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| ID | Type | Description | Link |
|---|---|---|---|
| 12-N-0033 |
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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.
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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Study Phase | Experimental |
| |
| Alternate Study Phase | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Buspirone | Drug |
| ||
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Seizure Frequency in the Buspirone (Active) and Placebo Periods | Participants utilized a seizure calendar to record the number of seizures that occurred during the three month treatment period, i.e., while participants were either taking Buspirone or Placebo. Seizure frequency was calculated as the total number of seizures occurring during each three month period. For each period a mean was calculated across subjects. | Three months |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Score on the Hamilton Anxiety Rating Scale (HAM-A) at the End of the Active and Placebo Periods. | Participants were administered the Hamilton Anxiety Rating Scale (HAM-A) at the end of each three month treatment period, i.e., while participants were either on Buspirone or Placebo. The HAM-A measures an individual's severity of anxiety symptoms. The scale consists of 14 parameters, each defined by a series of symptoms. Each group of symptoms is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild anxiety, 18-24 mild to moderate anxiety and 25-30 moderate to severe anxiety. |
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EXCLUSION CRITERIA:
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| Name | Affiliation | Role |
|---|---|---|
| William H Theodore, M.D. | National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | 20892 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17223086 | Background | Alper K, Schwartz KA, Kolts RL, Khan A. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol Psychiatry. 2007 Aug 15;62(4):345-54. doi: 10.1016/j.biopsych.2006.09.023. Epub 2007 Jan 16. | |
| 20196795 | Background | 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. |
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Nine participants were consented to the protocol. Two participants decided not to participate prior to baseline and randomization.
Participants were recruited from referrals to the NINDS Clinical Epilepsy Section. In addition, self-referral was permitted.
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| ID | Title | Description |
|---|---|---|
| FG000 | Buspirone Then Placebo | Participants were administered Buspirone, followed by a washout period, and then administered Placebo |
| FG001 | Placebo Then Buspirone | Participants were administered Placebo, followed by a washout period, and then administered Buspirone |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1st Intervention |
|
| |||||||||||||||||||||
| 2nd Intervention |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants | All participants enrolled in the study |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Seizure Frequency in the Buspirone (Active) and Placebo Periods | Participants utilized a seizure calendar to record the number of seizures that occurred during the three month treatment period, i.e., while participants were either taking Buspirone or Placebo. Seizure frequency was calculated as the total number of seizures occurring during each three month period. For each period a mean was calculated across subjects. | Posted | Mean | Standard Deviation | number of seizures | Three months |
|
Intervention 1 was 3 months, followed by a two week titration and 2 week Washout period. Intervention 2 was 3 months, followed by a two week titration and 1 day washout period.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Buspirone | Events occurring while participants on Buspirone x3 months | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Confusion | Nervous system disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. William Theodore | NIH/NINDS | 301-496-1505 | theodorw@ninds.nih.gov |
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| ID | Term |
|---|---|
| D001008 | Anxiety Disorders |
| D012640 | Seizures |
| D004827 | Epilepsy |
| D004828 | Epilepsies, Partial |
| D003863 | Depression |
| D004833 | Epilepsy, Temporal Lobe |
| ID | Term |
|---|---|
| D001523 | Mental Disorders |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
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| ID | Term |
|---|---|
| D002065 | Buspirone |
| ID | Term |
|---|---|
| D013141 | Spiro Compounds |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
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|
| Three months |
| Mean Score on the Hamilton Depression Rating Scale (HAM-D) at the End of the Active and Placebo Periods | The Hamilton Depression Rating Scale (HAM-D) was administered to participants at the end of each treatment period. The HAM-D is a multiple item questionnaire used to provide an indication of depression. The questionnaire is designed for adults and is used to rate the severity of their depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. Although the HAM-D form lists 21 items, the scoring is based on the first 17 items. Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine items are scored from 0-2 with 0 = absent and 2 = frequent or severe. Scores range from 0 to 50 with a score of 0-7 representing normal and a score >/= 23 representing very severe depression. | Three months |
| Mean Score on the Beck Depression Inventory (BDI) at the End of the Active and Placebo Periods | The Beck Depression Inventory (BDI) is a 21-item test presented in multiple-choice format, which measures presence and degree of depression in adolescents and adults. The BDI evaluates 21 symptoms of depression. The 21 items cover sadness, pessimism, past failure, self-dislike, self-criticism, suicidal thoughts or wishes, crying, agitation, loss of interest, indecisiveness, worthlessness, loss of energy, changes in sleeping patterns, irritability, changes in appetite, difficulty concentrating, tiredness or fatigue, and loss of interest in sex. Each answer is scored on a scale value of 0-3 with 0 indicating absence of symptom and a 3 indicating severe symptom. The total range of possible scores is 0-63. A total score of <10 indicates no or minimal depression,10-18 indicates mild-to-moderate depression,19-29 indicates moderate-to-severe depression, and 30+ indicates severe depression. | Three months |
| Mean Score on the Cancellation Task Following 3 Months on Active Drug and 3 Months on Placebo | The WAIS-IV Cancellation Subtest assesses processing speed and attention. It is a timed test with two sequential forms, A & B. Each form requires the participant to scan an array of colored shapes (e.g., triangle, circle) randomly arranged. The participant is given 45 seconds to mark (i.e. cross out) as many of the two designated geometric shapes in the total array as possible. Cancellation scores are based on the number of correct responses minus the number of incorrect responses completed in the allotted time. The total correct for the two forms is converted to a single scaled score based on age-corrected normative data with a mean of 10 +/- 3 and a range of 1 to 19. The mean is 10 +/-3; thus a typical age corrected score is between 8 and 11; the higher the number the better the score. A low score (<8) is progressively more impaired, the lower the score. A high score (>12) indicates more efficiency and better attention than compared to others the same age. | Three months |
| Mean Score on the Trail Making Test-A (TMT-A) Following 3 Months on Active Drug and 3 Months on Placebo | The Trail Making Test-A (TMT-A) measures visual scanning and rote memory. The participant is asked to draw a line between 24 consecutive numbered circles randomly arranged on a page. The TMT-A is scored by how long it takes to complete the test. An average score for TMT-A is 29 seconds and a deficient score is >78 seconds. | Three months |
| Mean Score on the Trail Making Test-B (TMT-B) Following 3 Months on Active Drug and 3 Months on Placebo | The Trail Making Test-B (TMT-B) measures visual scanning and executive functioning. The participant is asked to draw a line between 24 consecutive numbered and lettered circles randomly arranged on a page. The participant is required to switch between numbers and letters in consecutive order. The TMT-B is scored by how long it takes to complete the test. An average score for TMT-B is 75 seconds and a deficient score is >273 seconds. | Three months |
| 15042104 | Background | 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. |
| NOT COMPLETED |
|
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Secondary | Mean Score on the Hamilton Anxiety Rating Scale (HAM-A) at the End of the Active and Placebo Periods. | Participants were administered the Hamilton Anxiety Rating Scale (HAM-A) at the end of each three month treatment period, i.e., while participants were either on Buspirone or Placebo. The HAM-A measures an individual's severity of anxiety symptoms. The scale consists of 14 parameters, each defined by a series of symptoms. Each group of symptoms is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild anxiety, 18-24 mild to moderate anxiety and 25-30 moderate to severe anxiety. | One participant in the Placebo group did not complete the HAM-A scale. | Posted | Mean | Standard Deviation | score on a scale | Three months |
|
|
|
| Secondary | Mean Score on the Hamilton Depression Rating Scale (HAM-D) at the End of the Active and Placebo Periods | The Hamilton Depression Rating Scale (HAM-D) was administered to participants at the end of each treatment period. The HAM-D is a multiple item questionnaire used to provide an indication of depression. The questionnaire is designed for adults and is used to rate the severity of their depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. Although the HAM-D form lists 21 items, the scoring is based on the first 17 items. Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine items are scored from 0-2 with 0 = absent and 2 = frequent or severe. Scores range from 0 to 50 with a score of 0-7 representing normal and a score >/= 23 representing very severe depression. | Posted | Mean | Standard Deviation | score on a scale | Three months |
|
|
|
| Secondary | Mean Score on the Beck Depression Inventory (BDI) at the End of the Active and Placebo Periods | The Beck Depression Inventory (BDI) is a 21-item test presented in multiple-choice format, which measures presence and degree of depression in adolescents and adults. The BDI evaluates 21 symptoms of depression. The 21 items cover sadness, pessimism, past failure, self-dislike, self-criticism, suicidal thoughts or wishes, crying, agitation, loss of interest, indecisiveness, worthlessness, loss of energy, changes in sleeping patterns, irritability, changes in appetite, difficulty concentrating, tiredness or fatigue, and loss of interest in sex. Each answer is scored on a scale value of 0-3 with 0 indicating absence of symptom and a 3 indicating severe symptom. The total range of possible scores is 0-63. A total score of <10 indicates no or minimal depression,10-18 indicates mild-to-moderate depression,19-29 indicates moderate-to-severe depression, and 30+ indicates severe depression. | Posted | Mean | Standard Deviation | score on a scale | Three months |
|
|
|
| Secondary | Mean Score on the Cancellation Task Following 3 Months on Active Drug and 3 Months on Placebo | The WAIS-IV Cancellation Subtest assesses processing speed and attention. It is a timed test with two sequential forms, A & B. Each form requires the participant to scan an array of colored shapes (e.g., triangle, circle) randomly arranged. The participant is given 45 seconds to mark (i.e. cross out) as many of the two designated geometric shapes in the total array as possible. Cancellation scores are based on the number of correct responses minus the number of incorrect responses completed in the allotted time. The total correct for the two forms is converted to a single scaled score based on age-corrected normative data with a mean of 10 +/- 3 and a range of 1 to 19. The mean is 10 +/-3; thus a typical age corrected score is between 8 and 11; the higher the number the better the score. A low score (<8) is progressively more impaired, the lower the score. A high score (>12) indicates more efficiency and better attention than compared to others the same age. | Posted | Mean | Standard Deviation | score on a scale | Three months |
|
|
|
| Secondary | Mean Score on the Trail Making Test-A (TMT-A) Following 3 Months on Active Drug and 3 Months on Placebo | The Trail Making Test-A (TMT-A) measures visual scanning and rote memory. The participant is asked to draw a line between 24 consecutive numbered circles randomly arranged on a page. The TMT-A is scored by how long it takes to complete the test. An average score for TMT-A is 29 seconds and a deficient score is >78 seconds. | Posted | Mean | Standard Deviation | Seconds | Three months |
|
|
|
| Secondary | Mean Score on the Trail Making Test-B (TMT-B) Following 3 Months on Active Drug and 3 Months on Placebo | The Trail Making Test-B (TMT-B) measures visual scanning and executive functioning. The participant is asked to draw a line between 24 consecutive numbered and lettered circles randomly arranged on a page. The participant is required to switch between numbers and letters in consecutive order. The TMT-B is scored by how long it takes to complete the test. An average score for TMT-B is 75 seconds and a deficient score is >273 seconds. | Posted | Mean | Standard Deviation | Seconds | Three months |
|
|
|
| 7 |
| 0 |
| 7 |
| 6 |
| 7 |
| EG001 | Washout Period Following Buspirone | Events occurring during the washout period following 3 months of Buspirone | 0 | 7 | 0 | 7 | 4 | 7 |
| EG002 | Placebo | Events occurring while participants were taking Placebo x3 months | 0 | 5 | 0 | 5 | 3 | 5 |
| EG003 | Washout Period Following Placebo | Events occurring during the washout period following 3 months of Placebo | 0 | 5 | 0 | 5 | 3 | 5 |
| Nausea with/without vomitting | Gastrointestinal disorders | Non-systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Sleepy | Nervous system disorders | Non-systematic Assessment |
|
| Headache | Nervous system disorders | Non-systematic Assessment |
|
| Fatigue | General disorders | Non-systematic Assessment |
|
| Arthritis | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Poor Memory | Nervous system disorders | Non-systematic Assessment |
|
| Palpitations | Cardiac disorders | Non-systematic Assessment |
|
| Shortness of Breath | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Fall with seizure | Nervous system disorders | Non-systematic Assessment |
|
| Labile | Psychiatric disorders | Non-systematic Assessment |
|
| Difficulty breathing | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Chest pain | Cardiac disorders | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | Non-systematic Assessment |
|
| Lightheaded | Nervous system disorders | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | Non-systematic Assessment |
|
| Endometriosis | Reproductive system and breast disorders | Non-systematic Assessment |
|
| Poor balance | Nervous system disorders | Non-systematic Assessment |
|
| Congestion | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Throat swelling | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Sore throat | Infections and infestations | Non-systematic Assessment |
|
| Skin burn | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Combative | Psychiatric disorders | Non-systematic Assessment |
|
| Itchy eyes | Eye disorders | Non-systematic Assessment |
|
| Insomnia | Psychiatric disorders | Non-systematic Assessment |
|
| Dysphasia | Nervous system disorders | Non-systematic Assessment |
|
| Vivid dreams | Psychiatric disorders | Non-systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
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| D013568 |
| Pathological Conditions, Signs and Symptoms |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D001526 | Behavioral Symptoms |
| D001519 | Behavior |
| D000073376 | Epileptic Syndromes |
| D010879 |
| Piperazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011743 | Pyrimidines |
| D011083 | Polycyclic Compounds |