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Trial registered on ANZCTR


Registration number
ACTRN12623000382673
Ethics application status
Approved
Date submitted
3/03/2023
Date registered
14/04/2023
Date last updated
25/06/2024
Date data sharing statement initially provided
14/04/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of the NaviFUS System in drug resistant epilepsy
Scientific title
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
Secondary ID [1] 309074 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Drug Resistant Temporal Lobe Epilepsy 329134 0
Temporal Lobe Epilepsy 329135 0
Condition category
Condition code
Neurological 326112 326112 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Investigational Device:
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).
The NaviFUS System consists of three major parts:
1. the Cabinet
2. the Console - computer device with 21.5-inch LCD monitor
3. the Exposure head with a coupling membrane attached to it – the component sits on the patient’s head to deliver FUS
The NaviFUS System does not contain medicinal substances, human, or animal tissues or their derivatives, or other biologically active substances.

Duration of Study:
The study consists of two (2) cohorts. The only difference between the two cohorts is the overall number of weeks of treatment (2 weeks for Cohort 1 vs. 3 weeks for Cohort 2). The study investigator will advise on which cohort the patients are enrolling into as it will depend on when the patients enter the study. The safety monitoring committee (SMC) will review all safety data for Cohort 1 and confirm that it is safe to proceed with the study before the study treatment for Cohort 2 can start.

Patients will undergo a 60-day screening period (from Day -60 to Day -1) for baseline observation and assessments prior to FUS treatment.
• 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.
• 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.

Method of Treatment:
- The NaviFUS System will be operated by trained and qualified study investigators at the investigational site.
- Intracranial spatial-peak temporal-average intensity (Ispta) ceiling level: 2.8 W/cm2 (the focused ultrasound intensity in brain area considering transcranial attenuation).
- The maximum total treatment exposure duration is thirty (30) minutes per treatment region.
Intervention code [1] 325515 0
Treatment: Devices
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 333981 0
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) assessed through the review of medical records and participant self-reporting in seizure diary
Timepoint [1] 333981 0
Post each FUS treatment, and 1, 2, and 3 months after the last treatment session
Primary outcome [2] 334130 0
Incidence of treatment discontinuation due to AEs and SAEs
Timepoint [2] 334130 0
Post each FUS treatment, and 1, 2, and 3 months after the last treatment session
Primary outcome [3] 334131 0
Incidence of clinically significant abnormal findings from physical and neurologic examinations
Timepoint [3] 334131 0
Baseline Visit, treatment period, and 1, 2, and 3 months after the last treatment session
Secondary outcome [1] 419438 0
Primary outcome: Incidence of clinically significant abnormal vital sign measurements, and abnormal vital signs reported as AEs and SAEs
Timepoint [1] 419438 0
Baseline Visit, treatment period, and 1, 2, and 3 months after the last treatment session
Secondary outcome [2] 419439 0
Primary outcome: Incidence of 12-lead electrocardiogram (ECG) with clinically significant abnormal findings
Timepoint [2] 419439 0
Baseline Visit, treatment period, and 1, 2, and 3 months after the last treatment
Secondary outcome [3] 419704 0
Primary outcome: Incidence of Magnetic Resonance Imaging (MRI) with clinically significant abnormal findings
Timepoint [3] 419704 0
Baseline Visit and 3 months after the last treatment session
Secondary outcome [4] 419705 0
Primary outcome: Clinically significant changes in cognitive functions from baseline assessed by a composite outcome of Boston Naming Test-Second Edition (BNT-2), Auditory Naming Test (ANT), Sentence Repetition Test (SRT), Controlled Oral Word Association Test (COWAT), Wechsler Memory Scale-4 (WMS-4) and Rey Auditory Verbal Learning Test (RAVLT)
Timepoint [4] 419705 0
Baseline Visit and 3 months after the last treatment session
Secondary outcome [5] 419706 0
Exploratory outcome: Change in seizure frequency after FUS treatment compared to baseline assessed through the review of medical records and participant self-reporting in seizure diary
Timepoint [5] 419706 0
From Baseline Visit until 3 months after the last treatment session
Secondary outcome [6] 419707 0
Exploratory outcome: Responder rate (defined as at least 50% seizure reduction) assessed through the review of medical records and participant self-reporting in seizure diary
Timepoint [6] 419707 0
From Baseline Visit until 3 months after the last treatment session
Secondary outcome [7] 419708 0
Exploratory outcome: Percentage change in days seizure-free assessed through the review of medical records and participant self-reporting in seizure diary
Timepoint [7] 419708 0
From Baseline Visit until 3 months after the last treatment session
Secondary outcome [8] 419709 0
Exploratory outcome: Subjective scoring of seizure intensity assessed through the review of medical records and participant self-reporting in seizure diary
Timepoint [8] 419709 0
From Baseline Visit until 3 months after the last treatment session
Secondary outcome [9] 419710 0
Exploratory outcome: Frequency of interictal epileptiform discharges or electrographic seizures on 24 hour ambulatory electroencephalogram (aEEGs)
Timepoint [9] 419710 0
Baseline Visit, and 1, 2, and 3 months after the last treatment session
Secondary outcome [10] 419711 0
Exploratory outcome: The 31-item Quality of Life in Epilepsy (QOLIE-31) assessment
Timepoint [10] 419711 0
Baseline Visit, and 1, 2, and 3 months after the last treatment session
Secondary outcome [11] 419712 0
Exploratory outcome: Beck Anxiety Inventory (BAI) assessment
Timepoint [11] 419712 0
Baseline Visit, and 1, 2, and 3 months after the last treatment session
Secondary outcome [12] 419714 0
Exploratory outcome: Beck Depression Inventory-2 (BDI-2) assessment
Timepoint [12] 419714 0
Baseline Visit, and 1, 2, and 3 months after the last treatment session

Eligibility
Key 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 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not Applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
21/08/2023
Actual
2/10/2023
Date of last participant enrolment
Anticipated
1/01/2025
Actual
Date of last data collection
Anticipated
1/05/2025
Actual
Sample size
Target
18
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 24166 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 39698 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 313280 0
Commercial sector/Industry
Name [1] 313280 0
Genovate-NaviFUS (Australia) Pty Ltd
Country [1] 313280 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Genovate-NaviFUS (Australia) Pty Ltd
Address
Cohort, Health & Knowledge Precinct
16 Nexus Way
Southport, Queensland 4215, Australia
Country
Australia
Secondary sponsor category [1] 315017 0
None
Name [1] 315017 0
Address [1] 315017 0
Country [1] 315017 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312509 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 312509 0
Ethics committee country [1] 312509 0
Australia
Date submitted for ethics approval [1] 312509 0
23/11/2022
Approval date [1] 312509 0
27/03/2023
Ethics approval number [1] 312509 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124914 0
Prof Terence O’Brien
Address 124914 0
The Alfred Centre
Level 6, 99 Commercial Rd
Melbourne Victoria 3004
Country 124914 0
Australia
Phone 124914 0
+61 3 9903 0855
Fax 124914 0
Email 124914 0
te.obrien@alfred.org.au
Contact person for public queries
Name 124915 0
Toni Lay
Address 124915 0
Study Coordinator
The Alfred Centre
Level 4, 55 Commercial Rd
Melbourne VIC 3004
Country 124915 0
Australia
Phone 124915 0
+61 3 9076 2470
Fax 124915 0
Email 124915 0
T.Lay@alfred.org.au
Contact person for scientific queries
Name 124916 0
Tony Lo
Address 124916 0
Genovate-NaviFUS (Australia) Pty Ltd
c/o
Genovate Biotechnology Co., Ltd.
9F, No. 12, Sec. 2, Renai Rd.
Taipei 10060, Taiwan, R.O.C.
Country 124916 0
Taiwan, Province Of China
Phone 124916 0
+886 2 2321 1978
Fax 124916 0
Email 124916 0
TonyLo@genovate-bio.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Due to intellectual property concerns, IPD will not be shared.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.