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Trial registered on ANZCTR


Registration number
ACTRN12616000679482
Ethics application status
Approved
Date submitted
13/05/2016
Date registered
25/05/2016
Date last updated
30/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of 12-month daily resveratrol supplementation on brain health in post-menopausal women (Supporting healthy ageing in women with resveratrol - RESHAW)
Scientific title
Effect of 12-month daily resveratrol supplementation on brain health in post-menopausal women
Secondary ID [1] 289210 0
None
Universal Trial Number (UTN)
U1111-1182-8860
Trial acronym
RESHAW Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Menopause 298767 0
Condition category
Condition code
Alternative and Complementary Medicine 298816 298816 0 0
Other alternative and complementary medicine
Neurological 298817 298817 0 0
Dementias
Musculoskeletal 298820 298820 0 0
Osteoporosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A 12 month randomised, double-blind, placebo-controlled, crossover dietary intervention trial. The active group will receive a 150mg dose of eveResveratrol Trademark (taken as two 75mg capsules) per day. The control group will receive a placebo. At the end of visit 5, at 12 months, participants will crossover to the alternate treatment arm for another 12 months. There is no washout period between treatments. At each visit following the dispensing of the supplement, participants will return their supplement bottle and supplement diary to check compliance.
Intervention code [1] 294746 0
Treatment: Other
Comparator / control treatment
Placebo (an inert filler consisting of calcium hydrogen phosphate, microcrystalline cellulose, prosolv 50 and hydrated magnesium silicate)
Mode - taken orally with water
Control group
Placebo

Outcomes
Primary outcome [1] 298287 0
Overall performance of a neuropsychological test battery following resveratrol supplementation: The neuropsychological test battery will consist of Rey Auditory Verbal Learning Test (verbal memory), the Trail Making Task (measure of attentional and executive functions, which becomes impaired with age), the N-back task and the NIH Toolbox Battery of cognitive function.
Timepoint [1] 298287 0
12 months and 24 months (due to crossover, half the participants will have completed resveratrol supplementation at 12 months and the other half at 24 months)
Secondary outcome [1] 323753 0
Composite Secondary Outcome: Clinic Systolic blood pressure (SBP), Diastolic blood pressure (DBP) and heart rate (HR), assessed using sphygmomanometry. Large and small artery elasticity indices, assessed using a Cardiovascular Profiler.
Timepoint [1] 323753 0
0, 6, 12, 18 and 24 months
Secondary outcome [2] 323754 0
Composite secondary outcome: basal cerebral blood flow velocities, pulsatility and resistive indexes in the anterior and posterior cerebral circulation, assessed using transcranial doppler (TCD) ultrasound.
Timepoint [2] 323754 0
0, 6, 12, 18 and 24 months
Secondary outcome [3] 323755 0
CVR to hypercapnia at the level of the middle cerebral artery (MCA; anterior circulation), assessed using TCD ultrasound.
Timepoint [3] 323755 0
0, 6, 12, 18 and 24 months
Secondary outcome [4] 323756 0
CVR to photic stimulation (neurovascular coupling) at the level of the posterior cerebral artery (PCA; posterior circulation), assessed using TCD ultrasound.
Timepoint [4] 323756 0
0, 6, 12, 18 and 24 months
Secondary outcome [5] 323757 0
blood flow velocity changes in cerebral vessels in response to a neuropsychological test battery (CVR to neuropsychological tests), assessed using TCD ultrasound.
Timepoint [5] 323757 0
0, 12 and 24 months. TCD ultrasound measurement is performed immediately prior to and during the whole of each neuropsychological test.
Secondary outcome [6] 323758 0
Global cognition (using Addenbrooke’s Cognitive Examination 2012 version 3, ACE-III)
Timepoint [6] 323758 0
0, 12 and 24 months
Secondary outcome [7] 323759 0
Composite outcome: Performance on domain-specific cognitive tests. The neuropsychological test battery will consist of Rey Auditory Verbal Learning Test, the Trail Making Task, the N-back task and the NIH Toolbox Battery of cognitive function, consisting of the Picture Vocabulary Test, Flanker Inhibitory Control and Attention Test, List Sorting Working Memory Test, Dimensional Change Card Sort Test, Pattern Comparison Processing Speed Test and the Picture Sequence Memory Test.
Timepoint [7] 323759 0
0, 12 and 24 months
Secondary outcome [8] 323760 0
Bone mineral density (overall and region specific), assessed using Dual Energy X-Ray Absorbtomitory (DEXA) scanning.
Timepoint [8] 323760 0
0, 12 and 24 months
Secondary outcome [9] 323761 0
Adiposity (fat mass versus fat free mass and body mass index), assessed using Dual Energy X-Ray Absorbtomitory (DEXA) scanning.
Timepoint [9] 323761 0
0, 12 and 24 months
Secondary outcome [10] 323764 0
Composite secondary outcome: Physical function will be assessed using the NIH Toolbox Motor Assessment (balance, assessed using an accelerometer; grip strength, assessed using a hand dynamometer; fine motor dexterity, assessed using a 9-hole Pegboard; gait speed , assessed using a stopwatch; and aerobic endurance, assessed by distance walked in 2 minutes).
Timepoint [10] 323764 0
0, 6, 12, 18 and 24 months
Secondary outcome [11] 323882 0
Questionnaire: Mood and depressive symptoms. Profile of Mood States (POMS) Questionnaire and the Center for Epidemiological Studies Depression Scale (CES-D).
Timepoint [11] 323882 0
0, 12, and 24 months
Secondary outcome [12] 323883 0
Questionnaire: Sleep quality (Pittsburgh Sleep Quality Index Questionnaire)
Timepoint [12] 323883 0
0, 12 and 24 months
Secondary outcome [13] 323884 0
Questionnaire: Pain (McGill Pain Questionnaire).
Timepoint [13] 323884 0
0, 12 and 24 months
Secondary outcome [14] 323885 0
Questionnaire: Menopausal symptoms (Menopause Rating Scale).
Timepoint [14] 323885 0
0, 12 and 24 months
Secondary outcome [15] 323886 0
Questionnaire: Quality of Life (using the SF-36).
Timepoint [15] 323886 0
0, 12 and 24 months
Secondary outcome [16] 323887 0
Composite secondary outcome: Fasting glucose, insulin and HbA1C; Assessed by serum assay which will be outsourced to commercial pathology laboratories for analysis.
Timepoint [16] 323887 0
0, 12 and 24 months
Secondary outcome [17] 323888 0
Fasting lipids: Assessed by serum assay which will be outsourced to commercial pathology laboratories for analysis.
Timepoint [17] 323888 0
0, 12 and 24 months
Secondary outcome [18] 323889 0
Nitric oxide metabolites: Assessed by serum assay which will be done on campus
Timepoint [18] 323889 0
0, 12 and 24 months
Secondary outcome [19] 323890 0
Bone formation biomarker (Osteocalcin, alkaline phosphatase): Assessed by serum assay which will be outsourced to commercial pathology laboratories for analysis.
Timepoint [19] 323890 0
0, 12 and 24 months
Secondary outcome [20] 323891 0
Plasma resveratrol concentrations will be measured on campus - Total trans-resveratrol (sum of aglycone and conjugates) will be measured in plasma derived from venous blood samples obtained at baseline and at the end of each treatment arm. Labelled internal standard will be added to an aliquot of plasma and a ß-glucuronidase digestion will be performed before the liquid-liquid extraction. After centrifugation an aliquot of the organic phase will be evaporated to dryness, re-dissolved in injection solvent and then analyse on LC-MS/MS system on a C18 column.
Timepoint [20] 323891 0
0, 12 and 24 months
Secondary outcome [21] 323892 0
Composite secondary outcome: Follicle stimulating hormone and estradiol levels: Assessed by serum assay which will be outsourced to commercial pathology laboratories for analysis.
Timepoint [21] 323892 0
0, 12 and 24 months
Secondary outcome [22] 323893 0
Markers of inflammation (hs-CRP, cytokines): Assessed by serum assay which will be outsourced to commercial pathology laboratories for analysis.
Timepoint [22] 323893 0
0, 12 and 24 months

Eligibility
Key inclusion criteria
Women aged 45-85 years old. Post-menopausal (cessation of menses for > 12 months), with no change in medication type or dose for 3 months before the intervention.
Minimum age
45 Years
Maximum age
85 Years
Gender
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Consuming HRT or seeking alternative therapy for the relief of postmenopausal symptoms (within the past three months).
Pregnant or breastfeeding.
Clinic BP >160mmHg systolic or 100mmHg diastolic (determined at screening).
BMI>40kg/m2 (determined at screening).
Dementia.
History of breast or cervical cancer, mastectomy or hysterectomy (not due to prolapse).
Smokers or currently on nicotine therapy.
Neurological conditions.
Kidney/liver disease.
Insulin therapy.
Warfarin therapy.
Regularly consuming more than four standard alcoholic drinks per day.
Major depression as diagnosed by a health care professional.
Illiterate.
Physical difficulty that will impede motor and locomotive performance.
Unable to walk without assistance from people (walking aids okay).
Unwilling to maintain pre-enrolment physical activity levels and dietary habits for the duration of the trial.
Unwilling to refrain from consuming stimulants before each clinic visit.
Currently consuming resveratrol containing supplements.
Have any other medical condition or treatments (including supplements) which, in the investigators’ opinion, may confound the outcome of the study.

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 concealment by numbered containers.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Allocation to either treatment phase is based on the minimisation method (years since onset of menopause and BMI) to ensure well-balanced groups (Altman & Bland, BMJ 2005;330;843).
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
Crossover
Other design features
This is a randomised, double-blind, placebo-controlled, crossover dietary intervention trial.
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Baseline data:
Baseline measures of age, years since onset of menopause, menopausal symptoms, hormone levels, BMI, years of education and scores on the ACE-III and other potentially confounding variables may be added as covariates if they are significantly correlated with the outcome measures.
Pre-supplementation data obtained at the screening/baseline visit 1 and 2 will be used in regression analysis to evaluate the associations between outcome measures. The correlations may include the relationships between cerebrovascular function (arterial stiffness, basal hemodynamics and CVR to hypercapnia, cognitive and photic stimuli) and cognitive performance, clinic BP and AC, 24-ABP, adiposity, physical function, mood, menopausal symptoms, pain, overall wellbeing, cardiometabolic biomarkers, hormonal and plasma resveratrol levels.
Treatment effects:
The primary outcome will be the intra-individual effect of treatment on cognitive performance (sum of Z-scores from all cognitive tests), analysed by ANCOVA (generalized linear model, linear regression with main predictor treatment, and baseline, order of treatment and time since onset of menopause, hormonal levels as covariates, and other covariates as appropriate). False discovery rate estimations will be made to determine the significance of the following secondary outcomes: effect of treatment on CVR to hypercapnia, cognitive and photic stimuli, basal cerebral hemodynamics, performance on individual cognitive tests, bone mineral density, adiposity, clinic BP and AC, 24-ABP, physical function assessments, mood, assessments of menopausal symptoms, pain, quality of life and sleep quality, cardiovascular biomarkers, hormonal and plasma resveratrol levels. The efficacy of resveratrol supplementation on outcome measures will also analysed by ANCOVA in early (<10 years since onset of menopause) and late postmenopausal women.
Changes in cerebrovascular function will be correlated with changes in cognitive and physical functions, mood states, quality of life, menopausal symptoms, sleep quality and pain reduction. Relationships between changes in circulatory and cognitive, anthropometric and mood parameters will be analysed by linear regression with false discovery rate estimations.
Subject Population(s) for Analysis:
Data collected from participants who completed all study time points will be used for per-protocol analysis. An interim analysis using ANCOVA will be performed at the end of the first stage of the crossover (after 12 months) to determine the within-individual treatment changes (post-pre supplementation) between the placebo and resveratrol arm.
Two of the major challenges to any long-term study are the recruitment and retention of eligible volunteers for the duration of the study. A 12-month crossover dietary intervention in overweight adults to assess the effects of a high diary intake had a 49% attrition rate. In our pilot study (H-2015-0002), we failed to detect an acoustic temporal window for TCD assessments in 32% of our cohort. Taken together, we will recruit 170 postmenopausal women for this study. This will provide 80% power at alpha = 0.05, based on the effect size differences of 0.43 to 0.44 in the cognitive and cerebrovascular function outcomes in our pilot study.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 13238 0
2308 - Newcastle University

Funding & Sponsors
Funding source category [1] 293591 0
Government body
Name [1] 293591 0
NHMRC-ARC Dementia Research Fellowship 2016
Address [1] 293591 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 293591 0
Australia
Primary sponsor type
University
Name
University of Newcastle
Address
Clinical Nutrition Research Centre MS514
University of Newcastle
University Drive
Callaghan NSW 2308
Country
Australia
Secondary sponsor category [1] 292407 0
Commercial sector/Industry
Name [1] 292407 0
Evolva SA
Address [1] 292407 0
Evolva SA
Duggingerstrasse 23, CH-4153
Reinach, Switzerland
Country [1] 292407 0
Switzerland
Other collaborator category [1] 279007 0
Individual
Name [1] 279007 0
Peter Howe
Address [1] 279007 0
University of Newcastle
School of Biomedical Sciences & Pharmacy
Callaghan, NSW 2308
Country [1] 279007 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295032 0
University of Newcastle Human Research Ethics Committee
Ethics committee address [1] 295032 0
Chancellery
University of Newcastle
University Drive
Callaghan NSW 2308
Ethics committee country [1] 295032 0
Australia
Date submitted for ethics approval [1] 295032 0
31/03/2016
Approval date [1] 295032 0
04/07/2016
Ethics approval number [1] 295032 0
H2016-0019

Summary
Brief summary
The decline in estrogen production at menopause heightens a woman’s risk of osteoporosis, heart disease, hypertension, stroke and dementia. We have now identified postmenopausal women as another vulnerable population at risk of dementia who may also benefit from resveratrol supplementation – a strategy that can be easily incorporated into the daily diet. We aim to gather evidence for the efficacy of vasoactive nutrients in maintaining optimal circulatory function to reduce the risk of developing dementia. Given that resveratrol supplements are available over-the-counter to consumers in Australia, the anticipated outcomes will offer a non-pharmaceutical approach for managing menopause-related symptoms and counteracting accelerated cognitive and physical decline and loss of bone mineral density in women post-menopausally, which can be readily implemented by clinicians and the public.
We will recruit 170 post-menopausal women aged between 45 and 85 years old. A 24 month randomised, double-blind, placebo-controlled, crossover dietary intervention trial will be conducted at the University of Newcastle. A crossover intervention means that all participants will receive the resveratrol treatment.
The primary objective of the study is to determine in postmenopausal women the ability of resveratrol supplementation for 12 months to improve cognitive function.
The secondary objectives are:
To determine whether improvements in cognition, mood, overall well-being (sleep quality, menopausal symptoms and pain) and physical function are accompanied by improvements in cerebrovascular responsiveness to cognitive demands, photic stimulation and/or to hypercapnia.
To determine whether resveratrol supplementation can attenuate global cognitive decline.
To determine whether resveratrol supplementation can change body bone mineral density and body composition.
To determine the effects of resveratrol supplementation on clinic blood pressure and arterial compliance.
To determine whether the improvements in the outcomes are related to changes in biomarkers of cardiovascular and bone health, hormone levels and plasma resveratrol concentration.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 65842 0
Dr Rachel Wong
Address 65842 0
Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
University of Newcastle,
University Drive
Callaghan NSW 2308
Country 65842 0
Australia
Phone 65842 0
+61 2 4921 6408
Fax 65842 0
Email 65842 0
rachel.wong@newcastle.edu.au
Contact person for public queries
Name 65843 0
Prof Peter Howe
Address 65843 0
Clinical Nutrition Research Centre
School of Biomedical Sciences and Pharmacy
University of Newcastle, University Drive
Callaghan, NSW 2308
Country 65843 0
Australia
Phone 65843 0
+61 2 49217309
Fax 65843 0
Email 65843 0
peter.howe@newcastle.edu.au
Contact person for scientific queries
Name 65844 0
Dr Rachel Wong
Address 65844 0
Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
University of Newcastle,
University Drive
Callaghan NSW 2308
Country 65844 0
Australia
Phone 65844 0
+61 2 4921 6408
Fax 65844 0
Email 65844 0
rachel.wong@newcastle.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary