant, Newborn; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000077236:Topiramate
chemical_list: D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose