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

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ClinicalTrials.gov Identifier: NCT02531880
Recruitment Status : Suspended
First Posted : August 25, 2015
Last Update Posted : March 29, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )

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
  • Are enrolled in protocol 01-N-0139
  • Healthy volunteers

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 (not for healthy volunteers)
  • 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 determine if (1) administration of mangafodipir is well tolerated by healthy volunteers and patients with epilepsy and if (2) 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 and comparison with healthy volunteers.

Study population: 16 patients with drug-resistant epilepsy, and up to 16 healthy controls.

Design: Screening of enrolled participants will include a medical history, physical exam, blood and urine laboratory testing. Patients and healthy volunteers will be imaged interictally with a gadolinium enhanced MRI session. For patients, the administration of mangafodipir will be done as an inpatient during long-term video EEG recording, to ensure administration in the peri-ictal period. Patients and controls 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) clinical safety parameters of mangafodipir administration, and (2) 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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
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
Study Start Date : August 22, 2015
Estimated Primary Completion Date : June 30, 2018
Estimated Study Completion Date : June 28, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Epilepsy MRI Scans
Drug Information available for: Manganese
U.S. FDA Resources


Intervention Details:
    Drug: Mangafodipir
    A contrast agent previously approved for liver imaging with MRI, which contains manganese.


Primary Outcome Measures :
  1. The laterality index, measuring the difference between normalized T1-weighted signal intensity, between the clinically defined epileptogenic zone and the contralateral homologous region. [ Time Frame: 10 days ]
  2. Subjects will be clinically monitored during and after administration of mangafodipir for adverse events. Patients will have close neurological monitoring in the first 24 hours as well. [ Time Frame: 10 days ]

Secondary Outcome Measures :
  1. MEMRI b) Comparison of MEMRI localization with standard presurgical localization. [ Time Frame: 10 days ]
  2. MEMRI c) Difference in enhancement patterns between healthy volunteers and people with epilepsy. [ Time Frame: 10 days ]
  3. DCE/DSC - a) Permeability parameters (Ktrans, K2) in homologous brain regions. [ Time Frame: 1 day ]
  4. DCE/DSC - b) Comparison between permeability measures and presurgical localization. [ Time Frame: 1 day ]
  5. DCE/DSC - c) Difference in permeability patterns between healthy volunteers and people with epilepsy. [ Time Frame: 1 day ]
  6. MEMRI a) Spatiotemporal evolution of enhancement over scans at baseline and days 0-10. [ Time Frame: 10 days ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

HEALTHY VOLUNTEER:

  • Age 18-60
  • Able to give written informed consent directly.

PATIENTS:

  • 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 the NINDS Clinical Epilepsy Section outpatient clinic under protocol 01-N-0139, and if necessary, inpatient video- EEG monitoring. Seizure focus localization will be determined by standard clinical, neurophysiologic, and imaging studies. Prior or concurrent enrollment in 01-N-0139 is required.

EXCLUSION CRITERIA:

HEALTHY VOLUNTEER:

  • No current or history of neurological disease, including epilepsy and multiple sclerosis
  • Same exclusion criteria as patients

PATIENTS:

General exclusions:

  • A history of drug or alcohol abuse/dependence
  • History of brain disease other than epilepsy.
  • Known cause for seizures, other than mesial focal sclerosis, such as tumor or infection.
  • Positive test for HIV.
  • History of post-ictal psychosis or post-ictal aggression
  • Brain abnormality such as a brain tumor, stroke, brain damage from head trauma or blood vessel abnormalities, on an 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 medical disorders other than epilepsy, such as liver or kidney disease, that could potentially increase the risk of CNS damage due to manganese exposure
  • major lab abnormality, including clinically significant abnormal range values in 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

Gadolinium enhanced MRI component specific exclusions:

  • Estimated GFR > 60, tested within 1 week of scan
  • allergy to gadolinium

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): NCT02531880


Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
Principal Investigator: Daniel M Goldenholz, M.D. National Institute of Neurological Disorders and Stroke (NINDS)

Additional Information:
Responsible Party: National Institute of Neurological Disorders and Stroke (NINDS)
ClinicalTrials.gov Identifier: NCT02531880     History of Changes
Other Study ID Numbers: 150177
15-N-0177
First Posted: August 25, 2015    Key Record Dates
Last Update Posted: March 29, 2018
Last Verified: June 21, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ):
MRI
Manganese Enhanced MRI
Seizure Disorder
Seizures
Epileptic Focus

Additional relevant MeSH terms:
Epilepsy
Drug Resistant Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Manganese
Trace Elements
Micronutrients
Growth Substances
Physiological Effects of Drugs