Clinical trial NCT01496612: Buspirone Therapy for Localized Epilepsy
Official title: A Phase Two Clinical Trial of Buspirone Therapy in Localization-Related Epilepsy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Anxiety Disorder
Seizures
Epilepsy
Partial Epilepsy
Depression
Keywords: Epilepsy
Temporal Lobe Epilepsy
Serotonin 1A Receptor
Seizures
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2011-12-21
Enrollment: 9
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:

Buspirone is a drug that is approved for the treatment of anxiety in adults. Studies suggest that buspirone might act on parts of the brain that can increase certain levels of brain activity. Increasing this brain activity may help decrease epileptic seizures that come from certain parts of the brain. Researchers want to see if buspirone can reduce seizure frequency in people with seizures who are already taking antiseizure medication.

Objectives:

To test whether buspirone can reduce the frequency of seizures in people whose seizures seem to start from one part of the brain.

Eligibility:

Individuals between 18 and 65 years of age who have seizures coming from one or more places in the brain.

Participants must have tried at least two different antiseizure medications.

Participants must also have had at least three seizures during a 1-month observation period while on current medicines.

Design:

Participants will have a screening visit with a physical exam and medical history. Participants will complete mood and memory testing scales. Blood, urine, and saliva samples will be collected.

Participants will have a magnetic resonance imaging scan to evaluate brain structures that relate to epilepsy. They will also have a positron emission tomography scan to look at parts of the brain that are affected by buspirone.

Participants will start taking a study drug (either buspirone or placebo) twice daily. They will keep a calendar of seizures and record any side effects. Treatment will be monitored with clinic visits and blood samples.

After 12 weeks on the study drug, participants will gradually stop taking either the placebo or buspirone over two weeks. They will stay off the drug for another 2 weeks.

After 2 weeks, participants will start taking a study drug that is the opposite of the one they had before. They will keep a calendar of seizures and record any side effects. Treatment will be monitored with clinic visits and blood samples.

After 12 weeks on the study drug, participants will gradually stop taking either the placebo or buspirone.

Participants will have a final followup visit with additional blood tests, mood and memory testing scales and imaging studies.

Detailed description: OBJECTIVE:

To initiate a pilot clinical trial assessing the safety, tolerability and efficacy of the 5HT1A receptor agonist buspirone in patients with localization-related epilepsy. Buspirone is a 5HT1A receptor agonist that is approved for the treatment of anxiety disorders. Patients with localization-related epilepsy have reduced 5HT1A receptor binding on 18FCWAY positron emission tomography (PET). Increasing neurotransmitter activity at 5HT1A receptor sites may ameliorate seizures.

STUDY POPULATION:

Forty patients with localization-related epilepsy

DESIGN:

A randomised, double-blind, placebo-controlled cross-over, phase II clinical trial.

The trial will have a screening phase in which each patient will undergo physical and neurological examination, and standard blood tests, followed by a one month baseline phase. At the end of baseline, patients who qualify will have neuropsychological, anxiety, and mood evaluation, FCWAY PET and MRI (if imaging was not performed already). During the subsequent first study phase, patients will be randomized to buspirone or matching placebo. After completion of the first study phase, patients will be crossed over to the alternate study arm. At the end of the study, any patient who wishes to do so may remain on open-label buspirone.

OUTCOME MEASURES:

1. Difference in seizure rate comparing the 3 month placebo and active study phases
2. Neuropsychological, anxiety, and mood indices comparing the 3 month placebo and active study drug phases

Eligibility criteria: * INCLUSION CRITERIA:
* Patients may be male or female.
* Patients will be aged 18 65
* Patients must have at least 3 seizures during the one-month baseline.
* Localization-related epilepsy diagnosed by standard clinical criteria that has not responded to treatment with two standard antiepileptic drugs either sequentially or in combination.
* Patients must be able to provide informed consent
* Patients must be able to remain on their baseline AED drugs and doses throughout the study
* Patients must be able to use seizure calendars to record seizures throughout the trial.

EXCLUSION CRITERIA:

* Pregnant patients will not participate in the study.
* During the study, women of child-bearing potential must use a reliable method of birth control and will have pregnancy testing throughout the protocol.
* Use of any alcohol or recreational drugs starting two weeks before entering baseline and for the duration of the study.
* Patients on medications with potential for a clinically significant interaction with buspirone, including MAO inhibitors, clozapine, zolpidem, hypnotics, hydromorphone derivatives, oxycodone, and diltiazem.
* Current treatment for psychiatric disorder other than depression, anxiety or bipolar disorder.
* Patients with a diagnosis of schizophrenia.
* Current treatment for another significant medical disorder, such as diabetes, or heart disease, or an untreated disorder, that might interfere with the study.
* Calculated Creatinine clearance of less than 80 ml/min calculated with the Cockcroft-Gault formula:
* Clcr = \[(140-age) times ideal body weight in Kg\] times (0.85 if female) divided by (72 times serum Cr in mg/dL)
* Evidence of impaired liver function based on serum chemistries.
* Inability to participate in the study procedures, such as MRI, PET, seizure and adverse event recording, or drug titration

Primary outcomes:
measure: Seizure Frequency in the Buspirone (Active) and Placebo Periods
timeFrame: Three months
Secondary outcomes:
measure: Mean Score on the Hamilton Anxiety Rating Scale (HAM-A) at the End of the Active and Placebo Periods.
timeFrame: Three months
measure: Mean Score on the Hamilton Depression Rating Scale (HAM-D) at the End of the Active and Placebo Periods
timeFrame: Three months
measure: Mean Score on the Beck Depression Inventory (BDI) at the End of the Active and Placebo Periods
timeFrame: Three months
measure: Mean Score on the Cancellation Task Following 3 Months on Active Drug and 3 Months on Placebo
timeFrame: Three months
measure: Mean Score on the Trail Making Test-A (TMT-A) Following 3 Months on Active Drug and 3 Months on Placebo
timeFrame: Three months
measure: Mean Score on the Trail Making Test-B (TMT-B) Following 3 Months on Active Drug and 3 Months on Placebo
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:
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citation: Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW, Moshe SL, Nordli D, Plouin P, Scheffer IE. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010 Apr;51(4):676-85. doi: 10.1111/j.1528-1167.2010.02522.x. Epub 2010 Feb 26.
citation: Bhagwagar Z, Rabiner EA, Sargent PA, Grasby PM, Cowen PJ. Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol Psychiatry. 2004 Apr;9(4):386-92. doi: 10.1038/sj.mp.4001401.