title: Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial.
abstract: BACKGROUND
  Preclinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures.
  
  
  METHODS
  In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225.
  
  
  RESULTS
  Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0·05 mg/kg, n=4; 0·1 mg/kg, n=3; 0·2 mg/kg, n=6; 0·3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0·05 mg/kg, one on 0·1 mg/kg and three on 0·2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0·05 mg/kg and one on 0·3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction.
  
  
  CONCLUSIONS
  Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials.
  
  
  BACKGROUND
  European Community's Seventh Framework Programme.
authors.affiliation: Section of Clinical Neurosciences and Neonatal Unit, University College London, London, UK. Electronic address: r.pressler@ucl.ac.uk.
authors.forename: Ronit M
authors.initials: RM
authors.lastname: Pressler
authors.affiliation: Irish Centre for Fetal and Neonatal Translational Research, University College Cork, Cork, Ireland.
authors.forename: Geraldine B
authors.initials: GB
authors.lastname: Boylan
authors.affiliation: Section of Clinical Neurosciences and Neonatal Unit, University College London, London, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Marlow
authors.affiliation: Neonatology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Blennow
authors.affiliation: Inserm U1129, Paris, France; University Paris Descartes, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chiron
authors.affiliation: Section of Clinical Neurosciences and Neonatal Unit, University College London, London, UK.
authors.forename: J Helen
authors.initials: JH
authors.lastname: Cross
authors.affiliation: Neonatology, University Medical Centre Utrecht, Utrecht, Netherlands.
authors.forename: Linda S
authors.initials: LS
authors.lastname: de Vries
authors.affiliation: Neonatology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Boubou
authors.initials: B
authors.lastname: Hallberg
authors.affiliation: Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Hellström-Westas
authors.affiliation: Inserm U1129, Paris, France; University Paris Descartes, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jullien
authors.affiliation: Irish Centre for Fetal and Neonatal Translational Research, University College Cork, Cork, Ireland.
authors.forename: Vicki
authors.initials: V
authors.lastname: Livingstone
authors.affiliation: Duke Clinical Research Institute, Duke University, NC, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Mangum
authors.affiliation: Irish Centre for Fetal and Neonatal Translational Research, University College Cork, Cork, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: Murphy
authors.affiliation: Irish Centre for Fetal and Neonatal Translational Research, University College Cork, Cork, Ireland.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Murray
authors.affiliation: Inserm U1129, Paris, France; University Paris Descartes, Paris, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pons
authors.affiliation: Section of Clinical Neurosciences and Neonatal Unit, University College London, London, UK.
authors.forename: Janet
authors.initials: J
authors.lastname: Rennie
authors.affiliation: Neonatology, Erasmus University Medical Centre Rotterdam, Rotterdam, Netherlands.
authors.forename: Renate
authors.initials: R
authors.lastname: Swarte
authors.affiliation: Neonatology, University Medical Centre Utrecht, Utrecht, Netherlands.
authors.forename: Mona C
authors.initials: MC
authors.lastname: Toet
authors.affiliation: Children's Clinical Neurophysiology, Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Sampsa
authors.initials: S
authors.lastname: Vanhatalo
authors.affiliation: Department for Statistics, Inserm, Inserm U1138, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Zohar
mesh_terms: D002034:Bumetanide / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D004334:Drug Administration Schedule; D004357:Drug Synergism; D057239:Early Termination of Clinical Trials; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000188:drug therapy*; D007231:Infant, Newborn; D008297:Male; D010634:Phenobarbital / Q000627:therapeutic use*; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D017211:Treatment Failure
chemical_list: D049994:Sodium Potassium Chloride Symporter Inhibitors; D002034:Bumetanide; D010634:Phenobarbital