ANZCTR - Registration

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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

2/07/2019

Date data sharing statement initially provided

2/07/2019

Date results information initially provided

2/07/2019

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]

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

Condition category

Condition code

Alternative and Complementary Medicine

Other alternative and complementary medicine

Neurological

Dementias

Musculoskeletal

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]

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]

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]

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]

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]

0, 6, 12, 18 and 24 months

Secondary outcome [2]

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]

0, 6, 12, 18 and 24 months

Secondary outcome [3]

CVR to hypercapnia at the level of the middle cerebral artery (MCA; anterior circulation), assessed using TCD ultrasound.

Timepoint [3]

0, 6, 12, 18 and 24 months

Secondary outcome [4]

CVR to photic stimulation (neurovascular coupling) at the level of the posterior cerebral artery (PCA; posterior circulation), assessed using TCD ultrasound.

Timepoint [4]

0, 6, 12, 18 and 24 months

Secondary outcome [5]

blood flow velocity changes in cerebral vessels in response to a neuropsychological test battery (CVR to neuropsychological tests), assessed using TCD ultrasound.

Timepoint [5]

0, 12 and 24 months. TCD ultrasound measurement is performed immediately prior to and during the whole of each neuropsychological test.

Secondary outcome [6]

Global cognition (using Addenbrooke’s Cognitive Examination 2012 version 3, ACE-III)

Timepoint [6]

0, 12 and 24 months

Secondary outcome [7]

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]

0, 12 and 24 months

Secondary outcome [8]

Bone mineral density (overall and region specific), assessed using Dual Energy X-Ray Absorbtomitory (DEXA) scanning.

Timepoint [8]

0, 12 and 24 months

Secondary outcome [9]

Adiposity (fat mass versus fat free mass and body mass index), assessed using Dual Energy X-Ray Absorbtomitory (DEXA) scanning.

Timepoint [9]

0, 12 and 24 months

Secondary outcome [10]

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]

0, 6, 12, 18 and 24 months

Secondary outcome [11]

Questionnaire: Mood and depressive symptoms. Profile of Mood States (POMS) Questionnaire and the Center for Epidemiological Studies Depression Scale (CES-D).

Timepoint [11]

0, 12, and 24 months

Secondary outcome [12]

Questionnaire: Sleep quality (Pittsburgh Sleep Quality Index Questionnaire)

Timepoint [12]

0, 12 and 24 months

Secondary outcome [13]

Questionnaire: Pain (McGill Pain Questionnaire).

Timepoint [13]

0, 12 and 24 months

Secondary outcome [14]

Questionnaire: Menopausal symptoms (Menopause Rating Scale).

Timepoint [14]

0, 12 and 24 months

Secondary outcome [15]

Questionnaire: Quality of Life (using the SF-36).

Timepoint [15]

0, 12 and 24 months

Secondary outcome [16]

Composite secondary outcome: Fasting glucose, insulin and HbA1C; Assessed by serum assay which will be outsourced to commercial pathology laboratories for analysis.

Timepoint [16]

0, 12 and 24 months

Secondary outcome [17]

Fasting lipids: Assessed by serum assay which will be outsourced to commercial pathology laboratories for analysis.

Timepoint [17]

0, 12 and 24 months

Secondary outcome [18]

Nitric oxide metabolites: Assessed by serum assay which will be done on campus

Timepoint [18]

0, 12 and 24 months

Secondary outcome [19]

Bone formation biomarker (Osteocalcin, alkaline phosphatase): Assessed by serum assay which will be outsourced to commercial pathology laboratories for analysis.

Timepoint [19]

0, 12 and 24 months

Secondary outcome [20]

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]

0, 12 and 24 months

Secondary outcome [21]

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]

0, 12 and 24 months

Secondary outcome [22]

Markers of inflammation (hs-CRP, cytokines): Assessed by serum assay which will be outsourced to commercial pathology laboratories for analysis.

Timepoint [22]

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

Sex

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

Completed

Date of first participant enrolment

Anticipated

1/07/2016

Actual

18/11/2016

Date of last participant enrolment

Anticipated

31/12/2017

Actual

26/05/2017

Date of last data collection

Anticipated

30/06/2019

Actual

7/06/2019

Sample size

Target

170

Accrual to date

Final

151

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment postcode(s) [1]

2308 - Newcastle University

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

NHMRC-ARC Dementia Research Fellowship 2016

Address [1]

National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601

Country [1]

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]

Commercial sector/Industry

Name [1]

Evolva SA

Address [1]

Evolva SA
Duggingerstrasse 23, CH-4153
Reinach, Switzerland

Country [1]

Switzerland

Other collaborator category [1]

Individual

Name [1]

Peter Howe

Address [1]

University of Newcastle
School of Biomedical Sciences & Pharmacy
Callaghan, NSW 2308

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

University of Newcastle Human Research Ethics Committee

Ethics committee address [1]

Chancellery
University of Newcastle
University Drive
Callaghan NSW 2308

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

31/03/2016

Approval date [1]

04/07/2016

Ethics approval number [1]

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

Dr Rachel Wong

Address

Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
University of Newcastle,
University Drive
Callaghan NSW 2308

Country

Australia

Phone

+61 2 4921 6408

Fax

[email protected]

Contact person for public queries

Name

Prof Peter Howe

Address

Clinical Nutrition Research Centre
School of Biomedical Sciences and Pharmacy
University of Newcastle, University Drive
Callaghan, NSW 2308

Country

Australia

Phone

+61 2 49217309

Fax

[email protected]

Contact person for scientific queries

Name

Dr Rachel Wong

Address

Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
University of Newcastle,
University Drive
Callaghan NSW 2308

Country

Australia

Phone

+61 2 4921 6408

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

Current Study Results

No documents have been uploaded by study researchers.

Update to Study Results

Doc. No.	Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
4605	Study results article	Yes		Long-term resveratrol supplementation improves pai... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Resveratrol-Induced Suppression of C-type Natriuretic Peptide Associates With Increased Vertebral Bone Density in Postmenopausal Women.	2023	https://dx.doi.org/10.1002/jbm4.10732
Embase	Natural anti-inflammatory products for osteoarthritis: From molecular mechanism to drug delivery systems and clinical trials.	2023	https://dx.doi.org/10.1002/ptr.7935
Embase	Long-term resveratrol supplementation improves pain perception, menopausal symptoms, and overall well-being in postmenopausal women: Findings from a 24-month randomized, controlled, crossover trial.	2021	https://dx.doi.org/10.1097/GME.0000000000001643
Embase	Sustained cerebrovascular and cognitive benefits of resveratrol in postmenopausal women.	2020	https://dx.doi.org/10.3390/nu12030828
Embase	Regular Supplementation With Resveratrol Improves Bone Mineral Density in Postmenopausal Women: A Randomized, Placebo-Controlled Trial.	2020	https://dx.doi.org/10.1002/jbmr.4115

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically