PRX-00023 Therapy in Localization-Related Epilepsy
PRX-00023 Therapy in Localization-Related Epilepsy
Background:

 - The brain chemical serotonin helps nerve cells communicate. Previous research suggests that
 serotonin activity may be lower in brain areas where seizures start, and that increasing
 activity at the serotonin receptor site on nerve cells may help prevent seizures. Researchers
 are interested in determining whether the experimental medication PRX-00023, which increases
 the activity of serotonin receptors, can reduce seizure frequency in people whose seizures
 are not well-controlled on antiseizure medication. PRX-00023 has not previously been studied
 in people with epilepsy and has not previously been given to people taking antiseizure
 medication at the same time.

 Objectives:

 - To evaluate the effectiveness of PRX-00023 in reducing the frequency of epileptic seizures
 that start from only one part of the brain.

 Eligibility:

 - Individuals between 18 and 65 years of age who have frequent epileptic seizures even after
 trying at least two different standard anti-seizure medications (either at the same time or
 one after the other).

 Design:

 -  The study requires 9 outpatient visits to the NIH Clinical Center over a 34-week period.
 Individuals who choose to participate in additional studies may be an inpatient during
 some of these visits.

 -  Participants will be screened with a medical history and physical examination, blood and
 urine samples, ECG, EEG, neuropsychological studies, imaging studies, including PET and
 MRI scans

 -  Participants will have a 6-week observation and evaluation period before starting the
 study medication. Participants who have at least four seizures during this period will
 be eligible for the treatment portion of the study.

 -  All participants will receive either PRX-00023 or a placebo pill twice daily for 12
 weeks, and will have regular clinic visits with blood samples and imaging studies.

 -  After the 12-week period, participants will have a 2- to 3-week washout period without
 any study medication.

 -  Participants will then have another study medication period, and will receive the
 opposite pill (PRX-00023 or placebo) from the one taken in the first treatment phase.
 Participants will continue to have regular clinic visits with blood samples, ECG, EEG
 and neuropsychologicalstudies.

 -  One month after the end of the second study medication phase, participants will have a
 followup evaluation with a physical examination, blood tests, ECG, EEG, mood and
 neuropsychological tests.

 Outcome measures:

 The primary outcome measure for drug efficacy will be:

 Mean difference in seizure frequency comparing the active and placebo periods.

 Secondary outcome measures for efficacy will be:

 Proportion of patients with greater than or equal to 50% lower seizure rate on PRX-00023 than
 placebo

 Hamilton Depression and Anxiety Rating scales

 Performance on mood and neuropsychological testing scales
Introduction:

 PRX-00023 is a selective 5HT1A agonist being developed as an oral therapeutic treatment for
 epilepsy.

 Objective:

 To initiate a pilot clinical trial assessing the safety, tolerability and efficacy of the
 5HT1A receptor agonist PRX-00023 in patients with localization-related epilepsy. PRX-00023 is
 a 5HT1A receptor agonist that has shown promise in clinical trials of depression. Patients
 with localization-related epilepsy have reduced 5HT1A receptor binding on 18FCWAY positron
 emission tomography (PET). Increasing neurotransmitter activity at 5HT1A receptor sites might
 ameliorate seizures. Moreover, depression is a common co-morbidity in people with epilepsy.
 Altered 5HT1A receptor binding has been found in depression.

 Study Population:

 Thirty adults with localization-related epilepsy.

 Design:

 A randomized, double-blind, placebo-controlled cross-over, phase II clinical trial. Subjects
 will be screened under protocol 01-N-0139 and will undergo medical and epilepsy history and
 physical examination, vital signs, ECG, clinical laboratory studies including standard
 clinical chemistry and hematology studies, urinalysis, pregnancy test for females of
 childbearing potential, and MRI scan and eo EEG monitoring will be performed if not
 previously completed successfully, and measurement of plasma AED levels (for those AEDs in
 which an assay is available at NIH).

 The trial will have a baseline phase, which will last up to 6 weeks. Baseline may occur
 concurrent with screening procedures. The baseline phase will include measurement of seizure
 frequency (patient will record via seizure calendar). In addition the following will be
 administered, unless previously completed: Columbia Suicide Severity Rating Scale,
 neuropsychological and mood evaluations, FCWAY PET (if not already performed), EEG,
 measurement of plasma AED levels (if assay available), and pregnancy test (for women of child
 bearing potential), saliva samples will be obtained for genetic testing (if not previously
 obtained) and blood samples will be obtained during the PET procedure for cortisol and ACTH
 levels.

 Following baseline, patients will begin the treatment phase (consisting of Period 1 and
 Period 2). Patients will be randomized to PRX-00023 (120mg BID) or matching placebo. After
 completion of the first treatment period, patients will undergo a washout period after which
 patients will be crossed over to the alternate treatment period.

 Outcome measures:

 1. Seizure frequency counts during the 3-month placebo and active treatment phases

 2. Neuropsychological and mood indices

 3. Safety assessment will include adverse events, vital signs, laboratory signs and
 physical examination.
-  INCLUSION CRITERIA:

 1. Enrolled in protocol 01-N-0139

 2. Age 18 to 65

 3. Localization-related epilepsy diagnosed by standard clinical criteria that has
 not responded to treatment with up to two standard antiepileptic drugs either
 sequentially or in combination.

 4. Patients must be able to provide informed consent.

 5. Patients must be able to remain on their baseline AED drugs and doses for the
 duration of the study

 6. Patients must be able to use seizure calendars to record seizures throughout the
 trial.

 7. Experiences 4 seizures within a 6-week period

 EXCLUSION CRITERIA:

 1. Pregnancy or lactation

 2. Women of child-bearing potential and men who are unable or unwilling to take adequate
 contraceptive precautions, including one of the following:

 -  hormonal contraception (birth control pills, injected hormones or vaginal ring);

 -  intrauterine device;

 -  barrier methods (condom or diaphragm) combined with spermicide;

 -  surgical sterilization (hysterectomy, tubal ligation, or vasectomy in a partner

 3. Current treatment for another significant medical disorder, such as diabetes, or heart
 disease, or an untreated disorder, that is discovered during the screening examination
 and might interfere with the study and is determined by the PI to warrant exclusion of
 the participant.

 4. An abnormality on clinical laboratory tests, physical examination, EEG or ECG that
 might increase the risk associated with trial participation or investigational product
 administration, such as hepatic enzyme elevation greater than twice normal, or
 hematocrit lower than 30.

 5. A level 4 or 5 on the Columbia Suicide Severity Rating Scale rating for symptoms
 during the last month

 6. Concomitant treatment with more than 2 AEDs

 7. Evidence for a potentially progressive neurologic disorder, such as an astrocytoma

 8. Use of sublingual lorazepam for seizure clusters more than once per wee

 9. Use of any of the following prohibited medications/classes with less than required
 interval period:

 -  Any other Investigational drugs; required interval period (weeks prior to
 baseline) is 4

 -  benzodiazepines; required interval period (weeks prior to baseline) is 4

 -  MAO Inhibitors anti depressant; required interval period (weeks prior to
 baseline) is 4

 -  Buspirone; required interval period (weeks prior to baseline) is 2

 -  other psychotropic medicines; required interval period (weeks prior to baseline)
 is 2

 -  potent CYP3A4 inducers/inhibitors; required interval period (weeks prior to
 baseline) is 2 for:

 -  Itraconazole

 -  ketoconazole

 -  HIV antivirals

 -  clarithromycin

 -  phenytoin

 -  Prornolol is 2