None listed
Conditions
Brief summary
The present study aim is to evaluate the tolerability and feasibility of repeat LIFU treatments in participants with AD using a bespoke low frequency transcranial LIFU investigational device termed Ceretas Device. To evaluate the efficacy of the Ceretas device on the overall neuropsychiatric symptom burden in probable Alzheimer patients.
Interventions
Neuromodulation using the Ceretas device (second-generation) delivering precise non-invasive low-intensity focused ultrasound (LIFU).
The derated spatial-peak pulse-average (ISPPA) intensity of the pulses is less than or equal to 18.3 W/cm2 in the brain tissue; generated by a defined ultrasound waveform of 10 Hz administered to the region of interest, each pulse is approximately 6 s.
The treatment duration is 30 - 60 minutes per treatment session.
For the first 4 weeks the treatment is applied
Neuromodulation using the Ceretas device (second-generation) delivering precise non-invasive low-intensity focused ultrasound (LIFU). The derated spatial-peak pulse-average (ISPPA) intensity of the pulses is less than or equal to 18.3 W/cm2 in the brain tissue; generated by a defined ultrasound waveform of 10 Hz administered to the region of interest, each pulse is approximately 6 s. The treatment duration is 30 - 60 minutes per treatment session. For the first 4 weeks the treatment is applied weekly and then the last 2 treatments monthly. To monitor adherence to the intervention a caregiver is provided the treatment schedule. The intervention will be administered in a clinical setting by a trained technician, under the direct supervision of the Principal Investigator who will both be extensively trained in the protocol. A checklist and questions will be completed in each treatment session to ensure compliance with the required steps, and targeted treatment locations will be saved in the IGN software. Sessions of treatment with LIFU last approximately 30-60 minutes in total including setting up navigation, preparing the patient and administering LIFU. LIFU will be delivered to the bilateral precuneus and temporo-parietal association cortex via application of the transducer to the patient’s head and the administration of sonication to the brain region. These participants will receive 100 ultrasound pulses of 10 Hz administered to the region of interest, each pulse is approximately 6 s. A total of 6 treatments is planned over a 12 week period. The planned sample size is 66 (2:1 ratio) with a minimum sample size of 60 with participants randomised in a ratio of 2 : 1 (active treatment : sham control) with stratification by baseline symptom score (Neuropsychiatric Inventory (NPI) total score is equal or greater than 12). The 2 : 1 allocation ratio was chosen to support recruitment.
Sponsors
Ceretas Ltd
Study design
Allocation
Randomised controlled trial
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
All of the following inclusion criteria must be met for enrolment: 1. Mini-Mental State (MMSE) 10-25. 2. Age 50 years or older. 3. An outpatient living at home or in an assisted living facility, has a knowledgeable informant and is ambulatory. 4. Has a live-in caregiver/informant or, if in assisted living, has a caregiver/informant who spends at least 10 hours per week (spread over at least 5 days/week) in direct contact with the participant and can maintain this through the course of the study. Caregiver/informant must also be able to attend study visits and the same caregiver/informant for all NPI and CMAI (Cohen Mansfield Agitation Inventory) visits. 5. Probable Alzheimer’s disease diagnosis obtained from a clinician according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA). 6. Clinically significant symptoms present that cause clinically meaningful distress/impairment and are judged to warrant a treatment trial as assessed by Neuropsychiatric Inventory: NPI-12 total score equal or greater than 12 at screening and equal or greater than 12 at Baseline and 1 core domain Frequency and Severity (FxS) equal or greater than 4 at Baseline. 7. The investigator considers the individual medically stable, although BPSD symptoms are present. 8. Individuals who are currently prescribed anti-dementia medications or other psychoactive agents will be eligible for inclusion only if they have been on a stable dose of each medication for a minimum of eight weeks prior to enrolment. 9. Participant’s person responsible 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. 10. Ability to comply with study regimen and provide contact phone number. 11. Ability to communicate during procedures.
Exclusion criteria
Exclusion Criteria None of the following exclusion criteria must be met for enrolment: 1. Where the source of BPSD symptoms are considered to relate to an acute medical disorder (e.g. active infection, pain). 2. 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). 3. Haemorrhages (including microhaemorrhages) on MRI scan (expected to be rare). 4. 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, meningeal enhancement, intracranial hypotension. 5. Paget’s disease of bone. 6. Clotting/bleeding disorder (including oral anti-coagulants; anti-platelet therapy such as low-dose aspirin permitted). 7. Uncontrolled HbA1c outside local laboratory normal reference ranges at baseline. 8. 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. 9. Other neurological diseases (or history of): severe traumatic brain injury, seizure disorders, stroke, tumours, transient ischemic attack: a. Clinically significant Cerebral pathology unrelated to Alzheimer’s disease 10. History of major psychiatric disorders (such as schizophrenia or bipolar disorder). 11. History of drug or alcohol abuse. 12. An active inflammatory disease. 13. Recurrent or recent history (within four weeks prior to screening) of a clinically significant bacterial, fungal, or mycobacterial infection. 14. Change of allowed, chronic, concomitant medication within 28 days prior to screening. 15. Pregnancy or breast-feeding. 16. 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.). 17. Any conditions that render the participant unable to lie flat for scanning. 18. Known cerebral or systemic vasculopathy. 19. Corticosteroid treatment within last 6 weeks before first treatment. 20. Increased intracranial pressure. 21. Known skin allergies or sensitivity to silicone, ultrasound gel or depilation cream. 22. Participation in other clinical trials within 90 days from the screening date. 23. An inability to communicate during a treatment procedure. 24. A body weight exceeding 135 kg. 25. Other conditions implying increased risk according to the judgement of the investigator.
Outcome results
None listed