Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000065796
Ethics application status
Approved
Date submitted
18/11/2021
Date registered
20/01/2022
Date last updated
3/04/2024
Date data sharing statement initially provided
20/01/2022
Date results information initially provided
3/04/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Food for Thought: Assessing the effect of diet and dietary advice on cognitive function in older people at risk
Scientific title
Food for Thought: Assessing the effect of diet and dietary advice on cognitive function in older people at risk
Secondary ID [1] 305827 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cognitive impairment

 324350 0
Condition category
Condition code
Neurological 321833 321833 0 0
Neurodegenerative diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
(1) High anthocyanin diet ('purple diet') for 6 months; or
(2) Freeze dried product derived from blackcurrants for 6 months; or

To minimise potential barriers to participation and to maximise participant retention in the study, we sought the feedback of a consumer advisory group which comprised one older male carer of a person with dementia, a female hospital dietitian who mainly supported older patients and who had an interest in dementia risk reduction, and a female PhD student who cared for an elderly parent with MCI. The group reviewed the entire protocol as part of a 2 hour online discussion group, and provided valuable advice to enhance planned recruitment strategies, to promote perceived benefits to participants and to enhance support especially for those involved in the ‘purple diet’ arm.

Intervention arm 1 will receive intensive dietary counselling by nutrition professionals to consume a “purple diet” that includes foods that are rich in anthocyanin content that are convenient, tasty, and affordable - to provide daily intakes of ~250mg of anthocyanins per day. Dietary advice will consist of face-to-face counselling at the baseline and 3-month visits, as well as follow-up phone calls and emails to participants during the 6 months of intervention. At baseline, participants will receive the ‘Purple Food Guide’ a supermarket friendly guide, as well as the ‘Purple Food for Thought’ cookbook to support their consumption of readily available anthocyanin rich foods. Participants will be asked to consume a minimum of 2 servings of ‘low anthocyanins’ foods or 1 serving of a ‘high anthocyanins’ food daily, either from the recipes provided or from lists of ‘low’ (<100mg/100g serve) and ‘high’ (=100mg/100g serve) anthocyanin foods. Serves are derived from the portion size guide in the Australian Guide to Healthy Eating. Seasonal anthocyanin-rich fresh produce will be discussed during phone calls and with hand-outs throughout the duration of the trial. The individual phone calls scripts will be developed by dietitians and administered by the researchers. If requested or necessary, participants may be referred to one of the dietitians in the research team for the individual phone consultations. During individual phone calls, participants will be encouraged to ask any questions about the material and information provided. Additional material will be sent to participants in follow-up emails, such as seasonal recipes and food purchasing tips. Suggestions from the consumer advisory group included: exploring options to lower costs and promote access to low-cost purple foods/ingredients; promoting opportunities for support to improve cooking and preparation skills and motivation; and also exploring options within the study to support social connections between participants . These suggestions were incorporated into the final participant resources and an AU$100 gift voucher was provided to participants in this arm to assist with food-related costs.

Intervention arm 2 will receive 6 g of freeze-dried product derived from New Zealand grown blackcurrants (Neuroberries™; Arepa Pty Ltd., Auckland, providing ~250 mg anthocyanins/day, comprising approximately equal quantities of delphinidin and cyanidin subclasses). We have conducted preliminary investigations to evaluate the acceptance of this product among older adult consumers. This product can be consumed in various ways, including as a beverage added to water or in other foods, such as smoothies and yoghurt. Participants in this intervention arm will be guided to maintain their usual diet throughout the study.
Intervention code [1] 322234 0
Treatment: Other
Comparator / control treatment
Control: Equating the sensory characteristics of a control substance for a food-based intervention can be challenging. We will provide a freeze-dried product with similar colour, taste and texture, and with identical packaging. The control product will be matched in macronutrients and vitamin C with the freeze-dried product from Intervention arm 1. Participants in the control group will be guided to maintain their usual diet throughout the study. To monitor compliance, participants will be required to measure out remaining powder and document this (intervention arm 1 and control)
Control group
Placebo

Outcomes
Primary outcome [1] 329611 0
Cognitive function (Composite primary outcome)

• Buschke and Grober Free and Cued Selective Reminding Test-Immediate Recall (FCSRT+IR) (auditory anterograde memory functioning).
o Participants are presented with the same set of 16 pictures, a number of times and after each presentation are asked to recall the items. During each presentation, the items are presented 4 at a time and participants are asked to identify the item that belongs to a category (e.g. animal, item f clothing) so that the category name will act as a cue during retrieval. At recall they are asked to recall the items without any prompting and then with the category as a cue.

• Spot the Word-2 (premorbid estimate)
o Allows to assess premorbid verbal abilities, using a robust lexical decision task.
o The test involves presenting an individual with pairs of items comprising one word and one non-word, for example, ‘flonty – xylophone’, the individual is required to point to the real word in the pair.
o This format allows lexical decisions to be made through multiple methods including; meaning, familiarity, appearance and sound of words.

• Oral Symbol Digit Test (speed of processing)
o A coding key with nine abstract symbols is presented - each paired with a number between 1 and 9. Participants are asked to orally indicate which numbers go with symbols that are presented in a long string on the computer screen. The participant is given 120 seconds to call out as many numbers that go with the corresponding symbols as he/she can – in order, without skipping any. This test is administered to ages 8-85 and takes approximately three minutes. The task measures speed of processing, which is a fundamental determinant of performance on many cognitive tasks.

• List Sorting (working memory)
o Requires to sort and sequence information. Participants are presented with a series of stimuli (i.e., illustrated pictures of an animal or a piece of food), each of which is both visually and auditorily presented by computer. A picture of each stimulus is displayed on the computer monitor for 2 s while the name of the stimulus is simultaneously being read via a computerized voice; stimuli are presented one after another, in a seamless manner. The examinee is required to remember each stimulus in a series, mentally re-order them from smallest to largest, and recite the names of the stimuli in this order. If the participant is unable to sequence the string correctly, they are provided with a second trial of the same number of items in the string; the task is discontinued when the participant provides incorrect responses on two trials with the same number of items in the string or when the participant correctly sequences all seven items. List Sorting scores are based upon a sum of the total correct across two lists, which comprise the List Sorting “Total Score.” The raw sum score is then transformed to a standardized t-metric (mean = 50, 50 and SD = 10). The test measures working memory which is correlated with performance on many cognitive tasks.

• Trail Making Test A & B (speed of processing/executive)
o Both parts of the Trail Making Test consist of 25 circles distributed over a sheet of paper. In Part A, the circles are numbered 1 – 25, and the patient should draw lines to connect the numbers in ascending order. In Part B, the circles include both numbers (1 – 13) and letters (A – L); as in Part A, the patient draws lines to connect the circles in an ascending pattern, but with the added task of alternating between the numbers and letters (i.e., 1-A-2-B-3-C, etc.). The patient should be instructed to connect the circles as quickly as possible, without lifting the pen or pencil from the paper. Time the patient as he or she connects the "trail." If the patient makes an error, point it out immediately and allow the patient to correct it. Errors affect the patient's score only in that the correction of errors is included in the completion time for the task. It is unnecessary to continue the test if the patient has not completed both parts after five minutes have elapsed. The difference in time taken between Parts A and B is taken as a measure of executive control, particularly attentional task switching ability.

• Verbal Fluency (language/semantic memory)
o Application: This task is a sensitive measure of executive dysfunction and control processes. The task requires the participant to produce as many words starting with a particular letter or category as possible in one minute.
o Scoring: This task assigns each word that is produced a score of 1. This score is added, where a higher score indicates high executive function.

• MAC-Q.
o This questionnaire was devised to assess age-related memory decline. It is composed of six questions related to memory functioning in everyday situations (e.g., to remember a telephone number that he/she uses at least once a week) in which the subject is asked to compare and rate his/her current ability to when he/she was 40 years old. The total score on the MAC-Q ranges from 7 to 35, where greater scores indicate subjective memory loss. Scores greater than or equal to 25 have been found to be suggestive of age-associated memory impairment.
Timepoint [1] 329611 0
3 and 6 months after commencement of intervention
Secondary outcome [1] 403159 0
Mood

• Geriatric Depression Scale (GDS)
o The GDS Long Form is a brief, 30-item questionnaire in which participants are asked to respond by answering yes or no to items related to their feelings over the past week. A Short Form GDS consisting of 15 questions was developed in 1986. Questions from the Long Form GDS, which had the highest correlation with depressive symptoms in validation studies were selected for the short version. Of the 15 items, 10 indicated the presence of depression when answered positively, while the rest (question numbers 1, 5, 7, 11, 13) indicated depression when answered negatively. Scores of 0-4 are considered normal, depending on age, education, and complaints; 5-8 indicate mild depression; 9-11 indicate moderate depression; and 12-15 indicate severe depression. The Short Form is more easily used by physically ill and mildly to moderately demented patients who have short attention spans and/or feel easily fatigued. It takes about 5 to 7 minutes to complete.
Timepoint [1] 403159 0
3 and 6 months after commencement of intervention
Secondary outcome [2] 403163 0
Blood pressure

BP will be measured while fasting using a Welch Allyn Connex 6700 Vital Signs Monitors (Welch Allyn, NSW, Australia). Participants will be rested in supine position for 5 minutes, in a quiet room with a correctly fitting arm cuff. BP was measured on both arms, and a repeat measure taken on the arm with the higher reading, with the average of the two readings recorded.
Timepoint [2] 403163 0
3 and 6 months after commencement of intervention
Secondary outcome [3] 403164 0
Gut microbiota

Faecal samples will be collected at baseline and 12 weeks using commercial sampling kits (Microba, QLD) that use a proprietary method that preserves DNA within the microbial sample without cold storage. The company will provide DNA extraction, library preparation and shotgun metagenomic sequencing of samples. Downstream profiling and bioinformatic analysis will be performed at the Microbiome Research Centre, UNSW by bioinformatician, Dr Jiang. Raw shotgun metagenomics sequences will be processed by fastp with default parameters to remove or trim the low-quality reads. Host contamination will be removed by mapping reads against the human reference genome with minimap2. Taxonomic profiles will be generated with StrianPhlan by mapping reads against clade-specific marker genes. Functional pathways and metabolic potential will be analyzed with HUMAnN2.
Timepoint [3] 403164 0
3 months after commencement of the intervention
Secondary outcome [4] 403165 0
Inflammatory biomarkers

Plasma levels of pro-inflammatory cytokines related to dementia pathology (tumour necrosis factor-alpha (TNF-a), interleukin-1 and -6 (IL-1, IL-6), circulating levels of butyrate (produced by microbiota) and BDNF, as well as vascular markers of endothelial function including C-Reactive Protein (CRP), vascular cell adhesion molecule 1 (VCAM-1) and E-Selectin, as well as full fatty acid profile and ApoE (Cardinal Laboratories, Queensland).
Timepoint [4] 403165 0
3 and 6 months after commencement of the intervention
Secondary outcome [5] 403166 0
Vascular endothelial function

Endothelial function will be evaluated by ultrasound measures of flow-mediated endothelium-dependent vasodilation (FMD) of the brachial artery, using high-resolution ultrasound. Reactive hyperaemia will be induced by inflating a BP cuff on the forearm to >60 mmHg systolic pressure for 5 min. The diameter of the brachial artery and blood flow velocity will be assessed continuously before and 3 min following cuff deflation.
Timepoint [5] 403166 0
3 and 6 months after commencement of the intervention
Secondary outcome [6] 404003 0
Microvascular blood flow

Microvascular blood flow will be measured using Laser Speckle Imaging (Pericam, Perimed) with the post-occlusive reactivity hyperaemia conducted in the forearm when a transient increase in cutaneous blood flow occurs following release of a brief occlusion in the brachial artery.
Timepoint [6] 404003 0
3 and 6 months after commencement of the intervention
Secondary outcome [7] 404004 0
Dietary Intake

Participants will be using a computer-based app that will collect their 24hr recall dietary intake across three different days at each data collection point. This will be requested to be completed before the sessions, during the study and at the end of the study. A researcher will assist the participants on how to use this online dietary assessment instrument.
Timepoint [7] 404004 0
3 and 6 months after commencement of intervention

Eligibility
Key inclusion criteria
1) a) Diagnosis of amnestic MCI (single or multidomain) by a geriatrician, neuropsychiatrist or neuropsychologist; b) or be deemed as eligible by achieving a score equivalent to MCI status following completion of the Montreal Cognitive Assessment (T-MoCa) screening test administered via a validated telephone interview tool. A person scoring 13 or less on the Memory Index Score (MIS) within the T-MoCA will be considered to the study.
2) Self-reported subjective memory complaints
3) English-speaking;
4) Aged 60 - 85 y;
5) Able to complete all or all but one of the following basic activities of daily living (unless for physical reason, e.g. arthritis, poor vision): ‘Do you need help to manage everyday activities such as: Personal hygiene?; Dressing?; Taking medication?; Shopping and preparing food?; Transport?; Telephoning?; Finances?; Housekeeping?
Minimum age
60 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

1) Non-English speaking;
2) History of psychiatric (other than mood) disorder in the past 5 y;
3) Underlying additional neurodegenerative condition such as Parkinson’s disease;
4) Other significant neurological history including head injury, epilepsy, or tumour.
5) Taking any of the following medications: donepezil, galantamine, rivastigmine or memantine
6) Scoring 11 or less at the overall T-MoCA or have been diagnosed with Alzheimer’s disease or any other dementia

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation of participants will be conducted using central randomisation by computer by a researcher not involved in recruitment of participants, in order to implement a randomization sequence in a way that conceals the treatments until patients have been formally assigned to their groups.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation of participants will be conducted by an independent biostatistician using a randomisation table created by computer software.
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
Treating clinicians and scientific investigators will be blinded to participants’ randomised allocation (intervention arms 1 and 3). After randomisation, the names and details of participants will be provided to the commercial partners, Arepa Ltd, that will send the freeze-dried products directly to home addresses (intervention arms 1 and 3). Participants allocated in purple foods dietary intervention arm cannot be blinded (intervention arm 2).
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Cognitive outcomes, data from the biomarkers and vascular tests will be evaluated using repeated measures ANOVA and/or mixed linear modelling to evaluate changes due to the interventions. Covariates will be included in these analyses as appropriate. Restricted maximum likelihood estimation will be used in the mixed model to incorporate partial datasets when subjects have been lost to follow up or have missing data. Correlation and regression methods will also be used to examine the relationships between measures, particularly between changes in cognitive measures and biomarkers and vascular outcomes. Results of the 24hr dietary recalls will be assessed using FoodWorks Professional (version 9, 2018 Xyris Software (Australia) Pty Ltd) and PhenolExplorer flavonoid food composition database. For microbiota analyses, Dr Jiang will use univariate Kruskal–Wallis non-parametric testing, as well as multivariate PERMANOVA to analyse difference of alpha diversity, microbial taxa, function, metabolites, and metadata before and after the diet intervention. In all cases, significance will be considered as a P-value < 0.05.

Power Calculation
GPower was used to calculate power for the critical interaction between group and time according to our previous studies in which the primary outcome measure was the the Rey Auditory Verbal Learning Test (RAVLT). Our previous studies have demonstrated a strong effect of anthocyanin treatment on this measure in groups with memory impairment. Power is set conservatively (0.95) to detect a small to medium effect (f =.15) on this measure, requiring 96 participants (32 participants per experimental condition). To account for a large drop-out rate in this patient group, 50 participants will be recruited per arm. We estimate 5-10 eligible patients to be recruited at each of the clinical sites monthly.

Primary analyses will be conducted based on the intention-to-treat principle. Secondary analyses will be conducted including participants with a minimum compliance of interventions as following: minimum daily consumption of 75mg of anthocyanins for participants allocated to arm 1 (based on the intake24 reports); minimum intake of 800g (out of 1,008g, >80%) across the 6 months of intervention for participants allocated to arms 2 and 3. Compliance will be measured by asking participants to return the powder containers/packages. Participants will be excluded of secondary analyses if discontinues the intervention for a period longer than 14 days (all arms).

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
2/09/2022
Actual
6/02/2024
Date of last participant enrolment
Anticipated
8/09/2023
Actual
6/02/2024
Date of last data collection
Anticipated
6/08/2024
Actual
Sample size
Target
150
Accrual to date
Final
114
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 35986 0
1466 - Unsw Sydney
Recruitment postcode(s) [2] 35985 0
2500 - Wollongong

Funding & Sponsors
Funding source category [1] 310176 0
Other Collaborative groups
Name [1] 310176 0
Dementia Centre for Research Collaboration
Country [1] 310176 0
Australia
Primary sponsor type
University
Name
University of Wollongong
Address
Northfields Ave, Wollongong NSW 2522
Country
Australia
Secondary sponsor category [1] 311262 0
University
Name [1] 311262 0
University of New South Wales
Address [1] 311262 0
UNSW Sydney High St Kensington, NSW 2052
Country [1] 311262 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309863 0
Joint University of Wollongong and Illawarra Shoalhaven Local Health District Health and Medical Human Research Ethics Committee
Ethics committee address [1] 309863 0
Research Services Office
Level 1, Building 20
Northfields Avenue
Wollongong NSW 2522
Ethics committee country [1] 309863 0
Australia
Date submitted for ethics approval [1] 309863 0
11/11/2021
Approval date [1] 309863 0
01/02/2022
Ethics approval number [1] 309863 0

Summary
Brief summary
We propose a world-first dietary intervention clinical trial to investigate whether anthocyanins can sustainably delay or prevent memory loss progression in people at high risk for dementia. Anthocyanins (which provide deep-red and purple-blue pigmentation in plants and fruits) show promise for their pro-cognitive effects and therapeutic potential for diseases that manifest cognitive impairment. Our clinical trials have already demonstrated that consumption of anthocyanin-rich fruit significantly improves both short- and long-term memory, and verbal fluency in older adults with mild to moderate Alzheimer’s dementia (AD) and mixed dementia. However, it is unknown whether anthocyanins can prevent the progression of cognitive decline in persons with mild cognitive impairment. The findings of this study will be critical to underpin dietary advice that better informs prevention of dementia in Australia and allow translation to dietary advice on plant-based foods for better brain health
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 115650 0
Prof Karen Charlton
Address 115650 0
Northfields Ave, University of Wollongong NSW 2522
Building 41 Room 315.
Country 115650 0
Australia
Phone 115650 0
+61 2 4221 4754
Fax 115650 0
Email 115650 0
karenc@uow.edu.au
Contact person for public queries
Name 115651 0
Dr Vinicius do Rosario
Address 115651 0
Northfields Ave, University of Wollongong NSW 2522
Building 41
Country 115651 0
Australia
Phone 115651 0
+61 2 0414054123
Fax 115651 0
Email 115651 0
vinicius@uow.edu.au
Contact person for scientific queries
Name 115652 0
Dr Vinicius do Rosario
Address 115652 0
Northfields Ave, University of Wollongong NSW 2522
Building 41
Country 115652 0
Australia
Phone 115652 0
+61 2 0414054123
Fax 115652 0
Email 115652 0
vinicius@uow.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?
De-identified data of all outcomes
When will data be available (start and end dates)?
Immediately following publication, no end date
Available to whom?
Journal reviewers and other researchers, or other in a case-by-case basis
Available for what types of analyses?
Any purpose in a case-by-case basis
How or where can data be obtained?
Contacting the principal researcher (karenc@uow.edu.au) or corresponding author from publications


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
14150Study protocol  vinicius@uow.edu.au or karenc@uow.edu.au
14151Ethical approval  vinicius@uow.edu.au or karenc@uow.edu.au



Results publications and other study-related documents

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