Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000827730
Ethics application status
Approved
Date submitted
9/05/2022
Date registered
10/06/2022
Date last updated
23/06/2024
Date data sharing statement initially provided
10/06/2022
Date results information initially provided
23/06/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Neuromodulation using scanning ultrasound in Alzheimer’s disease
Scientific title
Neuromodulation using Scanning Ultrasound (SUSonly) in Alzheimer’s disease: Determining the safety and tolerability of repeat SUSonly treatments
Secondary ID [1] 307084 0
None
Universal Trial Number (UTN)
U1111-1277-9917
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimer’s disease 326247 0
Condition category
Condition code
Neurological 323548 323548 0 0
Alzheimer's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Neuromodulation using Scanning Ultrasound (SUSonly) is being investigated as a potential non-invasive therapy for Alzheimer’s disease (AD) as it has been shown to restore memory in senescent mice with memory impairment (Blackmore, Mol Psy, 2021). A mechanism has been identified that is relevant for AD pathology. The present study aim is to evaluate the safety, tolerability and feasibility of repeat SUSonly treatments in participants with AD using a bespoke low frequency transcranial SUS investigational device termed UltraTheraPilot. The SUSonly intervention will be delivered across several face-to-face sessions with each individual participant.

Therapy consists of four SUSonly treatments administered fortnightly for an overall duration of 6 weeks. The first 4 participants will be allocated to Cohort 1 targeting the precuneus (30 cubic centimetres of brain volume) and the following 8 participants will be allocated to Cohort 2 targeting the precuneus and flanking superior parietal lobe (100 cubic centimetres of brain volume). Participants in cohort 1 will receive 30 ultrasound pulses of 10 Hz administered to the region of interest, each pulse is approximately 6 s. Participants in cohort 2 will receive 100 ultrasound pulses of 10 Hz administered to the region of interest. The ultrasound parameters are the same for all participants, however, the sonication targets are individualised to target the region of interest using image guided navigation and the participant’s MRI data.

Once inducted into the study, participants will undergo baseline assessments, including cognitive tests, EEG and MRI. Participant cognitive tests and EEGs will be conducted at the Queensland Brain Institute by qualified personnel, while MRI will be conducted at the Centre for Advanced Imaging. Participant screening and each SUSonly treatment session will be administered at the Mater Hospital Brisbane by the Principal Investigator. The principal investigator is a clinical neurologist who will monitor and document adherence to the intervention in the case report forms. The Principle Investigator has been trained by device technicians to use the UltraTheraPilot system to deliver SUSonly to the regions of interest.

The safety of SUSonly will be determined by clinical assessment, MRI and behavioural tests. Participant tolerability of both the device and the SUSonly procedure will include MRI assessment.
Intervention code [1] 323538 0
Treatment: Devices
Intervention code [2] 323539 0
Treatment: Other
Comparator / control treatment
The first 4 participants will be allocated to Cohort 1 targeting the precuneus (30 cubic centimetres of brain volume). These participants will receive 30 ultrasound pulses of 10 Hz administered to the region of interest, each pulse is approximately 6 s.
Control group
Active

Outcomes
Primary outcome [1] 331303 0
To determine the safety and tolerability of repeat treatments of SUSonly of two treatment volumes as determined by clinical assessment of cognition and adverse effects such as scalp discomfort
Timepoint [1] 331303 0
Upon intervention commencement day 0, and 1, 14, 28, and 42 days post intervention commencement
Primary outcome [2] 331304 0
To determine the safety and tolerability of repeat treatments of SUSonly of two treatment volumes as determined by MRI
Timepoint [2] 331304 0
Baseline, 1 day post intervention commencement and end of study assessment (43-49 days post intervention commencement)
Primary outcome [3] 331556 0
To determine the safety and tolerability of repeat treatments of SUSonly of two treatment volumes as determined by behavioural tests - Alzheimer’s disease assessment scale-cognitive subscale (ADAS-Cog)
Timepoint [3] 331556 0
Baseline, 1 day post intervention commencement and end of study assessment (43-49 days post intervention commencement)
Secondary outcome [1] 409477 0
Assessment of target engagement. Exploratory analysis will assess perturbations in the cognitive test battery (ADAS-Cog, ACE-III and NPI)
Timepoint [1] 409477 0
Baseline, and at intervention completion (43-49 days post intervention commencement)
Secondary outcome [2] 409478 0
Any change in cognition as assessed by a cognitive test battery (ADAS-Cog, ACE-III and NPI).
Timepoint [2] 409478 0
Baseline, and at intervention completion (43-49 days post intervention commencement)
Secondary outcome [3] 410259 0
Assessment of target engagement. Exploratory analysis will assess perturbations in diffusion and resting state functional MRI
Timepoint [3] 410259 0
Baseline, and at intervention completion (43-49 days post intervention commencement)
Secondary outcome [4] 410260 0
Assessment of target engagement. Exploratory analysis will assess perturbations in electroencephalography (EEG)
Timepoint [4] 410260 0
Baseline, and at intervention completion (43-49 days post intervention commencement)
Secondary outcome [5] 410687 0
Primary outcome - To determine the safety and tolerability of repeat treatments of SUSonly of two treatment volumes as determined by behavioural test - Addenbrooke’s cognitive examination-III (ACE-III)
Timepoint [5] 410687 0
Baseline, 1 day post intervention commencement and end of study assessment (43-49 days post intervention commencement)
Secondary outcome [6] 410688 0
Primary outcome - To determine the safety and tolerability of repeat treatments of SUSonly of two treatment volumes as determined by behavioural test - Neuropsychiatric Inventory (NPI)
Timepoint [6] 410688 0
Baseline, 1 day post intervention commencement and end of study assessment (43-49 days post intervention commencement)

Eligibility
Key inclusion criteria
All of the following inclusion criteria must be met for enrolment:
1. Biomarker confirmed AD: Clinical profile consistent with AD plus either (i) Positive amyloid scan (NAV4694 F18, florbetaben F18, florbetapir F18, or flutametamol F18) at or prior to screening, as read by the certified, site-designated PET scan reader or (ii) AD diagnosis by CSF biomarker analysis prior to screening.
2. MMSE equal or > 10
3. Age 50-85
4. Clinically stable in the investigator’s opinion
5. If on anti-dementia drugs or other psychoactive medications such as Aricept participants must be on stable doses of drug for at least 2 months
6. Participant’s legally designated representative must be able to freely give written informed consent; additionally, if, in the clinical judgment of the Principal Investigator, the participant themselves has the mental capacity to provide consent, they will also provide consent
7. Ability to comply with study regimen and provide contact phone number
8. Ability to communicate during procedures
9. Presence of a regular caregiver (in contact with participant daily) who can attend appointments and provide information about adverse events.
Minimum age
50 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
None of the following exclusion criteria must be met for enrolment:
1. MRI contraindications:
a. Metallic objects in head, or presence of unknown or MR unsafe devices anywhere in body or,
b. Unable to tolerate MRI scanning (e.g. claustrophobia or known inability to lie sufficiently still from previous MRI scans)
2. Haemorrhages (including microhaemorrhages) on MRI scan (expected to be rare)
3. Any other MRI findings that in the opinion of the clinician may be contributing to the clinical profile, including severe ischemic changes, active or chronic infection/inflammation, tumour/space occupying lesion
4. Paget’s disease of bone
5. Clotting/bleeding disorder (including use of oral anticoagulants; anti-platelet therapy such as low-dose aspirin permitted)
6. Scalp or skull abnormalities
a. Prior neurosurgical intervention of the brain / craniotomy or,
b. Skull area traversed by the sonication pathway is covered by scars, scalp disorders (e.g., eczema), open wounds, or atrophy of the scalp
7. Other neurological diseases (or history of): severe traumatic brain injury, seizure disorders, stroke, tumours, transient ischemic attack
a. Cerebral pathology unrelated to Alzheimer’s disease
8. History of major psychiatric disorders (such as major depression or schizophrenia)
9. History of drug or alcohol abuse
10. An active inflammatory disease
11. Recent history (within four weeks prior to screening) of a clinically significant bacterial, fungal, or mycobacterial infection
12. Change of allowed, chronic, concomitant medication within 28 days prior to screening
13. Pregnancy or breast-feeding
14. Any other major medical illness that in the opinion of the clinician could interfere with the intended use (e.g. unstable cardiovascular, pulmonary, hepatic or renal disease, active cancer etc.)
15. Any conditions that render the participant unable to lie flat for scanning
16. Known cerebral or systemic vasculopathy
17. Corticosteroid treatment within last 6 weeks before first treatment
18. Increased intracranial pressure
19. Known skin allergies or sensitivity to silicone, ultrasound gel or depilation cream
20. Participation in other clinical trials within 90 days from the screening date
21. An inability to communicate during a treatment procedure
22. A body weight exceeding 200 kg
23. Other conditions implying increased risk according to the judgement of the investigator

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Single arm with two cohorts done sequentially with dose escalation
Cohort 1 receives 30 cc treatment
Cohort 2 receives 100 cc treatment
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
No formal sample size calculation has been performed, and the sample size is empirical and based on other clinical trials done in neuromodulation. However, the sample size selected of 12 participants in two cohorts (4 participants in cohort 1 and 8 participants in cohort 2) is considered sufficient to adequately characterize the general safety profile of the UltraTheraPilot system.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
20/06/2022
Actual
25/10/2022
Date of last participant enrolment
Anticipated
Actual
10/04/2024
Date of last data collection
Anticipated
Actual
29/05/2024
Sample size
Target
12
Accrual to date
Final
12
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 22336 0
Mater Private Hospital - South Brisbane
Recruitment postcode(s) [1] 37497 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 311392 0
Government body
Name [1] 311392 0
Australian Department of Health, Medical Research Future Fund – Emerging Priorities and Consumer Driven Research
Country [1] 311392 0
Australia
Funding source category [2] 311393 0
Charities/Societies/Foundations
Name [2] 311393 0
The Brazil Family Foundation
Country [2] 311393 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
Sir Fred Schonell Dr
St Lucia
QLD 4072
Country
Australia
Secondary sponsor category [1] 312783 0
None
Name [1] 312783 0
Address [1] 312783 0
Country [1] 312783 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310875 0
Bellberry Ltd
Ethics committee address [1] 310875 0
123 Glen Osmond Rd
Eastwood
SA, 5063
Ethics committee country [1] 310875 0
Australia
Date submitted for ethics approval [1] 310875 0
10/11/2021
Approval date [1] 310875 0
01/02/2022
Ethics approval number [1] 310875 0

Summary
Brief summary
The present study aim is to evaluate the safety, tolerability and feasibility of repeat SUSonly treatments in participants with AD using a bespoke low frequency transcranial SUS investigational device termed UltraTheraPilot.
Trial website
Trial related presentations / publications
Public notes
To be considered for enrolment, participants must be fully vaccinated against Covid-19, and willing to maintain vaccination status with booster vaccine if required.

Contacts
Principal investigator
Name 119186 0
Prof Peter Nestor
Address 119186 0
Mater Misericordiae Ltd
Mater Hospital, Raymond Tce
South Brisbane QLD 4101
Country 119186 0
Australia
Phone 119186 0
+61 7 34432505
Fax 119186 0
Email 119186 0
p.nestor@uq.edu.au
Contact person for public queries
Name 119187 0
Prof Peter Nestor
Address 119187 0
Mater Misericordiae Ltd
Mater Hospital, Raymond Tce
South Brisbane QLD 4101
Country 119187 0
Australia
Phone 119187 0
+61 7 31638111
Fax 119187 0
Email 119187 0
MCFNadmin@mater.org.au
Contact person for scientific queries
Name 119188 0
Prof Jürgen Götz
Address 119188 0
The Queensland Brain Institute
QBI Building, 79
The University of Queensland
St Lucia QLD 4072
Country 119188 0
Australia
Phone 119188 0
+61 7 3346 6300
Fax 119188 0
Email 119188 0
scanningultrasound@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data is not planned to be shared. Results will be published in the context of similar ultrasound neuromodulation trials.


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.