Clinical trial NCT01281956: PRX-00023 Therapy in Localization-Related Epilepsy
Official title: A Phase II Clinical Trial of PRX-00023 Therapy in Localization-Related Epilepsy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Epilepsy
Epilepsy, Temporal Lobe
Partial Epilepsy
Keywords: Epilepsy
Drug Trial
Serotonin
Serotonin 1A Receptor
Temporal Lobe Epilepsy
Partial Epilepsy
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2011-01-24
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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

Detailed description: 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.

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

Primary outcomes:
measure: Seizure Frequency in the Active and Placebo Periods
timeFrame: Three months
Secondary outcomes:
measure: Number of Participants With > 50% Lower Seizure Rate on PRX-0023.
timeFrame: Three months
measure: Mean Score on the Hamilton Anxiety Rating Scale at the End of the Active and Placebo Periods.
timeFrame: Three months
measure: Mean Score on the Hamilton Depression Rating Scale at the End of the Active and Placebo Periods
timeFrame: Three months
measure: Mean Score on the Hopkins Verbal Learning Test-Revised (HVLT-R) at the End of the Active and Placebo Periods
timeFrame: Three months
measure: The Mean Score on the Brief Visuospatial Memory Test-Revised (BVMT-R), at the End of the Active and Placebo Period.
timeFrame: Three months
measure: Mean Score on the Columbia Suicide Severity Rating Scale at the End of the Active and Placebo Periods
timeFrame: Three months
measure: Results of Clinical Examination of the Nervous System at the End of the Active and Placebo Treatment Periods
timeFrame: Three months
measure: Results of Clinical Examination of the Respiratory System at the End of the Active and Placebo Treatment Periods
timeFrame: Three months
measure: Results of Clinical Examination of the Cardiovascular System at the End of the Active and Placebo Treatment Periods
timeFrame: Three months
measure: Results of Clinical Examination of the Musculoskeletal System at the End of the Active and Placebo Treatment Periods
timeFrame: Three months
measure: Number of Subjects With an Abnormal CBC Result at the End of the Active and Placebo Periods
timeFrame: Three months
measure: Number of Subjects With Abnormal Clinical Chemistry Labs at the End of the Active and Placebo Periods
timeFrame: Three months
measure: Number of Subjects With an Abnormal ECG Result at the End of the Active and Placebo Periods
timeFrame: Three months
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Neurological Disorders and Stroke (NINDS)
name: William H Theodore, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Clinckers R, Smolders I, Meurs A, Ebinger G, Michotte Y. Anticonvulsant action of hippocampal dopamine and serotonin is independently mediated by D and 5-HT receptors. J Neurochem. 2004 May;89(4):834-43. doi: 10.1111/j.1471-4159.2004.02355.x.
citation: Giovacchini G, Toczek MT, Bonwetsch R, Bagic A, Lang L, Fraser C, Reeves-Tyer P, Herscovitch P, Eckelman WC, Carson RE, Theodore WH. 5-HT 1A receptors are reduced in temporal lobe epilepsy after partial-volume correction. J Nucl Med. 2005 Jul;46(7):1128-35.
citation: Hasler G, Bonwetsch R, Giovacchini G, Toczek MT, Bagic A, Luckenbaugh DA, Drevets WC, Theodore WH. 5-HT1A receptor binding in temporal lobe epilepsy patients with and without major depression. Biol Psychiatry. 2007 Dec 1;62(11):1258-64. doi: 10.1016/j.biopsych.2007.02.015. Epub 2007 Jun 22.