Pilot Study of Bumetanide for Newborn Seizures

Sponsor

Soul, Janet , M.D. (Other)

Overall Status

Completed

CT.gov ID

NCT00830531

Collaborator

Citizens United for Research in Epilepsy (Other), Harvard Catalyst- Harvard Clinical and Translational Science Center (Other), Translational Research Program, Boston Children's Hospital (Other), Charles H. Hood Foundation (Other), National Institute of Neurological Disorders and Stroke (NINDS) (NIH), Mooney Family Initiative for Translational Studies in Rare Diseases, Boston Children's Hospital (Other)

Enrollment

Locations

Arms

108

Duration (Months)

10.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

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 :

Jan 1, 2010

Actual Primary Completion Date :

Jan 1, 2019

Actual Study Completion Date :

Jan 1, 2019

Arms and Interventions

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 Names: 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 Names: 0.9% NaCl

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 Names:

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 Names:

0.9% NaCl

Outcome Measures

Primary Outcome Measures

The primary outcome is determination of the pharmacokinetics and safety of bumetanide in newborns with refractory seizures. [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

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. [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

Criteria

Ages Eligible for Study:

N/A to 44 Weeks

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Tufts Floating Hospital for Children at Tufts Medical Center	Boston	Massachusetts	United States	02111
2	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
3	Boston Children's Hospital	Boston	Massachusetts	United States	02115
4	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