Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000121864
Ethics application status
Approved
Date submitted
30/10/2020
Date registered
8/02/2021
Date last updated
20/09/2022
Date data sharing statement initially provided
8/02/2021
Date results information initially provided
20/09/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Action To promote brain HEalth iN Adults (ATHENA) trial: a pilot feasibility study to determine the effects of blood pressure lowering treatment provided by a Triple Pill strategy for attenuation of cognitive decline in participants at risk for dementia.
Scientific title
An investigator initiated and conducted study to determine the feasibility of online and telephone recruitment, videoconference-delivered neuropsychological assessments, and mailed trial medication and self-monitored blood pressure (BP) measures for a double-blinded, placebo-controlled, randomised controlled trial to determine the effects of BP lowering provided by a fixed low-dose combination antihypertensive pill strategy on top of standard of care, on cognitive decline in participants at risk for dementia (ATHENA Pilot).
Secondary ID [1] 301625 0
Nil Known
Universal Trial Number (UTN)
U1111-1258-7022
Trial acronym
ATHENA Pilot
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cognitive Dysfunction 318021 0
Cognitive Impairment 318022 0
Cognitive Decline 319909 0
Hypertension 319910 0
Condition category
Condition code
Cardiovascular 316046 316046 0 0
Hypertension
Neurological 316047 316047 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Triple Pill (active treatment) - telmisartan 20mg, amlodipine 2.5mg and indapamide 1.25mg: taken orally once daily for 4 weeks.

Medication adherence: At the end of study,
returned capsules will be counted and recorded by the study team. Additionally, participants will be provided with contact details of the responsible researcher so that they can make contact if for any reason they are unable to continue their study medication or have missed multiple doses and are unsure whether to continue.
Standard of care for participants is monotherapy with any blood pressure lowering medication and GP management.

Screening will involve the following:

Initial Online assessment: estimated 30 minutes
Telephone assessment: (Screening) estimated 40 minutes
First videoconference-(Consent and eligibility) estimated 40 minutes
Second videoconference: (Cognitive testing) estimated 90 minutes
At this point if the participant is eligible they will be randomised

Intervention code [1] 317927 0
Treatment: Drugs
Comparator / control treatment
Placebo - PROSOLV EASYtab SP (Microcrystalline Cellulose, Colloidal Silicon Dioxide NF/ Silica, Colloidal Anhydrous, Sodium Starch Glycolate and Sodium Stearyl Fumarate)
Control group
Placebo

Outcomes
Primary outcome [1] 325218 0
Feasibility: the percentage of participants randomised from those screened, assessed via the study database.
Timepoint [1] 325218 0
Week 0 - after online screening
week 4
Week 6
Secondary outcome [1] 387235 0
Adherence: the percentage of randomised participants who complete all remote assessments which will be measured by reporting from the study database for all participants at week 1 ,week 4 and week 6
Timepoint [1] 387235 0
Week 1
week 4
week 6
Secondary outcome [2] 387236 0
Tolerability during follow-up at 6 weeks:
a. Adverse events (e.g. headache, syncope/collapse, falls, pedal oedema/ankle
swelling, hyperkalaemia, hypokalaemia, hyponatraemia).
b. Participant withdrawal from treatment

These events would be identified as per the definition of AESI as in the protocol and on review by the study physician. They would be measured by one or more of the below
Participant self reporting
withdrawal from study request
lab results
feedback from the GP



Timepoint [2] 387236 0
week 1
week 4
week 6
Secondary outcome [3] 389394 0
Safety: any serious adverse event (SAE).
These events would be identified as per the protocol and by confirmation of the study physician.
They would be measured by one or more of the below
Participant self reporting
withdrawal from study request
lab results
feedback from the GP
Timepoint [3] 389394 0
week 1
week 4
week 6
Secondary outcome [4] 389395 0
Medication adherence: self-reported and pill count measures
Timepoint [4] 389395 0
4 and 6 weeks post-randomisation
Secondary outcome [5] 391146 0
Tertiary Outcome
Feasibility of videoconference neuropsychological assessments:
The percentage of participants who complete videoconference neuropsychological assessments once testing has begun
Reasons for failure to complete neuropsychological testing will also be collected.
this will be measured by database reporting and participant follow up
Timepoint [5] 391146 0
Screening visit 3,
week 4
Secondary outcome [6] 391148 0
Tertiary Outcome
Completion rates for the CogState brief battery independently online

Regular reporting from Cogstate database
Timepoint [6] 391148 0
Screening Visit 3
Week 4
Secondary outcome [7] 391149 0
Tertiary Outcome
Adherence to appropriate self BP monitoring at home.
database reporting
Timepoint [7] 391149 0
Screening visit 1 - week 6 of the study

Secondary outcome [8] 391151 0
Tertiary Outcome
Effect size change (with 95% confidence interval (CI) on neuropsychological composite score using the Preclinical Alzheimer Cognitive Composite (PACC5).

Database reporting/statistical analysis
Timepoint [8] 391151 0
Screening visit 3
week 4 visit
database reporting/statistical analysis
Secondary outcome [9] 391153 0
Tertiary Outcome

Effect size changes (with 95% CIs) on neuropsychological tests of processing speed, executive functioning and memory pre and post intervention
database reporting /statistical analysis
Timepoint [9] 391153 0
screening visit 3
Week 4
Secondary outcome [10] 391155 0
Tertiary Outcome

Effect size changes (and 95% CIs) on CogState brief battery pre and post intervention

CogState database reporting .statistical analysis
Timepoint [10] 391155 0
screening visit 3
week 4
Secondary outcome [11] 391156 0
Tertiary Outcome

Effect size changes (and 95% CIs) on Depression measures according to Patient health questionnaire (PHQ-9).
Database reporting / statistical analysis
Timepoint [11] 391156 0
Screening visit 3

week 4

Eligibility
Key inclusion criteria
Inclusion Criteria:
• Age 50 to 70 years.
• DSM-V diagnosis of Minor Neurocognitive Disorder:
o modest cognitive decline from a previous level of performance in at least one domain, based on the concerns of the individual, a knowledgeable informant or the clinician; and a decline in neurocognitive performance of >1 standard deviation below appropriate norms on formal testing or equivalent clinical evaluation.
o cognitive deficits are insufficient to interfere with daily activities, but that greater effort, compensatory strategies, or accommodation may be required to maintain independence.
o cognitive deficits do not occur exclusively in the context of a delirium.
o cognitive deficits are not primarily attributable to another mental disorder (for example major depressive disorder and schizophrenia).
• An additional enrichment factor indicating elevated risk for declining cognition, defined as one or more of self-reported: monotherapy treatment of hypertension, diabetes mellitus, elevated low-density lipoprotein cholesterol, obesity, current smoking, or first degree relative with dementia.
• Provision of online, verbal and electronic informed consent.
Minimum age
50 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria:
• Taking an ACE-I that cannot be:
o stopped, or
o switched to open label telmisartan 20-40mg, indapamide 1.25mg or 2.5mg, or amlodipine 2.5-5mg, or
o switched to a beta blocker
• Contraindication to any of the study medications, in the context of BP lowering medication currently prescribed by primary care physicians (e.g. those who are on regular NSAID prescription/consumption).
• Unable to complete the study procedures and/or follow-up.
• Significant abnormal kalaemia and/or natraemia, in the opinion of the responsible physician.
• Stage 3b renal failure (GFR < 45 ml/min/1.73m2).
• Severe liver disease (e.g. acute viral hepatitis, chronic active hepatitis, cirrhosis).
• Severe hepatic impairment (ALT or AST) >3x the upper limit of normal [ULN]).
• Pre-existing dementia, another neurodegenerative disease (e.g. Huntington’s, multiple sclerosis, Parkinson’s disease), cognitive decline due to substance use (measured on the World Health Organisation Alcohol Use Disorders Identification Test (WHO-AUDIT)), severe mental ill-health, or neurological or systemic disorder.
• Montreal Cognitive Assessment (MoCA) score <18.
• History of stroke within the last 6 months and/or history of stroke with any residual deficit.
• History of traumatic brain injury with loss of consciousness within the last 2 years.
• No ongoing serious medical or psychiatric cognition that would prevent full participation.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation via a secure web-based system.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be stratified by sex. , and completed by Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
The current global situation has challenged the undertaking of face-to-face visits for research studies and inevitably limits study recruitment opportunities. Videoconferencing technologies allow the delivery of medical, psychological and psychiatric services remotely. Recent studies have supported the validity and reliability of administering videoconference-based neuropsychological tests in rural and urban settings as an alternative to traditional face-to-face testing.
Diagnostic outcomes between videoconference and traditional face-to-face screenings for neurocognitive disorders are similar, in participants aged 65 to 75 years, and in studies that utilize high speed network connection
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The ATHENA study is a pilot feasibility study that has the purpose of (1) ensuring that the trial is feasible and (2) to gather information on cognitive measures to inform a sample size calculation of a further large-scale study.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
15/03/2021
Actual
17/12/2021
Date of last participant enrolment
Anticipated
Actual
11/03/2022
Date of last data collection
Anticipated
29/11/2021
Actual
25/05/2022
Sample size
Target
200
Accrual to date
Final
6
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 306059 0
Government body
Name [1] 306059 0
National Health and Medical Research Council
Country [1] 306059 0
Australia
Primary sponsor type
Other
Name
The George Institute for Global Health
Address
Level 10, King George V Building, 83-117 Missenden Road, Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 307371 0
None
Name [1] 307371 0
Address [1] 307371 0
Country [1] 307371 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306282 0
Sydney Local Health District Ethics Review Committee (Royal Prince Alfred Hospital (RPAH) Zone) Zone)
Ethics committee address [1] 306282 0
Royal Prince Alfred Hospital, Missenden Road, CAMPERDOWN NSW 2050
Ethics committee country [1] 306282 0
Australia
Date submitted for ethics approval [1] 306282 0
02/10/2020
Approval date [1] 306282 0
30/10/2020
Ethics approval number [1] 306282 0
X20-0284 & 2020/ETH00541

Summary
Brief summary
The Action To promote brain HEalth iN Adults (ATHENA) pilot trial uses an RCT design and involves treatment with a low-dose triple combination pill of BP lowering agents or placebos. ATHENA will evaluate the feasibility, applicability, tolerability, safety and adherence of a risk reduction approach in a high-risk target population, evaluating a BP lowering intervention. In the current study, we will also test the feasibility of recruitment and assessment of a population with higher than average risk of dementia (i.e. DSM-V diagnosis of Minor Neurocognitive Disorder) remotely. The screening will be made through online assessments with subsequent telephone calls to assess eligibility and videoconference neuropsychological assessments.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103358 0
Prof Craig Anderson
Address 103358 0
The George Institute for Global Health, Australia
Level 10 King George V Building, 83-117 Missenden Rd, Camperdown NSW 2050
Country 103358 0
Australia
Phone 103358 0
+61 2 8052 4521
Fax 103358 0
Email 103358 0
[email protected]
Contact person for public queries
Name 103359 0
Miss Rebecca Anderson
Address 103359 0
The George Institute for Global Health, Australia
Level 10 King George V Building, 83-117 Missenden Rd, Camperdown NSW 2050
Country 103359 0
Australia
Phone 103359 0
+61401401440
Fax 103359 0
Email 103359 0
[email protected]
Contact person for scientific queries
Name 103360 0
Prof Craig Anderson
Address 103360 0
The George Institute for Global Health, Australia
Level 10 King George V Building, 83-117 Missenden Rd, Camperdown NSW 2050
Country 103360 0
Australia
Phone 103360 0
+61 2 8052 4521
Fax 103360 0
Email 103360 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No IPD will 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.