A Pilot Study: Focused Ultrasound Thalamotomy for the Prevention of Secondary Generalization in Focal Onset Epilepsy

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and feasibility of Magnetic Resonance Imaging-guided focused ultrasound (MRgFUS) in patients with epilepsy whose medicines are not working well. The ExAblate transcranial system is the name of the device that will be used to create and send ultrasound waves through the scalp and skull precisely to a small structure located in the center of the brain. This structure is known as the Anterior Nucleus, and is an important region in the brain that may cause the seizures. Safety will be measured by recording and analyzing any adverse effects that may occur from the day of the experimental surgery through 12 months following the surgery.

Detailed Description
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This is a open-label prospective intervention study. Ten (10) adults with refractory, partial-onset epilepsy with secondary generalization and able to provide informed consent will be enrolled. In addition to the diagnosis of medically refractory epilepsy, these patients will need to meet protocol specific inclusion and exclusion criteria. These adults will be screened from the patients being cared for by the epilepsy program at the University of North Carolina at Chapel Hill or referred from elsewhere for enrollment in the study. Initially, 3 participants will be enrolled and followed for 3 months to assess the safety of study intervention. Pending review by the Data and Safety Monitoring Committee (DSMC), an additional 7 participants will be enrolled. This pilot study is being conducted to test the feasibility of this device in order to confirm the design and operating specifications of the device including the ability to identify and accurately ablate the target focus within the Anterior Nucleus. Safety will be assessed by the absence of side effects, e.g., new onset of neurological deficits, performance deterioration on neuropsychological testing. Feasibility is defined as the ability to create the desired lesion within the anterior nucleus. Seizure frequency data will be collected by seizure diary. Quality of life will be measured by the Quality of Life in Epilepsy Inventory (QOLIE-31). Imaging analysis will include study of changes in resting state functional connectivity (assessed by fMRI), as well as in structural (assessed by volumetric T1 and T2 weighted imaging) and microstructural (assessed by diffusion tensor imaging) brain anatomy.

Official Title
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A Pilot Open-label Clinical Trial Evaluating the ExAblate Model 4000 Type-1 Focused Ultrasound Thalamotomy for the Prevention of Secondary Generalization in Focal Onset Epilepsy

Conditions
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Partial Seizures With Secondary Generalization

Intervention / Treatment
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* Device: High Intensity Focused Ultrasound


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disabling, medically refractory epilepsy (≥2 anti-epileptic drug failures) Focal onset seizures with secondary generalization; with or without primary generalized seizures. ≥ 3 seizures/month on average within 3 months of enrollment. Stable medication dosage for 3 months before enrollment. Anterior Nucleus (AN) identifiable on MRI (structural T1 and T2 images). Willing to maintain seizure diary (3 months before & 3 months after). Involved care provider. Written informed consent to participate. High-definition MRI imaging/PET imaging Previous seizure work-up within 12 months of enrollment date to include: Home EEG or EMU video EEG or intracranial EEG. Baseline neuropsychological assessment, which includes the Wechsler Advanced Clinical Solutions - Test of Premorbid Functioning (TOPF). Participants obtaining an IQ score of ≥70 on the TOPF will be included. Exclusion Criteria: Low seizure frequency (<3 seizures/month). Previous vagal nerve stimulator. Severe untreated neuropsychiatric disorders (untreated depression or behavioral problems). Recent history of drugs or alcohol abuse. Primary generalized epilepsy (Lennox Gastaut, drop attacks). Post infectious epilepsy (post herpetic). Previous corpus callosotomy. Significant structural brain abnormalities. Unable or unwilling to maintain drug dosage for 3 months post treatment. Pregnant or not practicing birth control method acceptable to the principal investigator. History of claustrophobia. Known allergic reaction and/or hypersensitivity to IV dye and/or IV contrasting agent(s). MRI contraindicated implanted metal or medical device. Uncontrolled hypertension or other comorbid conditions Skull Density Ratio (SDR) <0.4. IQ score of <70 on the Wechsler Advanced Clinical Solutions - Test of Premorbid Functioning (TOPF), a measure conducted as part of baseline neuropsychological assessment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a pilot study. There are no statistical testing. Ten (10) adults with refractory, partial-onset epilepsy with secondary generalization and able to provide informed consent will be enrolled. Initially, 3 participants will be enrolled and followed for 3 months to assess the safety of study intervention. Pending review by the Data and Safety Monitoring Committee (DSMC) and the US Food and Drug Administration (FDA), an additional 7 participants will be enrolled.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: high intensity focused ultrasound<br>Initially, 3 patients will be enrolled and followed for 3 months to assess the safety of study intervention which is unilateral MR guides focused ultrasound thalamotomy (anterior nucleus). These data will be reviewed by the Data and Safety Monitoring Committee (DSMC) and the FDA. If approval is granted by the DSMC and FDA, then up to an additional 7 participants will be enrolled. | Device: High Intensity Focused Ultrasound<br>* Participants will undergo high intensity focused ultrasound surgery utilizing magnetic resonance (MR) imaging guidance using a 3 Tesla scanner.<br>* Other names: ExAblate Model 4000 Type-1 Focused Ultrasound;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Successful Lesion Creation | Feasibility is defined as the ability to create the desired lesion within the anterior nucleus in 80% or more of participants. | during the surgical procedure | 
| Number of Participants with Adverse Events | Safety will be assessed by the absence of side effects, e.g. new onset of neurological deficits, performance deterioration on neuropsychological testing. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Number of Seizures Reported Across Time | Captured by participant-recorded seizure diaries. Assessed at Baseline, and months 3, 6, and 12. | up to 12 months | 
| Total QOLIE-31-P Score Across Time | The Quality of Life in Epilepsy Inventory-31-Problems (QOLIE-31-P) is a survey of health-related quality of life for adults with epilepsy. The QOLIE-31-P is completed by the patient. It contains 39 items, of which a total of 30 are used to make up 7 different subscales. Scores range from 0-100, with higher scores indicating a greater level of functioning and QoL. Assessed at Baseline, and months 3, 6, and 12. | up to 12 months | 
| Change MRI parameter (Water Diffusivity) | Water Diffusivity assessed by structural and microstructural MRI in a voxel-wise manner and compared between pre and post operative MRI. | Baseline, (Day 1), Month 3 |