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Pilot Study of Bumetanide for Newborn Seizures

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00830531
Recruitment Status : Completed
First Posted : January 28, 2009
Last Update Posted : December 17, 2020
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
National Institute of Neurological Disorders and Stroke (NINDS)
Mooney Family Initiative for Translational Studies in Rare Diseases, Boston Children's Hospital
Information provided by (Responsible Party):
Soul, Janet , M.D.

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Seizures Drug: Bumetanide Drug: Normal Saline as Placebo Phase 1

Detailed Description:

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. The investigators 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).

The investigators 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, intracranial hemorrhage, CNS infection, genetic syndrome, focal or diffuse brain malformation, idiopathic or presumed genetic etiology of seizures, or metabolic disorder other than electrolyte disturbances or those caused by renal failure 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 loading dose of PB. Clinical, laboratory and continuous EEG monitoring data obtained after BTN administration will be analyzed to determine the pharmacokinetics (3) and safety of BTN by comparing data from treatment and standard therapy groups. This study addresses 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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 43 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Pilot Study of Bumetanide for Newborn Seizures: A Phase I Study of Pharmacokinetics and Safety of Bumetanide for Neonatal Seizures
Study Start Date : January 2010
Actual Primary Completion Date : January 2019
Actual Study Completion Date : January 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Seizures
Drug Information available for: Bumetanide

Arms and Interventions
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Arm Intervention/treatment
Experimental: 1
Standard phenobarbital combined with 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.
 Drug: Bumetanide
Bumetanide either 0.1 mg/kg, 0.2 mg/kg or 0.3 mg/kg IV administered together with standard phenobarbital therapy
Other Name: Bumex
Placebo Comparator: 2
Standard phenobarbital therapy combined with normal saline as placebo for bumetanide
 Drug: Normal Saline as Placebo
Normal Saline as placebo for bumetanide either 0.1 mg/kg, 0.2 mg/kg or 0.3 mg/kg IV administered together with standard phenobarbital therapy
Other Name: 0.9% NaCl


Outcome Measures
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Primary Outcome Measures :
  1. The primary outcome is determination of the pharmacokinetics and safety of bumetanide in newborns with refractory seizures. [ Time Frame: 6-7 years are anticipated for the collection of the neonatal data ]
    The investigators will determine the dose exposure, half-life, volume of distribution and clearance of bumetanide in newborns with refractory seizures. The investigators will determine if there is a significant effect of hepatic dysfunction or hypothermia on bumetanide pharmacokinetics. For evaluation of safety, the rate of adverse events will be compared between treatment and control groups.


Secondary Outcome Measures :
  1. A secondary outcome is determination of the feasibility of the study design to test antiepileptic drugs to treat neonatal seizures caused by acute hypoxic-ischemic encephalopathy in a clinical trial. [ Time Frame: 6-7 years are anticipated for collection of the neonatal data ]
    The investigators will determine the feasibility of enrolling and randomizing newborns early in the course of their refractory seizures.


Eligibility Criteria
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Ages Eligible for Study:   up to 44 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00830531


Locations
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United States, Massachusetts
Tufts Floating Hospital for Children at Tufts Medical Center
Boston, Massachusetts, United States, 02111
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
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)
Mooney Family Initiative for Translational Studies in Rare Diseases, Boston Children's Hospital
Investigators
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Principal Investigator: Janet Soul, MD,CM Boston Children's Hospital
More Information
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Additional Information:

Publications:

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Responsible Party: Soul, Janet , M.D.
ClinicalTrials.gov Identifier: NCT00830531    
Other Study ID Numbers: CURE 07120492
1R01NS066929-01A1 ( U.S. NIH Grant/Contract )
First Posted: January 28, 2009    Key Record Dates
Last Update Posted: December 17, 2020
Last Verified: December 2020
Keywords provided by Soul, Janet , M.D.:
Hypoxic-ischemic encephalopathy
Neonatal stroke
Intracranial hemorrhage
Perinatal asphyxia
Neonatal Seizures
Additional relevant MeSH terms:
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Seizures
Neurologic Manifestations
Nervous System Diseases
Bumetanide
Diuretics
 Natriuretic Agents
Physiological Effects of Drugs
Sodium Potassium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action