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.

Study Overview

• Status: Recruiting
• Conditions: Drug Resistant Epilepsy; Epilepsy, Temporal Lobe
• Intervention / Treatment: Device: NaviFUS System

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Caitlin Roberts, Ms.; Phone Number: +61 3 9076 2598; Email: cai.roberts@alfred.org.au
• Study Contact Backup: Name: Jack Germaine, Mr.; Phone Number: +61 3 9076 2029; Email: j.germaine@alfred.org.au

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Recruiting
      • The Alfred
      • Contact: Caitlin Roberts, Ms.; Phone Number: +61 3 9076 2598; Email: cai.roberts@alfred.org.au
      • Principal Investigator: Terence O'Brien, Prof.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of drug resistant temporal lobe epilepsy (TLE)
2. Patients must experience at least eight (8) 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 complete assessments and neuropsychological testing in English.
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. A study partner is a carer or family member of the patient.

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Eligible patients in Cohort 1 will receive two (2) FUS treatments per week for two (2) weeks on Day 1, 4, 8 and 11, followed by three (3) safety follow-up visits on Day 36, 64 and 92.	Device: NaviFUS System; NaviFUS System (Neuronavigation-Guided Focused Ultrasound System) is a new non-invasive device, which uses the neuronavigation principle to guide focused ultrasound (FUS) energy precisely delivering through the skull to selected brain tissues without surgery in real-time. In this clinical study, the NaviFUS System is intended to deliver low intensity FUS to generate neuromodulation effects on a predetermined treatment region (one or both of the hippocampi which are associated with seizure), for the treatment for drug-resistant temporal lobe epilepsy (TLE).
Experimental: Cohort 2; Eligible patients in Cohort 2 will receive two (2) FUS treatments per week for three (3) weeks on Day 1, 4, 8, 11, 15 and 18, followed by three (3) safety follow-up visits on Day 43, 71 and 99.	Device: NaviFUS System; NaviFUS System (Neuronavigation-Guided Focused Ultrasound System) is a new non-invasive device, which uses the neuronavigation principle to guide focused ultrasound (FUS) energy precisely delivering through the skull to selected brain tissues without surgery in real-time. In this clinical study, the NaviFUS System is intended to deliver low intensity FUS to generate neuromodulation effects on a predetermined treatment region (one or both of the hippocampi which are associated with seizure), for the treatment for drug-resistant temporal lobe epilepsy (TLE).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence, nature and severity of adverse events (AEs), serious adverse events (SAEs) and AE of special interest (seizures, headaches, mental state changes, language and memory changes, lethargy/fatigue, and nausea)	This outcome will be assessed through the review of medical records and participant self-reporting in seizure diary.	Up to 3 months after the last treatment session
Incidence of treatment discontinuation due to AEs and SAEs		Up to 3 months after the last treatment session
Incidence of clinically significant abnormal findings from physical and neurologic examinations		Up to 3 months after the last treatment session
Incidence of clinically significant abnormal vital sign measurements, and abnormal vital signs reported as AEs and SAEs		Up to 3 months after the last treatment session
Incidence of 12-lead electrocardiogram (ECG) with clinically significant abnormal findings		Up to 3 months after the last treatment
Incidence of Magnetic Resonance Imaging (MRI) with clinically significant abnormal findings	This outcome will be measured at Baseline Visit and 3 months after the last treatment session.	Up to 3 months after the last treatment session
Clinically significant changes in cognitive functions from baseline assessed by Boston Naming Test (BNT)	BNT is a 60-item/picture test to assess the ability to name common objects, with scores ranging from 0 to 60. Higher scores indicate better naming ability.	Up to 3 months after the last treatment session
Clinically significant changes in cognitive functions from baseline assessed by Auditory Naming Test (ANT)	ANT is a 50-item test requiring participants to name a specific item to a description, with scores ranging from 0 to 50. Higher scores indicate better naming ability.	Baseline Visit and 3 months after the last treatment session
Clinically significant changes in cognitive functions from baseline assessed by Sentence Repetition Test (SRT)	SRT tests immediate memory for sentences of increasing length (1-26 syllables), with scores ranging from 0 to 22. Higher scores indicate better performance.	Baseline Visit and 3 months after the last treatment session
Clinically significant changes in cognitive functions from baseline assessed by Controlled Oral Word Association Test (COWAT)	COWAT is an oral fluency test in which the participant is required to make verbal associations to different letters of the alphabet by saying as many words as they can think of beginning with a given letter. Greater number of words produced indicates better performance on the test.	Baseline Visit and 3 months after the last treatment session
Clinically significant changes in cognitive functions from baseline assessed by Wechsler Memory Scale-4 (WMS-4)	WMS-IV measures the ability to learn and remember information presented verbally and visually, with scores ranging from 60 to 140 (mean = 100; standard deviation = 15). Higher scores indicate better performance.	Baseline Visit and 3 months after the last treatment session
Clinically significant changes in cognitive functions from baseline assessed by Rey Auditory Verbal Learning Test (RAVLT)	RAVLT is a test using a 15-word list to assess non-verbal learning and memory, with scores ranging from 0 to 15. Higher scores indicate better performance.	Baseline Visit and 3 months after the last treatment session

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory outcome 1: Change in seizure frequency after FUS treatment compared to baseline	This outcome will be assessed through the review of medical records and participant self-reporting in seizure diary.	From Baseline Visit until 3 months after the last treatment session
Exploratory outcome 2: Responder rate (defined as at least 50% seizure reduction)	This outcome will be assessed through the review of medical records and participant self-reporting in seizure diary.	From Baseline Visit until 3 months after the last treatment session
Exploratory outcome 3: Percentage change in days seizure-free	This outcome will be assessed through the review of medical records and participant self-reporting in seizure diary.	From Baseline Visit until 3 months after the last treatment session
Exploratory outcome 4: Subjective scoring of seizure intensity	This outcome will be assessed through the review of medical records and participant self-reporting in seizure diary. The seizure intensity (severity) will be scored on a 7-point scale of 1 (very mild) to 7 (very severe).	From Baseline Visit until 3 months after the last treatment session
Exploratory outcome 5: Change in frequency of interictal epileptiform discharges or electrographic seizures on 24 hour ambulatory electroencephalogram (aEEGs) from baseline	This outcome will be measured at Baseline Visit, and 1, 2, and 3 months after the last treatment session.	Baseline Visit and 3 months after the last treatment session
Exploratory outcome 6: Change in the 31-item Quality of Life in Epilepsy (QOLIE-31) assessment from baseline	The QOLIE-31 includes 31 questions about epilepsy patient's health and daily activities, yielding a composite score from 0 to 100. Higher scores indicate a better quality of life. This outcome will be assessed at Baseline Visit, and 1, 2, and 3 months after the last treatment session.	Baseline Visit and 3 months after the last treatment session
Exploratory outcome 7: Change in Beck Anxiety Inventory (BAI) assessment from baseline	BAI contains 21 questions, each answer being scored on a scale value of 0 (not at all) to 3 (severely). Higher total scores indicate more severe anxiety symptoms. This outcome will be assessed at Baseline Visit, and 1, 2, and 3 months after the last treatment session.	Baseline Visit and 3 months after the last treatment session
Exploratory outcome 8: Change in Beck Depression Inventory-2 (BDI-2) assessment from baseline	BDI-2 consists of 21 questions, and a value of 0 to 3 is assigned for each answer, ranging in intensity. Higher total scores indicate more severe depressive symptoms. This outcome will be assessed at Baseline Visit, and 1, 2, and 3 months after the last treatment session.	Baseline Visit and 3 months after the last treatment session

Collaborators and Investigators

• Sponsor: Genovate-NaviFUS (Australia) Pty Ltd.
• Collaborators: Genovate Biotechnology Co., Ltd.,; NaviFUS Corporation
• Investigators: Principal Investigator: Terrence O'Brien, Prof., The Alfred

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2023
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): May 1, 2024

Study Registration Dates

• First Submitted: June 20, 2023
• First Submitted That Met QC Criteria: July 7, 2023
• First Posted (Actual): July 17, 2023

Study Record Updates

• Last Update Posted (Estimated): November 16, 2023
• Last Update Submitted That Met QC Criteria: November 14, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Focused Ultrasound; Temporal Lobe Epilepsy; Drug Resistant Temporal Lobe Epilepsy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes; Epilepsies, Partial; Epilepsy; Drug Resistant Epilepsy; Epilepsy, Temporal Lobe
• Other Study ID Numbers: GNIA22-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No