Human Epilepsy Project 3

Study Overview
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Brief Summary
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By carrying a careful, large-scale and ambitious prospective study of a cohort of participants with generalized epilepsy, the study team hopes to clarify the likelihood of response and remission in this type of epilepsy, and try to explore the underlying biological drivers of treatment response, including novel realms of exploration such as impact of the microbiome, and genetics. The identification of biomarkers that predict the likelihood of disease response would allow epilepsy patients to make more informed decisions about the factors affecting their quality of life, including plans for driving, relationships, pregnancy, schooling, work, and play. In addition to its impact on clinical care, the data and specimens collected in HEP3, including sequential electrophysiology, biochemical profiles and neuroimaging and banked DNA for future genomics studies, have the potential to provide new insights into the biological basis of IGE, thereby advancing the discovery of effective treatments and cures. By enrolling both newly diagnosed subjects (prognosis unknown) as well as subjects with established IGE who are already determined to be treatment resistant or treatment responsive, the study team can immediately test potential biomarkers in a confirmation cohort, which will accelerate identification of predictive biomarkers.

Official Title
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Human Epilepsy Project 3: Newly Diagnosed Idiopathic Generalized Epilepsy

Conditions
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Idiopathic Generalized Epilepsy

Participation Criteria
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Eligibility Criteria
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Cohort 1: Newly Diagnosed IGE Inclusion criteria: Age ≥13 years at time of enrollment Age ≥8 years at time of seizure onset Clinical seizure(s) and history consistent with IGE. The only permitted seizure types are absence, myoclonus or generalized tonic-clonic convulsions Occurrence of at least 1 seizure of any type in the 6 months prior to treatment Patients must have one of the following: GTCSs alone accompanied by generalized spike-wave consistent with IGE per adjudication review GTCSs with a history of absence and/or myoclonus, accompanied by generalized spike-wave consistent with IGE per adjudication review GTCSs associated with a history of absence and/or myoclonus, not accompanied by generalized spike-wave consistent with IGE per adjudication review A clear history of absence and/or myoclonus, accompanied by generalized spike-wave consistent with IGE per adjudication review Availability of a complete medication history since initiation of treatment, including doses and date of initiation No competing cause of epilepsy (e.g. traumatic brain injury) AED treatment (for seizures) instituted not more than 12 months before enrollment Exclusion Criteria Focal epilepsy Generalized/focal epilepsy mixed syndromes Progressive neurological disorder (brain tumor, Alzheimer's disease, progressive myoclonic epilepsy, etc.) Epileptic or developmental encephalopathy Major medical co-morbidities (e.g. renal failure requiring dialysis, metastatic cancer, HIV, or significant liver or renal disease) Autism Spectrum Disorder History of chronic drug or alcohol abuse (misuse or excessive use that interferes with activities of daily living) within the last 2 years Seizures only during pregnancy History of previous or current significant psychiatric disorder that would interfere with study requirements Cohort 2: Longstanding Treatment Responsive Inclusion Criteria: Age ≥13 years at time of enrollment Age ≥8 years at time of seizure onset Clinical seizure(s) and history consistent with IGE. The only permitted seizure types are absence, myoclonus or generalized tonic-clonic convulsions Patients must have had one of the following: GTCSs alone accompanied by generalized spike-wave consistent with IGE per adjudication review GTCSs with a history of absence and/or myoclonus, accompanied by generalized spike-wave consistent with IGE per adjudication review GTCSs associated with a history of absence and/or myoclonus, not accompanied by generalized spike-wave consistent with IGE per adjudication review A clear history of absence and/or myoclonus, accompanied by generalized spike-wave consistent with IGE per adjudication review Availability of a complete medication history since initiation of treatment, including doses and date of initiation No competing cause of epilepsy (e.g. traumatic brain injury) Two years of well-controlled seizures. No convulsive seizures in the last two years Myoclonic or absence seizures must be rare (<2 per year) and non-disabling Ongoing therapy with > 1 antiseizure medication Exclusion Criteria: Focal epilepsy Paroxysmal nonepileptic seizures Generalized/focal epilepsy mixed syndromes Progressive neurological disorder (brain tumor, Alzheimer's disease, progressive myoclonic epilepsy, etc.) Epileptic or developmental encephalopathy Major medical co-morbidities (e.g. renal failure requiring dialysis, metastatic cancer, HIV, or significant liver or renal disease) Autism Spectrum Disorder History of chronic drug or alcohol abuse (misuse or excessive use that interferes with activities of daily living) within the last 2 years Seizures only during pregnancy History of previous or current significant psychiatric disorder that would interfere with study requirements Cohort 3: Longstanding IGE, Treatment Resistant Inclusion Criteria: Age ≥13 years at time of enrollment Age ≥8 years at time of seizure onset Clinical seizure(s) and history consistent with IGE. The only permitted seizure types are absence, myoclonus or generalized tonic-clonic convulsions Occurrence of at least 1 seizure of any type in the 6 months prior to treatment onset Patients must have had one of the following: GTCSs alone accompanied by generalized spike-wave consistent with IGE per adjudication review GTCSs with a history of absence and/or myoclonus, accompanied by generalized spike-wave consistent with IGE per adjudication review GTCSs associated with a history of absence and/or myoclonus, not accompanied by generalized spike-wave consistent with IGE per adjudication review A clear history of absence and/or myoclonus, accompanied by generalized spike-wave consistent with IGE per adjudication review Availability of a complete medication history since initiation of treatment. This should include doses and date of initiation if possible, but minimum information would include name of drug, approximate duration of administration and reason for discontinuation, if applicable. No competing cause of epilepsy (e.g. traumatic brain injury) Treatment resistant IGE Initiation of treatment at least 2 years prior to enrollment Treatment resistance, as defined by failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination to achieve seizure freedom). ASMs taken at enrollment would count towards this minimum. Either or both of the following two: i. One GTCC per year over the last 2 years. ii. Any type of seizure at least every 3 months which can consist of either: disabling myoclonus or absence (in the opinion of the subject and investigator) or GTCC d. Such seizures were not primarily due to significant illness (e.g, URI is not significant unless temperature >101oF (38.3oC), nonadherence to antiseizure medications or >2 alcoholic beverages within 48 hrs of seizure e. Ongoing therapy with > 1 antiseizure medication Exclusion Criteria: Focal epilepsy Paroxysmal nonepileptic seizures Generalized/focal epilepsy mixed syndromes Progressive neurological disorder (brain tumor, Alzheimer's disease, progressive myoclonic epilepsy, etc.) Epileptic or developmental encephalopathy Major medical co-morbidities (e.g. renal failure requiring dialysis, metastatic cancer, HIV, or significant liver or renal disease) Autism Spectrum Disorder History of chronic drug or alcohol abuse (misuse or excessive use that interferes with activities of daily living) within the last 2 years Seizures only during pregnancy History of previous or current significant psychiatric disorder that would interfere with study requirements History of/suspicion of provoked seizures accounting for 25% or more of seizures over the prior 2 years (eg alcohol, non-adherence, significant sleep deprivation).

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort 1: Newly Diagnosed Idiopathic Generalized Epilepsy (IGE)<br>Cohort 1 will have IGE that was diagnosed within the prior year. We will follow these participants for a minimum of two years. | |
| Cohort 2: Longstanding Treatment Responsive<br>Cohort 2 will consist of subjects with established IGE who have been responsive to treatment. | |
| Cohort 3: Longstanding IGE, Treatment Resistant<br>Cohort 3 will consist of patients with established treatment-resistant IGE. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Individual Seizures | Self-reported via the Seer Seizure Diary App (https://app.seermedical.com) | Baseline | 
| Number of Cluster Seizures | Self-reported via the Seer Seizure Diary App (https://app.seermedical.com) | Baseline | 
| Number of episodes of non-adherence | Self-reported via the Seer Seizure Diary App (https://app.seermedical.com) | Baseline | 
| Average daily steps | Participants will be provided a Fitbit Inspire HR watch and will be trained to open an account on fitbit.com and synchronize their Fitbit watch data into their Fitbit cloud account. Daily steps is synchronized and collected for this study. | Baseline | 
| Average distance walked | Participants will be provided a Fitbit Inspire HR watch and will be trained to open an account on fitbit.com and synchronize their Fitbit watch data into their Fitbit cloud account. Daily steps is synchronized and collected for this study. | Baseline | 
| Average heart rate | Participants will be provided a Fitbit Inspire HR watch and will be trained to open an account on fitbit.com and synchronize their Fitbit watch data into their Fitbit cloud account. Daily steps is synchronized and collected for this study. | Baseline | 
| Average daily sleep duration | Participants will be provided a Fitbit Inspire HR watch and will be trained to open an account on fitbit.com and synchronize their Fitbit watch data into their Fitbit cloud account. Daily steps is synchronized and collected for this study. Using the Embleema Patient Web App, participants will be able to consult their activity and sleep data in interactive graphs. | Baseline | 
| Average daily wake duration | Participants will be provided a Fitbit Inspire HR watch and will be trained to open an account on fitbit.com and synchronize their Fitbit watch data into their Fitbit cloud account. Daily steps is synchronized and collected for this study. Using the Embleema Patient Web App, participants will be able to consult their activity and sleep data in interactive graphs. | Baseline | 
| Change in Quality of Life in Epilepsy Inventory-10 (QOLIE-10) Score | QOLIE-10 assesses the patient's quality of life. There are 11 total items. The total score range is 10-51; with higher scores indicating greater impairment. The total score is the sum of scores for all questions divided by the number of items answered. Thus, if a patient skipped an item, it is not reflected in the total score. | Baseline, Month 12 | 
| Change in Quality of Life in Epilepsy Inventory-10 (QOLIE-10) Score | QOLIE-10 assesses the patient's quality of life. There are 11 total items. The total score range is 10-51; with higher scores indicating greater impairment. The total score is the sum of scores for all questions divided by the number of items answered. Thus, if a patient skipped an item, it is not reflected in the total score. | Baseline, Month 24 | 
| Change in Quality of Life in Epilepsy Inventory-10 (QOLIE-10) Score | QOLIE-10 assesses the patient's quality of life. There are 11 total items. The total score range is 10-51; with higher scores indicating greater impairment. The total score is the sum of scores for all questions divided by the number of items answered. Thus, if a patient skipped an item, it is not reflected in the total score. | Month 12, Month 24 | 
| Change in General Anxiety Disorder-7 Screener (GAD-7) Score | This will only be reported for adults. GAD-7 consists of 7 problems. Participants report how often they have been bothered by the 7 problems over the last 2 weeks on a Likert Scale from 0 (not at all) to 3 (nearly every day). The total score range is 0-21; the higher the score, the more severe the anxiety. 0-4=minimal anxiety, 5-9=mild, 10-14=moderate, 15-21=severe anxiety. | Baseline, Month 12 | 
| Change in General Anxiety Disorder-7 Screener (GAD-7) Score | This will only be reported for adults. GAD-7 consists of 7 problems. Participants report how often they have been bothered by the 7 problems over the last 2 weeks on a Likert Scale from 0 (not at all) to 3 (nearly every day). The total score range is 0-21; the higher the score, the more severe the anxiety. 0-4=minimal anxiety, 5-9=mild, 10-14=moderate, 15-21=severe anxiety. | Baseline, Month 24 | 
| Change in General Anxiety Disorder-7 Screener (GAD-7) Score | This will only be reported for adults. GAD-7 consists of 7 problems. Participants report how often they have been bothered by the 7 problems over the last 2 weeks on a Likert Scale from 0 (not at all) to 3 (nearly every day). The total score range is 0-21; the higher the score, the more severe the anxiety. 0-4=minimal anxiety, 5-9=mild, 10-14=moderate, 15-21=severe anxiety. | Month 12, Month 24 | 
| Columbia Suicide Severity Rating Scale (C-SSRS) Score | C-SSRS systematically tracks suicidal ideation and behavior. The total score range is 0 (no ideation is present) - 5 (active suicidal ideation with specific plan and intent). The higher the score, the greater one's suicidal ideation. Any score greater than 0 is important and may indicate the need for mental health intervention | Baseline | 
| Columbia Suicide Severity Rating Scale (C-SSRS) Score | C-SSRS systematically tracks suicidal ideation and behavior. The total score range is 0 (no ideation is present) - 5 (active suicidal ideation with specific plan and intent). The higher the score, the greater one's suicidal ideation. Any score greater than 0 is important and may indicate the need for mental health intervention | Month 12 | 
| Columbia Suicide Severity Rating Scale (C-SSRS) Score | C-SSRS systematically tracks suicidal ideation and behavior. The total score range is 0 (no ideation is present) - 5 (active suicidal ideation with specific plan and intent). The higher the score, the greater one's suicidal ideation. Any score greater than 0 is important and may indicate the need for mental health intervention | Month 24 | 
| Cogstate Neuropsychological Assessment Score | The Cogstate is a battery of online computerized tests that assesses functions such as attention, memory, and processing speed. Scores are normalized to the range of 0-100th percentile based on speed of test completion and task accuracy. A higher percentile score indicates higher levels of cognitive functioning within the tested domain as compared to controls. | Baseline | 
| Cogstate Neuropsychological Assessment Score | The Cogstate is a battery of online computerized tests that assesses functions such as attention, memory, and processing speed. Scores are normalized to the range of 0-100th percentile based on speed of test completion and task accuracy. A higher percentile score indicates higher levels of cognitive functioning within the tested domain as compared to controls. | Month 12 | 
| Cogstate Neuropsychological Assessment Score | The Cogstate is a battery of online computerized tests that assesses functions such as attention, memory, and processing speed. Scores are normalized to the range of 0-100th percentile based on speed of test completion and task accuracy. A higher percentile score indicates higher levels of cognitive functioning within the tested domain as compared to controls. | Month 24 | 
| Wide Range Achievement Test (WRAT-4) Score | WRAT4 is an academic skills assessment which measures reading skills, math skills, spelling, and comprehension. Only the Word Reading portion of the assessment will be administered. The total raw score range is from 0-70, with a normalized score range of 55-145. The higher the score, the more advanced the participant's reading comprehension skills for their age range. | Baseline |