Optimizing Therapy in Epilepsy Using Seizure Forecasts Via EEG and Wearables

For most people with epilepsy, seizures do not appear to happen on a predictable schedule, but recent research shows that seizure risk may actually rise and fall in patterns over time, similar to other body rhythms. Right now, most people with drug-resistant epilepsy (epilepsy that has not responded well to medications) take antiseizure medication every day, whether or not their seizure risk is high that day, which means they deal with side effects every day even though seizures happen only sometimes. This study tests using a small implanted sensor and a wearable device to predict when a person's seizure risk is elevated, and then giving a fast-acting medication in advance, before a seizure happens. The goal is to find out whether this approach is safe and workable in everyday life.

This study will enroll adults with drug-resistant epilepsy that involves the temporal lobe, at Mayo Clinic in Rochester, Minnesota, Jacksonville, Florida, and Phoenix, Arizona.

Each participant has a small device called the UNEEG SubQ placed just under the scalp, in a minor surgical procedure. This device does not go into the brain itself. It sits under the skin and continuously records the brain's electrical activity. Participants also wear an smart watch to track heart rate and movement, and they keep a daily seizure diary on a smartphone.

The study takes place over about 12 months for each participant, in three parts.

Part 1, the first three months: The device and watch collect data in the background. No warnings or predictions are shown to the participant during this time. This information is used to build a personalized computer model that learns each person's individual patterns of seizure risk. For four weeks during this period, participants take a scheduled dose of VALTOCO (a nasal spray form of the medication diazepam) once a week, which helps the research team see how the medication affects the recorded brain activity.

Part 2, the next three months: The personalized computer model starts making daily predictions about seizure risk, but these predictions are reviewed only by the research team and are not shown to the participant yet. This lets the team check how accurate the predictions are before relying on them. As in Part 1, participants take one scheduled weekly dose of VALTOCO during a four week period.

Part 3, the final six months: Starting at a mid-study visit, participants begin receiving the daily predictions on their smartphone. On days when the model predicts a higher chance of seizures, the participant (or a caregiver) receives an alert and is asked to use VALTOCO nasal spray at that time, before a seizure occurs, rather than waiting for one to happen. To help keep the medication use safe, participants cannot use VALTOCO more than 10 times in a month, and the system will not allow the medication to be used on two days in a row.

At the end of the study, the implanted device is removed in a simple outpatient procedure and all study equipment is returned.

The main goal is to find out whether this forecast-guided approach to using rescue medication is safe and practical to use in daily life.

As additional goals, the study will also look at whether participants' quality of life and the impact epilepsy has on their daily life improve during the study, using standard questionnaires, and whether the rate of seizures during the final six month part of the study is lower than each participant's own personal baseline rate measured earlier in the study.

This study is conducted with authorization from the U.S. Food and Drug Administration under Investigational New Drug application number 170383, which allows the research team to study VALTOCO for this new, investigational use. The study is supported by a grant from the National Institutes of Health (UG3NS123066).

Inclusion criteria

Subjects enrolled in this study must have epilepsy involving the temporal lobe and will have undergone video-EEG monitoring within the past 3 years, and will have met the following criteria:

• Focal epilepsy, including complex partial, and secondarily generalized seizures, including:

• disabling seizure (i.e. involving loss of awareness, motor control, speech, or other essential functions) counts at least 2 per month on average over the preceding 3 months, established by verbal history or caregiver report.
• For 3 months prior to enrollment, subject's AED dosages have been stable (less than a 25% change in dosage) and subject has had at least two seizures per month, on average, with a seizure-free interval not to exceed 60 days. Seizures must be separated by a minimum of four hours not to be considered part of a cluster. A cluster, for the purpose of this criterion, shall be considered a single seizure.
• With the exception of epilepsy, subject must be medically and neurologically stable.
• Age 18 to 75.
• Ability and willingness to provide informed consent and participate in the study protocol. Subject is able to interpret and to respond, in accordance with the study protocol, to the advisory indicators provided by the device.
• Subject has seizures that are distinct, stereotypical events that can be reliably counted by the subject or caregiver, and have a distinct EEG pattern that can be recorded using subscalp EEG over the frontotemporal head region, established by video-EEG monitoring.
• Subject can reasonably be expected to maintain a seizure diary alone or with the assistance of a competent individual.
• Subject is able to complete regular office visits and telephone appointments in accordance with the study protocol requirements.
• Subject's seizure focus, based upon clinical semiology, scalp EEG, intracranial electroencephalographic (iEEG) findings, and/or neuroimaging, demonstrate consistent involvement of the temporal lobe with their EEG seizure pattern.
• Subject speaks and reads English.
• Subject has no reason to anticipate requiring a magnetic resonance imaging (MRI) evaluation within the next two years.
• Subject has EEG documentation of ictal events consistent with his or her predominant current seizure type.
• Subject's anatomy will permit implantation of the UNEEG SubQ device in the opinion of the study's neurosurgeon.
• Female subjects have a negative pregnancy test, have no plans to become pregnant, and use effective contraception during the study.

Exclusion criteria

• For 3 months prior to enrollment, subject's AED dosages have not been stable (greater than 25% change in dosage), or subject has had more than 30 disabling seizures per month, on average, or more than 10 seizure days per month, on average.
• Subject needs to have magnetic resonance imaging during the study period.
• Subject has a substance abuse history (alcohol, prescription, or illicit medications) within the preceding two years.
• Subject participated in another drug or device trial within the preceding 30 days.
• Subject has been hospitalized for a psychiatric condition within the preceding two years or has had a history of psychosis within the preceding two years (excluding post-ictal psychosis).
• Subject is implanted with pacemaker, implantable cardiac defibrillator, cardiac management product, brain stimulator, or other medical device that would interfere with the UNEEG device. This includes, but is not limited to, direct brain neurostimulators, spinal cord stimulators, and cochlear implants. Vagus nerve stimulators are not expected to interfere with the subscalp EEG device and will be permitted, as long as stimulation parameters can be reasonably expected to remain stable (25% or less change in amplitude) throughout the study.
• Subject has experienced unprovoked status epilepticus.
• Subject has had therapeutic surgery to treat epilepsy that may interfere with electrode placement in the judgement of the neurosurgeon.
• Subject is on anticoagulants and is unable to discontinue them perisurgically, as required by the neurosurgeon or Investigator.
• Subject has significant platelet dysfunction from medical conditions or medications (including, particularly, aspirin or sodium valproate). If platelet dysfunction is suspected, subject can be enrolled only if a hematologist, the Investigator, and the neurosurgeon judge it to be advisable. Blood tests to evaluate platelet and bleeding disorder issues will be obtained prior to enrollment.
• Subject is otherwise ineligible for cranial surgery, or the Investigators identify other medical or psychosocial factors that would counter indicate participation in the study.
• Subject has a known diagnosis of psychogenic nonepileptic seizures (PNES)
• Female subject is pregnant or plans to become pregnant.
• Subject is known to require rescue medication for seizure clusters
• Subject has a history of a paradoxical reaction to benzodiazepines including agitation, hyperactivity, or aggression.
• Subject has a known diagnosis of acute narrow-angle glaucoma