|- candidate number||13190|
|- NTR Number||NTR3553|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||1-aug-2012|
|- Secondary IDs||NL38803.029.11 METc VUmc and CCMO|
|- Public Title||Onderzoek ter evaluatie van de test -retest variatie van [11C]fenytoine in gezonde vrijwilligers.|
|- Scientific Title||Test-retest of the newly developed P-gp PET tracer [11C]phenytoin in healthy volunteers.|
|- hypothesis||Primary Objectives:|
1. To assess [11C]phenytoin plasma and brain kinetics in healthy volunteer(s), including assessment of the presence of radioactive metabolites in plasma;
2. To develop a tracer kinetic model for [11C]phenytoin in humans;
3. To determine inter- and intra-subject variation of [11C]phenytoin kinetics in humans.
|- Healt Condition(s) or Problem(s) studied||Pharmacoresistance, Epilepsy, Pharmacokinetics|
|- Inclusion criteria||1. Age between 18-65 years;|
2. Good physical health evaluated by medical history, physical (including neurological) examination and screening laboratory tests;
3. Weight >50 kg;
4. For all females of childbearing potential a negative pregnancy test must be obtained within 48 hours before starting the study;
5. Written informed consent of each subject;
6. Hb must be >8 mmol \ litre at the time of the screening for males and >7 mmol \ litre for females.
|- Exclusion criteria||1. Any clinical significant abnormality of any clinical laboratory test;|
2. Any subject who has received any investigational medication within 30 days prior to the start of this study, or who is scheduled to receive an investigational drug;
3. Major psychiatric or neurological disorder;
4. History of alcohol and/or drug abuse (DSM-IV criteria);
5. History of coagulation problems;
6. Any sign of cardiovascular disease;
8. Current use of any medication, other than contraceptive medication;
9. Breast feeding;
11. Blood donation or substantial blood loss within 3 months before the scan day;
12. Need for elective surgery within two months;
13. Unable to understand or read the Dutch language;
14. Metal objects in or around the body (braces, pacemaker, metal fragments).
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||Single arm|
|- planned startdate ||1-sep-2012|
|- planned closingdate||1-sep-2013|
|- Target number of participants||12|
|- Interventions||This is a single-centre test-retest study in healthy humans. We will include (at least) 12 healthy subjects to obtain 12 evaluable test-retest [11C]phenytoin PET scans. These subjects will receive paired [11C]phenytoin PET scans on one day at the Department of Nuclear Medicine & PET Research of the VUmc. All subjects will also undergo an MRI scan for localisation purposes that will be performed at the department of Radiology of the VUmc.|
|- Primary outcome||1. Plasma kinetics of [11C]phenytoin in humans, including assessment of the presence of radioactive metabolites;|
2. Brain kinetics of [11C]phenytoin in humans;
3. Determination of the most accurate tracer kinetic model for [11C]phenytoin in humans;
4. Determination of the most suitable parametric method for [11C]phenytoin in humans;
5. Assessment of inter- and intra-subject variation of [11C]phenytoin kinetics in humans.
|- Secondary outcome||N/A|
|- Timepoints||Positron Emmisson Tomography (PET) will be applied during after administration of the radiotracer [11C]phenytoin. This will be repeated on the same day.The complete procedure takes one day (9-17hr) per volunteer.|
Data will be analysed off-line and final anlysis of the inter-and itra-individualvariability will take place after scanning all volunteers.
|- Trial web site||N/A|
|- CONTACT FOR PUBLIC QUERIES||MD E.A.M. Froklage|
|- CONTACT for SCIENTIFIC QUERIES||Prof. PhD A.A. Lammertsma|
|- Sponsor/Initiator ||VU University Medical Center|
(Source(s) of Monetary or Material Support)
|EU FP 7 , VU University Medical Center|
|- Brief summary||Resistance to current drug therapy is an issue for approximately 30% of all people who develop epilepsy. Consequently, there is a pressing need to develop new and more effective treatments.
P-glycoprotein (P-gp) seems to be involved in drug resistance. P-gp is an efflux transporter (member of the multi-drug resistance (MDR) family), which is located at the blood-brain barrier (BBB) and transports substrates (including multiple CNS drugs) from brain to blood and cerebrospinal fluid. Overexpression of P-gp is thought to be an important mechanism of pharmacoresistance in epilepsy. Various invasive techniques used in animal studies of epilepsy showed upregulation of P-gp. At present, overexpression of P-gp in refractory patients has only been confirmed by examining brain tissue post-mortem or after surgical removal without resulting in direct information on P-gp functionality. Availability of non-invasive imaging methods that would allow for an in vivo assessment of distribution and function of P-gp in the brain is of vital importance.
At present only (R)-[11C]verapamil is routinely used for assessing P-gp function using PET. Verapamil is a substrate of P-gp and therefore cerebral concentrations are low. In case of upregulation of P-gp, it is likely that the signal will be reduced even further, but this is difficult to assess due to the low signal to noise ratio. The signal to noise ratio is even further reduced by cerebral uptake of radiolabelled metabolites of (R)-[11C]verapamil. |
Consequently, (R)-[11C]verapamil is not an ideal ligand for assessing P-gp function. Therefore novel PET probes, designed to specifically measure P-gp function, need to be developed.
It has been shown that phenytoin is a substrate of P-gp. Recently, phenytoin was labelled with carbon-11. PET studies in rats have shown that [11C]phenytoin has more favourable characteristics for measuring P-gp function than (R)-[11C]verapamil: First, [11C]phenytoin has a higher initial brain uptake in rats than (R)-[11C]verapamil, so an upregulation of P-gp would be easier to detect. Second, in animal experiments [11C]phenytoin has shown optimal brain kinetics, i.e. fast transport into the brain, reaching equilibrium well within the time span of a PET scan with an ideal rate of clearance (not too slow, not too fast) from the brain. Third, in rats, [11C]phenytoin is metabolically more stable than (R)-[11C]verapamil in both brain and plasma, causing less problems with labelled metabolites. Nevertheless, as the metabolite profile of (R)-[11C]verapamil in humans is completely different from that in rats, only direct studies in humans can determine whether [11C]phenytoin is indeed a more potent tracer to assess P-gp function in vivo. Furthermore, paired [11C]phenytoin scans are needed to determine inter- and intra-subject variation of [11C]phenytoin plasma and brain kinetics of [11C]phenytoin.
Volunteers will be recruited only in the Netherlands, mainly with some relation to the VU medical center.
|- Main changes (audit trail)|
|- RECORD||1-aug-2012 - 16-aug-2012|