PRX-00023 Therapy in Localization-Related Epilepsy
Condition: Epilepsy; Epilepsy, Temporal Lobe; Partial Epilepsy
MeSH terms: Epilepsy; Epilepsies, Partial; Epilepsy, Temporal Lobe
Intervention: PRX-00023; Placebo
Intervention description: PRX-00023 (Selective 5HT1A agonist); Placebo
Intervention MeSH terms: Naluzotan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Epilepsy; Drug Trial; Serotonin; Serotonin 1A Receptor; Temporal Lobe Epilepsy; Partial Epilepsy

Summary:

      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
    

Eligibility criteria:

        -  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