Pilot Study of Bumetanide for Newborn Seizures

• A secondary outcome is determination of the safety and tolerability of bumetanide as add-on therapy in newborns with refractory seizures. [ Time Frame: Two years is anticipated ] [ Designated as safety issue: Yes ]
• The secondary outcome will be to determine whether there is a dose-dependent effect of bumetanide compared with standard therapy alone for the control of seizures, quantified by EEG measures of seizure activity. [ Time Frame: Two and a half years is anticipated ] [ Designated as safety issue: No ]

The main goal of the study is to obtain pharmacokinetic and safety data of bumetanide in newborns with refractory seizures. The overall hypothesis is that bumetanide, added to conventional antiepileptic (antiseizure) medications, will be a safe and well tolerated medication, compared with conventional antiepileptic drugs alone.

Seizures occur more often during the newborn period (2-3.5 per 1000 live births) than at any later age. Neonatal seizures can lead to frequent and serious long-term consequences in survivors, such as later epilepsy and significant cognitive and motor disabilities. Unfortunately there are no completely effective drugs to treat neonatal seizures. Anti-epileptic drugs (AEDs) currently used to treat neonatal seizures are generally ineffective and have significant potential for side effects. Furthermore, many of these AEDs have never been tested in a randomized study. Numerous experts have thus emphasized in the last few years the urgent need for randomized trials of potential new treatments for neonatal seizures. We are conducting a pilot study of the drug bumetanide as one such potential and novel treatment. Bumetanide is a commercially available drug that has been used safely in newborns as a diuretic for many years with minimal side effects. Recent basic science research in animals has shown bumetanide to be very effective in reducing seizures in neonatal animals by blocking a specific chloride importer which is highly expressed in neonates but not in children and adults (1). Moreover, these experimental studies have shown bumetanide to be particularly effective against seizures when used in combination with phenobarbital (PB), which is the standard first drug given to treat neonatal seizures (2).

We will conduct a randomized, double-blind, controlled, dose escalation study of BTN as add-on therapy to treat refractory seizures caused by HIE, focal or multi-focal stroke, or intracranial hemorrhage not controlled by an initial loading dose of PB. The trial will test the feasibility of early enrollment of newborns with HIE, rapid application of a full montage EEG, and continuous review of EEG data to detect refractory seizures as soon as they occur following an initial loading dose of PB. When an EEG-proven seizure occurs at least 30 minutes following a loading dose of PB, the newborn will be randomized to receive either BTN or placebo in conjunction with a second dose of PB. Clinical, laboratory and continuous EEG monitoring data obtained after BTN administration will be analyzed to determine the pharmacokinetics and safety of BTN by comparing data from treatment and standard therapy groups. This study address important challenges in trial design and sets the stage for trials to improve treatment of neonatal seizures. Data from this pilot study will be used to guide design of a planned Phase III multicenter trial to test the efficacy of BTN to control refractory neonatal seizures.

1. Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, Mathews GC, Benke TA, Delpire E, Jensen FE, Staley KJ: NKCC1 transporter facilitates seizures in the developing brain. Nat Med 2005;11:1205-1213.
2. Dzhala VI, Brumback AC, Staley KJ: Bumetanide enhances phenobarbital efficacy in a neonatal seizure model. Ann Neurol 2008;63:222-235.

• Drug: Bumetanide
  Bumetanide IV given in addition to standard anticonvulsant medication
  Other Name: Bumex
• Other: Normal Saline
  Normal Saline IV given in addition to standard anticonvulsant medication

• Experimental: 1
  Standard phenobarbital plus either 0.1 mg/kg, 0.2 mg/kg, or 0.3 mg/kg of bumetanide as determined by the status of the dose escalation design.
  Intervention: Drug: Bumetanide
• Placebo Comparator: 2
  Standard phenobarbital therapy plus normal saline placebo
  Intervention: Other: Normal Saline

Inclusion Criteria:

• newborns with a post-conceptional age of 33-44 weeks
• condition with risk for seizure: hypoxic-ischemic encephalopathy, focal or multi focal stroke or intracranial hemorrhage
• suspected clinical seizure

Exclusion Criteria:

• suspected or confirmed brain malformation
• chromosomal anomaly or genetic syndrome
• congenital (in utero) infection
• meningitis, encephalitis or sepsis
• metabolic abnormalities (e.g., transient hypocalcemia as the sole cause of seizures)
• inborn error of metabolism
• newborns who have received diuretics such as furosemide or BTN
• newborns with a total serum bilirubin > 15 mg/dL at enrollment
• newborns given >40mg/kg of phenobarbital

• Citizens United for Research in Epilepsy
• Harvard Catalyst- Harvard Clinical and Translational Science Center
• Translational Research Program, Boston Children's Hospital
• Charles H. Hood Foundation
• National Institute of Neurological Disorders and Stroke (NINDS)