Investigation of Blood-Brain-Barrier Breakdown Using Manganese Magnetic Resonance Imaging in Drug-Resistant Epilepsy

Sponsor

National Institute of Neurological Disorders and Stroke (NINDS) (NIH)

Overall Status

Not yet recruiting

CT.gov ID

NCT02531880

Collaborator

(none)

Enrollment

Location

Arm

23.8

Anticipated Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Background:

The blood-brain barrier separates the brain from the rest of the body. Epilepsy is a neurological disease that causes seizures. It can affect this barrier. Researchers think a contrast agent called mangafodipir might be better able to show areas of the brain that epilepsy affects.

Objective:

To see if mangafodipir is well tolerated and safe. To see if it can show, on an MRI, areas of the brain that epilepsy affects.

Eligibility:

People ages 18-60 who:
Have epilepsy not controlled by drugs
Prior or concurrent enrollment in 18-N-0066 is required

Design:

Participants will be screened with:
Medical history
Physical exam
Blood and urine tests
Participants will have up to 6 visits in 1-3 months. Those with epilepsy will have an inpatient stay lasting 2-10 days. Visits may include:
Video-EEG monitoring for participants with epilepsy
An IV catheter put in place: a needle guides a thin plastic tube into an arm vein.
Getting mangafodipir through the IV.
5 MRI scans over a 10-day period: a magnetic field and radio waves take pictures of the brain. Participants lie on a table that slides into a metal cylinder. They are in the cylinder for 45-90 minutes, lying still for up to 10 minutes at a time. The scanner makes loud knocking sounds. Participants will get earplugs.
A final MRI at least 2 weeks after receiving mangafodipir. Gadolinium is given through an IV catheter.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Drug: Mangafodipir	Phase 1

Detailed Description

Objective: The primary goals of this pilot study is to (1) describe the safety profile of administration of mangafodipir in patients with epilepsy and (2) determine if peri-ictal administration will allow focal entry of mangafodipir through the blood-brain-barrier and manganese enhanced magnetic resonance imaging (MEMRI) visualization of seizure foci. Secondary objectives are further exploration of MEMRI properties in patients with epilepsy.

Study population: 16 patients with drug-resistant epilepsy.

Design: Screening of enrolled participants will include a medical history, physical exam, blood and urine laboratory testing. Patients will be imaged interictally with a gadolinium enhanced MRI session. The administration of mangafodipir will be done as an inpatient during long-term video EEG recording, to ensure administration in the periictal period. Patients will receive a baseline MRI scan, IV mangafodipir injection and will then be serially scanned with non-contrast MRI scans.

Outcome measures: The primary outcomes are (1) description of the safety profile of mangafodipir administration in patients with epilepsy, and (2) evaluation of the difference between T1-weighted signal intensity in the brain measured after mangafodipir administration in the seizure onset zone identified by standard clinical, EEG, and imaging studies, and the homologous contralateral region.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

Investigation of Blood-Brain-Barrier Breakdown Using Manganese Magnetic Resonance Imaging in Drug-Resistant Epilepsy

Anticipated Study Start Date :

Sep 6, 2022

Anticipated Primary Completion Date :

Apr 1, 2024

Anticipated Study Completion Date :

Aug 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Patients will be given the study drug	Drug: Mangafodipir Patients will be imaged interictally with a gadolinium enhanced MRI session. The administration of mangafodipir will be done as an inpatient during long-term video EEG recording, to ensure administration in the peri-ictal period.

Arm

Intervention/Treatment

Experimental: 1

Patients will be given the study drug

Drug: Mangafodipir

Patients will be imaged interictally with a gadolinium enhanced MRI session. The administration of mangafodipir will be done as an inpatient during long-term video EEG recording, to ensure administration in the peri-ictal period.

Outcome Measures

Primary Outcome Measures

evaluation of the difference between T1-weighted signal intensity in the brain measured after mangafodipir administration in the seizure onset zone identified by standard clinical, EEG, and imaging studies, and the homologous contralateral regio... [after mangafodipir administration]
evaluation of the difference between T1-weighted signal intensity in the brain measured after mangafodipir administration in the seizure onset zone identified by standard clinical, EEG, and imaging studies, and the homologous contralateral region.
description of the safety profile of mangafodipir administration in patients with epilepsy [after mangafodipir adminstration]
safety profile

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

INCLUSION CRITERIA:
Age 18-60
Able to give written informed consent directly.
Drug resistant epilepsy participants will be defined as having clinically documented seizures with consistent EEG evidence as defined by the 1981 International Classification of Epileptic Seizures, refractory to standard anti-seizure treatment for at least one year prior to enrolling in this study and with an average of at least one seizure per month. This criterion will be established by preliminary screening in NINDS Clinical Epilepsy Service under protocol 18-N-0066. Seizure focus localization will be determined by standard clinical, neurophysiologic, and imaging studies. Prior or concurrent enrollment in 18-N-0066 is required.

EXCLUSION CRITERIA:

General exclusions:

Patients with epilepsy who are not surgical candidates
Positive test for HIV.
History of post-ictal psychosis or post-ictal aggression
Significant structural brain abnormality such as a brain tumor, stroke, brain damage from head trauma or blood vessel abnormalities, on the baseline MRI scan.
Pregnancy or breast-feeding.
Planning to get pregnant in the next 2 months
Claustrophobia to a degree that the subject would feel uncomfortable in the MRI machine.
Cannot lie on their back for at least two hours.
Risk for MRI scan, (e.g., any non-organic implant or other device such as a cardiac pacemaker or infusion pump or other metallic implants, objects or body piercings that cannot be removed, or history of being a welder or metal worker due to small metal fragments in the eye)
History of clinically significant liver or kidney disease, that could potentially increase the risk of CNS damage due to manganese exposure
A history of drug or alcohol abuse/dependence (subjects scoring 8 or higher on the AUDIT scale)
Screening lab abnormalities, demonstrating values more than 2 times the upper limit of normal for AST, ALT, bilirubin, alkaline phosphatase, BUN, creatinine
Previous presumed occupational exposure to manganese (i.e., having worked in a mine, foundry, smelter, dry cell battery manufacturing facility, or agriculture)
Allergy to manganese
On-going treatment with calcium-channel blocker
Iron-deficiency anemia
Personal history of Parkinson's Disease or Parkinsonism or presence of this disease in a 1st degree relative
Unwilling to allow sharing and/or use in future studies of coded data that are collected for this study