Pilot Study of Bumetanide for Newborn Seizures

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Soul, Janet , M.D.
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
Soul, Janet , M.D.
ClinicalTrials.gov Identifier:
NCT00830531
First received: January 27, 2009
Last updated: April 23, 2014
Last verified: April 2014

January 27, 2009
April 23, 2014
January 2010
July 2015   (final data collection date for primary outcome measure)
The primary outcome is determination of the pharmacokinetics and safety of bumetanide in newborns with refractory seizures. [ Time Frame: Four to five years are anticipated for collection of the neonatal data ] [ Designated as safety issue: Yes ]
The primary outcome is determination of the pharmacokinetics of bumetanide in newborns with refractory seizures. [ Time Frame: Two years are anticipated for collection of the neonatal data ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00830531 on ClinicalTrials.gov Archive Site
A secondary outcome is determination of the feasibility of a novel study design to test antiepileptic drugs to treat neonatal seizures caused by acute hypoxic-ischemic encephalopathy in a clinical trial. [ Time Frame: Four to five years are anticipated for collection of the neonatal data. ] [ Designated as safety issue: No ]
  • 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 ]
Not Provided
Not Provided
 
Pilot Study of Bumetanide for Newborn Seizures
Pilot Study of Bumetanide for Newborn Seizures: A Phase I Study of Pharmacokinetics and Safety of Bumetanide for Neonatal Seizures

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.
Interventional
Phase 1
Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Seizures
  • 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
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
38
December 2015
July 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • newborns with a post-conceptional age of 33-44 weeks
  • condition with risk for seizure:

    • asphyxia
    • intracranial hemorrhage
    • suspected or confirmed stroke
    • CNS infection
    • genetic syndrome
    • focal or diffuse brain malformation
    • idiopathic or presumed genetic etiology of seizures
    • metabolic disorder other than electrolyte disturbances or those caused by renal failure
  • suspected clinical seizure

Exclusion Criteria:

  • have transient metabolic abnormalities (e.g., transient hypocalcemia) as the sole cause of seizures
  • are receiving ECMO (extracorporeal membrane oxygenation) therapy because of alteration of bumetanide pharmacokinetics by ECMO
  • have contraindications to bumetanide (as determined by treating physician)
  • 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
  • loading doses of AEDs other than phenobarbital (those who receive levetiracetam are still eligible since levetiracetam does not affect bumetanide pharmacokinetics)
Both
Not Provided
No
Contact: Janet Soul, MD,CM 617-355-8994 janet.soul@childrens.harvard.edu
Contact: Kevin Staley, MD 617-724-6699 Staley.Kevin@mgh.harvard.edu
United States
 
NCT00830531
CURE 07120492, 1R01NS066929-01A1
Yes
Soul, Janet , M.D.
Soul, Janet , M.D.
  • 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)
Principal Investigator: Janet Soul, MD,CM Children's Hospital Boston
Soul, Janet , M.D.
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP