Pilot Study of Bumetanide for Newborn Seizures

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2015 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 17, 2015
Last verified: April 2015
  Purpose

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 Intervention Phase
Seizures
Drug: Bumetanide
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by Soul, Janet , M.D.:

Primary Outcome Measures:
  • The primary outcome is determination of the pharmacokinetics and safety of bumetanide in newborns with refractory seizures. [ Time Frame: 5-6 years are anticipated for collection of the neonatal data ] [ Designated as safety issue: Yes ]
    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:
  • 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: 5-6 years are anticipated for collection of the neonatal data ] [ Designated as safety issue: No ]
    The investigators will determine the feasibility of enrolling and randomizing newborns early in the course of their refractory seizures.


Estimated Enrollment: 44
Study Start Date: January 2010
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 anticonvulsant medication
Other Name: Bumex
Placebo Comparator: 2
Standard phenobarbital therapy

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 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.

  Eligibility

Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00830531

Contacts
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

Locations
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Janet Soul, MD, CM    617-355-8994    janet.soul@childrens.harvard.edu   
Principal Investigator: Janet Soul, MD, CM         
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Helen Christou, MD    617-525-8129    HCHRISTOU@PARTNERS.ORG   
Principal Investigator: Helen Christou, MD         
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Kevin J Staley, MD       Staley.Kevin@mgh.harvard.edu   
Principal Investigator: Kevin J Staley, MD         
Tufts Floating Hospital for Children at Tufts Medical Center Recruiting
Boston, Massachusetts, United States, 02111
Contact: Jonathan Davis, MD       jdavis@tuftsmedicalcenter.org   
Principal Investigator: Jonathan Davis, MD         
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
Investigators
Principal Investigator: Janet Soul, MD,CM Children's Hospital Boston
  More Information

Publications:
Responsible Party: Soul, Janet , M.D.
ClinicalTrials.gov Identifier: NCT00830531     History of Changes
Other Study ID Numbers: CURE 07120492, 1R01NS066929-01A1
Study First Received: January 27, 2009
Last Updated: April 17, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Soul, Janet , M.D.:
Hypoxic-ischemic encephalopathy
Neonatal stroke
Intracranial hemorrhage
Perinatal asphyxia
Neonatal Seizures

Additional relevant MeSH terms:
Seizures
Brain Diseases
Central Nervous System Diseases
Epilepsy
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Bumetanide
Cardiovascular Agents
Diuretics
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sodium Potassium Chloride Symporter Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on August 27, 2015