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Pilot Study of Bumetanide for Newborn Seizures

This study is ongoing, but not recruiting participants.
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.
ClinicalTrials.gov Identifier:
NCT00830531
First received: January 27, 2009
Last updated: April 18, 2017
Last verified: April 2017
  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 Drug: Normal Saline as Placebo Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: 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

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 ]
    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 ]
    The investigators will determine the feasibility of enrolling and randomizing newborns early in the course of their refractory seizures.


Enrollment: 43
Study Start Date: January 2010
Estimated Study Completion Date: December 2017
Primary Completion Date: February 11, 2017 (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 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

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

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
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

Locations
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
Principal Investigator: Janet Soul, MD,CM Boston Children’s Hospital
  More Information

Publications:
Responsible Party: Soul, Janet , M.D.
ClinicalTrials.gov Identifier: NCT00830531     History of Changes
Other Study ID Numbers: CURE 07120492
1R01NS066929-01A1 ( US NIH Grant/Contract Award Number )
Study First Received: January 27, 2009
Last Updated: April 18, 2017

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

Additional relevant MeSH terms:
Seizures
Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Phenobarbital
Bumetanide
Anticonvulsants
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
GABA Modulators
GABA Agents
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP3A Inducers
Diuretics
Natriuretic Agents
Sodium Potassium Chloride Symporter Inhibitors
Membrane Transport Modulators

ClinicalTrials.gov processed this record on June 28, 2017