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Trial registered on ANZCTR


Registration number
ACTRN12622000274774
Ethics application status
Approved
Date submitted
29/11/2021
Date registered
14/02/2022
Date last updated
14/02/2022
Date data sharing statement initially provided
14/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Positron Emission Tomography (PET) imaging of neurodegenerative biomarkers in people ‘at risk’ for dementia
Scientific title
Positron Emission Tomography (PET) imaging of neurodegenerative biomarkers in people ‘at risk’ for dementia
Secondary ID [1] 305920 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Subjective memory complaints 324507 0
mild cognitive impairment 324508 0
Dementia 324509 0
Condition category
Condition code
Neurological 321987 321987 0 0
Dementias
Neurological 322147 322147 0 0
Neurodegenerative diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
PET imaging (Aß and/or tau) session: PET biomarkers are currently used to identify and characterise individuals with pre-clinical and clinical dementia. Therefore, our aim is to quantify global and regional Amyloid (Aß) and tau burden in older adults at various stages of dementia risk.

Participants will undergo ONE Aß PET scan using [18F]-NAV4694 or [18F]-Florbetaben, as determined by site and subject to tracer availability. Participants may also undergo ONE tau PET scan using [18F]-MK6240, as determined by site and subject to tracer availability.

Depending on funding, tracer availability, and participant willingness, they may be offered follow-up scans every two years for the duration of the study, leading to a maximum of three scanning sessions over five years (Year 1, Year 3, Year 5).

The imaging agent will be administered by a radiopharmacist and/or radiochemist or assigned Nuclear Medicine technologists on duty according to the below:

[18F]NAV4694 – with the participants lying supine in a quiet room, 200 +/-10% MBq of [18F]NAV4694 will be injected via the inserted cannula followed by a saline flush of 20 mL. A 20-minute scan will be acquired starting at 50 min post injection of [18F]-NAV4694.

OR

[18F]-Florbetaben – with the participants lying supine in a quiet room 300 +/-10% MBq [18F] - will be injected via the inserted cannula followed by a saline flush of 20 mL. A 20-minute scan will be acquired starting at 90 minutes post injection of [18F]-Florbetaben.

And, subject to availability,

[18F]-MK6240 - 185 MBq of MK6240 will be injected via the inserted cannula followed by a saline flush of 20 mL. A 20-minute scan will be acquired starting at 90 minutes post injection of [18F]-MK6240.
Intervention code [1] 322314 0
Diagnosis / Prognosis
Intervention code [2] 322315 0
Early detection / Screening
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 330299 0
Global Amyloid (Aß) burden as assessed by the Standardized uptake values ratios average of the area-weighted mean of frontal, superior parietal, lateral temporal, and posterior cingulate regions.
Timepoint [1] 330299 0
Baseline
Primary outcome [2] 330300 0
Global Tau burden as assessed by the Standardized uptake values ratios average of the area-weighted mean of frontal, superior parietal, lateral temporal, medial temporal lobes, and posterior cingulate regions.
Timepoint [2] 330300 0
Baseline
Secondary outcome [1] 405640 0
Regional Amyloid (Aß) burden as assessed by the Standardized uptake values ratios of the volumes of interest (frontal, posterior cingulate, parietal, lateral temporal, and cerebellar cortex).
Timepoint [1] 405640 0
Baseline
Secondary outcome [2] 405641 0
Regional Tau burden as assessed by the Standardized uptake values ratios of the volumes of interest (frontal, posterior cingulate, parietal, lateral temporal, medial temporal lobes, and cerebellar cortex).
Timepoint [2] 405641 0
Baseline
Secondary outcome [3] 405642 0
Global Amyloid (Aß) burden as assessed by the Standardized uptake values ratios average of the area-weighted mean of frontal, superior parietal, lateral temporal, and posterior cingulate regions.
Timepoint [3] 405642 0
3 and 5 years post-baseline scan
Secondary outcome [4] 405643 0
Regional Amyloid (Aß) burden as assessed by the Standardized uptake values ratios of the volumes of interest (frontal, posterior cingulate, parietal, lateral temporal, and cerebellar cortex).
Timepoint [4] 405643 0
3 and 5 years post-baseline scan
Secondary outcome [5] 405644 0
Global Tau burden as assessed by the Standardized uptake values ratios average of the area-weighted mean of frontal, superior parietal, lateral temporal, medial temporal lobes, and posterior cingulate regions.
Timepoint [5] 405644 0
3 and 5 years post-baseline scan
Secondary outcome [6] 405645 0
Regional Tau burden as assessed by the Standardized uptake values ratios of the volumes of interest (frontal, posterior cingulate, parietal, lateral temporal, medial temporal lobes, and cerebellar cortex).
Timepoint [6] 405645 0
3 and 5 years post-baseline scan

Eligibility
Key inclusion criteria
1. Adults aged between 50 and 90 years
2. Referred due to concerns about new onset of mood or cognitive problems (within the last 5-years) that are not due to other medical conditions
3. A MMSE score of greater than or equal to 20 (a widely used screening tool).
4. Willingness to give written informed consent and willingness to participate and comply with the study.
5. Have undergone the full Healthy Brain Ageing clinic assessment protocol including the collection of blood for genotyping.
6. Willing to undergo PET scanning within one month of Healthy Brain Ageing clinic assessment.
7. Subject to available funding.
8. Considered appropriate candidate by the treating clinician.
Minimum age
50 Years
Maximum age
90 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior head injury (with loss of consciousness of greater than 30min)
2. Stroke
3. Major non-affective mental health disorder such as schizophrenia, Bipolar Disorder, ADHD, Autism, PTSD, chronic fatigue syndrome or acute psychosis
4. Major neurological condition such as Parkinson’s disease, epilepsy
5. Current or past alcohol or substance misuse
6. Intellectual disability
7. Currently taking benzodiazepines
8. Currently taking antipsychotics
9. Currently consuming more than 14 standard drinks of alcohol per week
10. Females who have not yet undergone menopause
11. A history of cancer diagnosis within the past 5 years
12. Current or prior kidney disease or any history of poor renal function that in the opinion of the investigator may deem it unsafe to participate in the study.

Study design
Purpose of the study
Diagnosis
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
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size estimation:
Using the commonly used criterion of a statistical power level of 0.80, with alpha set to p=.05, a two-tailed point-biserial correlation model requires a sample size of 82 to detect a medium effect size (r=0.3). The point-biserial correlational model was chosen as it provides an effect size for the difference in means between two-groups. It involves correlating a binary variable with a continuous variable. As one of many possible examples, in our proposed study we could use a binary amyloid positive/amyloid negative variable and correlate it with a continuous variable of memory performance on a cognitive test. If the effect size was in fact larger than our r=0.3 conservative estimate, we would need a sample size of only 26 to detect an effect size of 0.5. Conversely, if our effect size was smaller than anticipated, then we would require a large sample. Nevertheless, given what has been previously shown in the ageing literature, when comparing clinical and modifiable risk factor variables with amyloid/tau burden, we believe that using an effect size estimate of at least 0.3 is justified, and most likely conservative. In any case, we expect that we will have a larger sample size than 82 by the end of the 5 years.

Image analysis:
Volumes of interest (VOIs) will be used to extract quantification from the PET data via an automated program previously developed by the CSIRO (CapAIBL). VOI will include frontal, posterior cingulate, parietal, lateral temporal and cerebellar cortex. Standardized uptake values (SUV) will be calculated for all brain regions examined and SUV ratios (SUVR) will be generated by the appropriate reference region for each tracer (e.g. typically cerebellar cortex SUV). Global neocortical amyloid burden will be expressed as the average SUVR of the area-weighted mean of frontal, superior parietal, lateral temporal, and posterior cingulate regions. A similar analysis will be used for the tau scan except that the medial temporal lobes will also be included in the composite neocortical VOI. A neocortical SUVR of >1.4 will define a scan as positive for brain amyloid and >1.15 for brain tau.

Statistical methods:
For assessment of Aß and tau accumulation over time, statistical models will be implemented using the general linear model, with alpha set at .05 two-tailed. Multiple comparisons will be adjusted using appropriate corrections, such as Bonferroni or false-discovery rate.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/03/2022
Actual
Date of last participant enrolment
Anticipated
1/03/2032
Actual
Date of last data collection
Anticipated
1/03/2032
Actual
Sample size
Target
82
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 310268 0
Government body
Name [1] 310268 0
National Health and Medical Research Council
Country [1] 310268 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
Camperdown, NSW 2006
Country
Australia
Secondary sponsor category [1] 311371 0
None
Name [1] 311371 0
Address [1] 311371 0
Country [1] 311371 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309939 0
South Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 309939 0
Locked Bag 7103 Liverpool BC NSW 1871
Ethics committee country [1] 309939 0
Australia
Date submitted for ethics approval [1] 309939 0
23/03/2020
Approval date [1] 309939 0
01/05/2020
Ethics approval number [1] 309939 0

Summary
Brief summary
PET biomarkers (i.e. Aß and tau) are currently used to identify and characterise individuals with pre-clinical and clinical dementia, particularly Alzheimer's disease (AD), for research purposes. Therefore, to get a better understanding of dementia, it is desirable to evaluate separately both the brain distribution of Aß and tau accumulation. The primary aim of this phase II trial is to quantify global and regional Amyloid (Aß) and tau in older adults at various stages of dementia risk. Further, we aim to analyse how PET markers change over time. This will allow for comprehensive clinical characterisation of a sample of older adults at-risk for developing dementia.

This 5-year study will recruit a subsample of participants involved in an ongoing long-term observational study being conducted through the Healthy Brain Ageing clinic, Sydney, Australia. Participants will be enrolled into the study after the informed consent process has been completed and met all inclusion criteria and none of the exclusion criteria. PET scans will be acquired at the imaging facility according to sites where PET tracers will be available (i.e. Macquarie University, Liverpool Hospital, Royal North Shore Hospital and North Shore Private Hospital). Depending on funding, tracer availability, and participant willingness, they may be offered follow-up scans every two years for the duration of the study, leading to a maximum of three scanning sessions over five years (Year 1, Year 3, Year 5).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 115914 0
Prof Sharon Naismith
Address 115914 0
Level 2 Building G, Brain & Mind Centre, 100 Mallet Street, Camperdown NSW 2050
Country 115914 0
Australia
Phone 115914 0
+61 02 9351 0781
Fax 115914 0
Email 115914 0
sharon.naismith@sydney.edu.au
Contact person for public queries
Name 115915 0
Dr Johannes Michaelian
Address 115915 0
Level 2, Charles Perkins Centre, Johns Hopkins Drive, Camperdown NSW 2050
Country 115915 0
Australia
Phone 115915 0
+61 02 9351 0621
Fax 115915 0
Email 115915 0
johannes.michaelian@sydney.edu.au
Contact person for scientific queries
Name 115916 0
Prof Sharon Naismith
Address 115916 0
Level 2 Building G, Brain & Mind Centre, 100 Mallet Street, Camperdown NSW 2050
Country 115916 0
Australia
Phone 115916 0
+61 02 9351 0781
Fax 115916 0
Email 115916 0
sharon.naismith@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results only
When will data be available (start and end dates)?
Available after main trial publication with no end date determined
Available to whom?
Only researchers who provide a methodologically sound proposal
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Professor Sharon Naismith | Co-ordinating Principal Investigator sharon.naismith@sydney.edu.au


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.