Brain P-gp and Inflammation in People With Epilepsy
|First Received Date ICMJE||August 8, 2012|
|Last Updated Date||February 9, 2016|
|Start Date ICMJE||July 2012|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
||Amount of differential [11C]dLop and [11C]PBR28 uptake between the epileptic focus and the homologous contralateral region [ Time Frame: study completion ] [ Designated as safety issue: No ]|
|Original Primary Outcome Measures ICMJE||Not Provided|
|Change History||Complete list of historical versions of study NCT01663545 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Secondary Outcome Measure: A secondary goal is to determine if inhibiting P-gp with tariquidar results in increased concentrations of anti-epileptic medications into the CSF, as a surrogate marker for increased penetration of these medication... [ Time Frame: study completion ] [ Designated as safety issue: No ]|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Brain P-gp and Inflammation in People With Epilepsy|
|Official Title ICMJE||Positron Emission Tomography Measurement of Neuroinflammation and P-glycoprotein in Localization-Related Epilepsy|
1) To investigate the relationship between permeability-glycoprotein (P-gp) function, neuroinflammation, and drug-resistance in participants with temporal lobe epilepsy (TLE). 2) To attempt to detect an increased level of inflammation in epileptic foci. 3) To assess theeffect of genetic polymorphisms of P-gp on brain uptake of [11C]dLop and of genetic polymorphisms of TSPO on brain uptake of [11C]PBR28.
25 participants with drug-resistant focal epilepsy; 25 participants with drug responsive focal epilepsy; and 25 healthy volunteers.
Screening of enrolled participants will include a medical history, physical exam, electrocardiogram (ECG), and blood and urine laboratory testing. Blood samples will also be used for genetic polymorphism study. Healthy volunteers will receive two brain positron emission tomography (PET) scans with [11C]dLop and [11C]PBR28. Epilepsy participants will receive three PET scans (2 with [11C]dLop and 1 with [11C]PBR28). Everyone will receive a brain magnetic resonance imaging (MRI). Because [11C]dLop uptake is influenced by blood flow, a [15O]H2O scan will also be performed to determine flow to the brain before each [11C]dLop scan. The [11C]dLop scan will be performed during infusion of intravenous tariquidar at up to 2 mg/kg, to partially block brain P-gp and ensure that some [11C]dLop enters the brain.
The primary outcome measure will be the amount of differential [11C]dLop and [11C]PBR28 uptake between the epileptic focus and the homologous contralateral region. [11C]dLop brain uptake will be measured in terms of standardized uptake values (SUV). SUV reflects the measured brain radioactivity after tracer injection, corrected for patient weight and injected activity. [11C]PBR28 distribution volume (VT) will be measured using an arterial input function. We want to quantify the tracer VT in regions of the brain distant from the epileptic focus, which may be affected by the disease. For this kind of quantification, the SUV is unsuitable, because it provides only a crude estimate of brain uptake, without taking into account the rate of delivery from the blood.
After P-gp blocking with tariquidar, we expect, in participants with drug-resistant epilepsy, that the amount of [11C]dLop uptake on the side of the epileptic focus will be lower than in the contralateral side. This difference will be significantly greater than the side-to side difference found in healthy participants. We expect an intermediate difference in the population of drug-responsive epilepsy participants. [11C]dLop uptake will be corrected for cerebral blood flow using [15O]H2 O PET.
We also hypothesize that TLE will be associated with brain inflammation and, therefore, that [11C]PBR28 uptake in the affected side of the brain will be higher than in the contralateral side. We will explore whether the degree of inflammation correlates with drug resistance and [11C]dLop uptake.
Finally, we will perform genetic testing to study the effect of polymorphisms of P-gp on brain uptake of [11C]dLop and with inhibition by tariquidar. The primary polymorphism (C3435T) of interest is the one that has been associated with drug resistance in epilepsy. We will also study the polymorphism of the translocator protein (TSPO), because TSPO polymorphism has an influence on [11C]PBR28 binding. This polymorphism is due to the non-conservative amino-acid substitution at position 147 from alanine to threonine (Ala147Thr) in the fifth transmembrane domain of the TSPO protein. If new genetic findings are published in the literature about epilepsy and its relationship with inflammation and efflux transporters, we may perform other types of genetic testing on the blood samples we have collected. Prospective approval from the IRB will be obtained for any genetic testing that has clinical implications for participants.
|Study Type ICMJE||Observational|
|Study Design ICMJE||Time Perspective: Prospective|
|Target Follow-Up Duration||Not Provided|
|Sampling Method||Not Provided|
|Study Population||Not Provided|
|Condition ICMJE||Epilepsies, Partial|
|Intervention ICMJE||Not Provided|
|Study Group/Cohort (s)||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||75|
|Completion Date||Not Provided|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
For healthy volunteers
For healthy volunteers
|Ages||18 Years to 60 Years|
|Accepts Healthy Volunteers||Yes|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01663545|
|Other Study ID Numbers ICMJE||120182, 12-N-0182|
|Has Data Monitoring Committee||Not Provided|
|Plan to Share Data||Not Provided|
|IPD Description||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||National Institute of Neurological Disorders and Stroke (NINDS)|
|Collaborators ICMJE||Not Provided|
|Information Provided By||National Institutes of Health Clinical Center (CC)|
|Verification Date||February 2016|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP