Evaluation of the NaviFUS System in Drug Resistant Epilepsy

An Open-label, Non-randomized, Single-arm Pilot Study to Evaluate the Safety and Efficacy of Multiple Pulsed Focused Ultrasound Treatment in Patients With Drug Resistant Temporal Lobe Epilepsy

Participants with drug-resistant epilepsy (DRE) enrolled in this study will receive focused ultrasound (FUS) treatment with the NaviFUS System, guided by the neuronavigation system to evaluate the safety and efficacy of using NaviFUS System. During the treatment, the FUS will electronically scan and target to the assigned zones on one or both of the hippocampi.

The study consists of a 60-day screening period for baseline observation prior to treatment, a FUS treatment period of 2 weeks for Cohort 1 or 3 weeks for Cohort 2 with 2 FUS treatments per week using the NaviFUS System, and a safety follow-up period of 81 days.

Up to 30% of patients with epilepsy are resistant to current anti-seizure medications, i.e. drug-resistant epilepsy (DRE). Resective surgery of the epileptogenic regions is the most effective option to treat patients with DRE. Unfortunately, up to 60% of DRE patients are not suitable for resective surgery.

Neuromodulation approaches are increasingly being utilized in patients with DRE. The current approved techniques use invasive neuromodulation, which require complex neurosurgery and could cause side effects, such as infection, bleeding, and non-target brain tissue damage.

Focused ultrasound is a novel, noninvasive, therapeutic technology with the potential to improve the quality of life and decrease the cost of care for patients with epilepsy. NaviFUS System (a neuro-navigation guided focused ultrasound system) is one of the FUS technologies that uses low-intensity focused ultrasound (LIFU) phased array system to deliver transcranial burst-mode ultrasound energy to induce neuromodulation effect and block signals in a specific area of the brain that cause symptoms of epilepsy such as seizures. The pilot clinical study has demonstrated that NaviFUS System safely delivered LIFU to the seizure onset zone and modulated the neuronal activity.

Inclusion Criteria:

1. Diagnosis of drug resistant temporal lobe epilepsy (TLE)
2. Patients must experience at least four (4) observable seizures over the 60-day baseline, each on a separate day.
3. Patients have focal-onset seizures with or without secondary generalization.
4. Patients have had at least 24 hours video-electroencephalography (EEG) monitoring and comprehensive epilepsy evaluation confirming TLE.
5. Seizure medication treatment is anticipated to remain stable during the trial, except for rescue medicines or occasional extra doses of ongoing medicines, as required.
6. Patients should be capable of and willing to completing assessments and neuropsychological testing in English either alone or with the help of the study partner (where appropriate), per local guidelines. A study partner is a carer or family member of the patient.
7. Patients and study partner (if applicable) who in the Investigator's opinion are reliable and able to use the seizure diary to record seizure throughout the study and are willing to comply with study procedures and visits.

Exclusion Criteria:

1. Patients who have primary generalized epilepsy or non-epileptic seizures in the last two (2) years.
2. More than two (2) seizure onset zones (foci) (except bitemporal foci) or unknown likely site of seizure onset, as determined by usual clinical, electroencephalography (EEG) and imaging practice.
3. Patients who have experienced tonic-clonic status epilepticus in the three (3) months leading up to enrollment in the study.
4. Presence of devices including but not limited to cardiac pacemaker, implantable cardioverter-defibrillator (ICD), permanent medication pumps, cochlear implants, responsive neurostimulator (RNS) or deep brain stimulation (DBS). Vagus nerve stimulators (VNS) do not represent an exclusion criterion, but settings should be stable throughout the trial.
5. Patients with clips or other metallic implanted objects in the FUS exposure path, except shunts.
6. Patients with more than thirty percent (30%) of the skull area traversed by the sonication pathway covered by scars, scalp disorders (e.g., eczema), or atrophy of the scalp at Screening.
7. Patients who have a medical or surgical history of severe systemic disease(s), such as (but not limited to) coronary artery disease, myocardial infarct, progressive heart failure, uncontrolled hypertension or abnormal ECG, severe pulmonary hypertension (pulmonary artery pressure > 90 mmHg), chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, hepatic and renal insufficiency (ALT or AST 3 times above normal range; serum creatinine > 1.3 mg/dL), diabetic patients with poor control of blood sugar (HbA1c > 8.5 %) at Screening.
8. History of intracranial hemorrhage.
9. History of multiple strokes, or a stroke within the six (6) months prior to Screening.
10. Patients with intracranial aneurysms requiring treatment or arterial venous malformations (AVMs) requiring treatment at any time.
11. Presence of central nervous system (CNS) disease(s) other than epilepsy including but not limited to infections of the CNS (e.g., syphilis, Lyme disease, borreliosis, viral or bacterial meningitis/encephalitis, human immunodeficiency virus [HIV] encephalopathy), cerebral vascular disease, Parkinson's disease, traumatic brain injury, alcoholic encephalopathy within three (3) years prior to Screening.
12. Patients with concurrent major psychiatric disorder, such as schizophrenia or bipolar disorder, severe depression, active suicidal ideation, active psychosis (excluding time-limited postictal psychosis) or psychiatric hospitalization within one (1) year before Screening.
13. Prior diagnosis of cancer within the past two (2) years and evidence of continued malignancy within the past two (2) years (except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or in situ prostate cancer with normal prostate-specific antigens post resection).
14. Patients who are not able or willing to tolerate the required prolonged stationary semi-supine position during treatment.
15. Inability to tolerate MRI procedures or contraindication to MRI (e.g. claustrophobia, too large for MRI scanner), including, but not limited to, presence of pacemakers (with the exception of MRI-safe pacemakers), aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or other areas of the body that would contraindicate an MRI scan.
16. Patients who had major surgery six (6) weeks before study enrollment or who are not fully recovered from a surgical procedure or with planned surgery during study period or within fourteen (14) days thereafter.
17. Patients who have received radiofrequency thermocoagulation (RFTC) within two (2) months of Screening.