Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615000291583
Ethics application status
Approved
Date submitted
9/02/2015
Date registered
27/03/2015
Date last updated
28/04/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Assisting post-menopausal women towards healthy aging - can resveratrol enhance mood, physical function and cerebrovascular function and counteract cognitive decline?
Scientific title
A randomised, double-blind, placebo-controlled, parallel dietary intervention trial to determine in postmenopausal women the ability of resveratrol supplementation for 14-weeks to improve cognitive abilities, specifically in the domain of memory.
Secondary ID [1] 285856 0
Nil
Universal Trial Number (UTN)
U1111-1165-2691
Trial acronym
ResFem Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Menopause 293770 0
Cognitive function 294507 0
Condition category
Condition code
Reproductive Health and Childbirth 294073 294073 0 0
Menstruation and menopause
Mental Health 294074 294074 0 0
Studies of normal psychology, cognitive function and behaviour

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Volunteers will arrive at the CNRC for further screening to determine study eligibility, having abstained from food or stimulants for at least an hour. Those who are required to consume regular medication will do so prior to their clinic visit. The timing of their last medication or supplement intake will be documented in the case report form. Anthropometric measurements of height, weight and waist circumference will be obtained prior to clinic BP measurements.

Volunteers with clinic BP less than 160/100mHg will then proceed to have their dementia status assessed using the Australian Version of the Modified Mini Mental State Examination (3MS). Those scoring below 78/100 (considered an indicator of suspected dementia) will be excluded from this study.

Volunteers will then be fitted with a headpiece supporting an ultrasound probe on each temporal region. The investigator will adjust the probes until a measurable blood flow signal is obtained in each MCA before CVR to hypercapnia in the MCA is obtained. If the investigator is unable to obtain a blood flow signal in either MCA, the participant will then proceed to do the neuropsychological tests. Volunteers with detectable blood flow signal will have continuous recordings of changes in mean blood flow velocities in their MCA during the neuropsychological test battery recorded (CVR to cognitive stimuli).

The investigator will then readjust the ultrasound probes to locate the posterior cerebral arteries [either the posterior cerebral arteries (PCA) or the basilar artery (BA)] on either side of the temporal window. Due to the anatomical depth of the BA, the transforaminal (occipital) window is usually the site of insonation; however, it may be possible to detect a blood flow signal from the transtemporal window (same window as the MCA). In the event that the BA cannot be detected, the PCA will be located. Studies have confirmed that CVR to hypercapnia is similar in the PCA and BA and therefore can be interchangeable. Once a suitable blood flow signal is located (on either or both sides), CVR to hypercapnia in the posterior arteries will be obtained. Volunteers will NOT be excluded if no blood flow signals from the posterior arteries are detected. Only volunteers with successful blood flow signal on either side of the PCA/BA will undergo the hypercapnic assessments.

Following the cognitive test assessments, participants will undergo a short battery of physical performance tests and complete six paper-based questionnaires that will measure various subjective perceptions on their current mood states, pain levels, sleep quality, quality of life and menopause-related symptoms on-site. The investigators will then provide the volunteers with their assigned supplements and a diary prior to their departure from the CNRC. The anticipated duration for this visit is estimated for 2.5 hrs.

Weeks 0 to 14 supplementation
Volunteers will be required to consume their allocated supplement capsules twice a day with meals and note the time of consumption in their supplement diary. Placebo and active capsules are identical in shape and colour. Enrolled participants will be required to consume 2 capsules daily (one in the morning and one in the evening), each containing 75mg of resveratrol or matching placebo. Every four weeks, they will also complete the questionnaires relating to sleep quality and menopausal symptoms to facilitate compliance. A study investigator will contact the volunteers midway through their intervention to check their well-being and to monitor compliance with treatment.

Visit 2
Participants will refrain from consuming their supplement on the day of their scheduled visit. They will also return the bottles and all remaining capsules. A study investigator will count the leftover capsules to determine compliance. All assessments of clinic BP, CVR to hypercapnia and neuropsychological test battery, physical performance test and questionnaires of mood, pain, menopausal symptoms, sleep quality and QoL will be repeated at the end of the 14 week intervention.
Intervention code [1] 290838 0
Treatment: Drugs
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
Frequency - Participants will take two capsules daily for 14-weeks - containing either 75mg of resveratrol or placebo
Control group
Placebo

Outcomes
Primary outcome [1] 293857 0
To assess the sustained effects of resveratrol supplementation on performance on a battery of neuropsychological tests: Rey Auditory Verbal Learning Test, Cambridge Semantic Memory Battery, The Visual Spatial Working Memory Task and Trail Making Task.
Timepoint [1] 293857 0
Baseline and 14 weeks (visit 2).
Secondary outcome [1] 312007 0
To assess the sustained effects of resveratrol supplementation on:

Clinic SBP, DBP and HR (Cardiovascular Profiler).

Method of assessment:
An appropriately sized blood pressure cuff will be placed firmly around the upper-left arm of the participant, centered over the left brachial artery to assess BP. After resting quietly in a seated position for 10 min, four consecutive BP and heart rate readings will be taken at 1 min intervals by a single observer using a Cardiovascular Profiler (Cardiovascular Profiler CR2000). The first reading will be discarded and an average of the remaining measurements recorded for analysis.
Timepoint [1] 312007 0
Baseline and 14 weeks (visit 2).
Secondary outcome [2] 312008 0
To assess the sustained effects of resveratrol supplementation on:

Blood flow velocity changes in the MCA in response to a battery of neuropsychological tests (CVR to neuropsychological tests).

Method of assessment:
Changes in mean blood flow velocity in the MCA during cognitive assessments will be recorded continuously using the TCD device. The neuropsychological test battery will consist of the Cambridge Semantic Memory Battery, visual spatial working memory, Rey Auditory Verbal Learning Test (verbal memory) and the Trail Making Task (measure of attentional and executive functions, which becomes impaired with age).
Timepoint [2] 312008 0
Baseline and 14 weeks (visit 2).
Secondary outcome [3] 313631 0
To assess the sustained effects of resveratrol supplementation on:

Basal cerebral blood flow velocities, pulsatility index in the anterior and posterior cerebral circulation.
Anterior circulation to CVR to hypercapnia at the level of the middle cerebral artery (MCA).
Posterior circulation to CVR to hypercapnia at the level of the posterior cerebral artery (PCA) or basilar artery (BA).
Differences in anterior and posterior circulation to CVR to hypercapnia.

Method of assessment:
Increases in blood flow velocity in the MCA and PCA/BA in response to vasodilator stimuli reflect endothelial dilatation in downstream anterior and posterior vascular beds respectively. Basal cerebral blood flow velocities for 10 cardiac cycles will first be recorded to determine the blood flow velocity (peak systolic, end diastolic and mean) at rest. The measures of cerebral pulsatility and resistive indexes will also be recorded simultaneously. During CVR to hypercapnia, participants breathe carbogen (5% CO2, 95% O2) for 150 seconds and the peak increase of blood flow velocity is recorded. This procedure is done in triplicate with a resting interval of at least 2min between each recording. CVR is calculated as follows: [(peak blood flow velocity during hypercapnia – resting blood flow velocity)/ resting blood flow velocity] x 100.
Note: these are composite outcomes.
Timepoint [3] 313631 0
Baseline and 14 weeks (visit 2).
Secondary outcome [4] 313632 0
To assess the sustained effects of resveratrol supplementation on:

Physical function (Physical Performance Battery).

Method of assessment:
The physical function test battery is a validated measure of functional performance of activities of daily living in community living older adult consisting of nine items. Volunteers will be given up to two chances to complete each task. Assistive devices are permitted in the locomotive task items. Volunteers will be asked to write a legible sentence, stimulate eating by picking up kidney beans with a teaspoon from a bowl and putting them in another bowl; lifting a heavy book (2.5kg) from the table and placing it on a shelf; put on and remove a jacket; pick up a coin from the floor; sit to stand and pivot 360 degree; walking 15m and climbing flights of stairs. They will be timed for each task. Higher scores will equate better physical performance.
Timepoint [4] 313632 0
Baseline and 14 weeks (visit 2).
Secondary outcome [5] 313633 0
To assess the sustained effects of resveratrol supplementation on:

Mood as measured by Profile of Mood States (POMS) and Centre for Epidemiological Studies Depression Scale questionnaires.

Method of assessment
Volunteers’ mood states will be assessed using the Profile of Mood States (POMS) Questionnaire and the Center for Epidemiological Studies Depression Scale (CES-D). The POMS questionnaire consisting of 65-adjectives that the participant will rate on a 5-point scale. Participants will be required to rate the level at which they have been feeling in the last week and including today according to the 1-5 Likert Scale (1 being “not at all” and 5 being “extremely). The POMS Standard has proven to be an excellent measure of mood states and their fluctuations. The CES-D scale is a commonly used tool to characterize depressive symptoms in the general population. The 20-item self-administered scale measures the major depressive symptomatology, including depressive mood, feelings of guilt and worthlessness, psychomotor retardation, loss of appetite and sleep disturbances. These will be administered on paper at the conclusion of the neuropsychological test battery.
Timepoint [5] 313633 0
Baseline and 14 weeks (visit 2).
Secondary outcome [6] 313634 0
To assess the sustained effects of resveratrol supplementation on:

Quality of Life (QoL) (using the SF-36).

The short-form 36 (SF-36) is a multi-purpose short-form health survey that measures an individual’s perception of functional health and physical and mental-wellbeing. This tool has been validated in postmenopausal women.
Timepoint [6] 313634 0
Baseline and 14 weeks (visit 2).
Secondary outcome [7] 313635 0
To assess the sustained effects of resveratrol supplementation on:

Sleep quality (Pittsburgh Sleep Quality Index Questionnaire).

The Pittsburgh Sleep Quality Index is a self-rated questionnaire that assesses the volunteers’ sleep quality and disturbances over a 1-month time interval. Volunteers will rate their sleep quality, duration, disturbances, latency, habitual sleep efficiency and daytime dysfunction in the 19-question survey.
Timepoint [7] 313635 0
Baseline and 14 weeks (visit 2).
Secondary outcome [8] 313636 0
To assess the sustained effects of resveratrol supplementation on:

Pain (short-form McGill Pain Questionnaire).

The volunteers’ pain symptomatology will be captured using the short-form McGill Pain Questionnaire, consisting of 11 sensory and 4 affective descriptors which the participants will rate on an intensity scale ranging from none=0, mild=1, moderate=3, or severe=4. The questionnaire will also ask the volunteer to rate the present pain intensity and their overall pain by marking a vertical line within a 10cm visual analogue scale.
Timepoint [8] 313636 0
Baseline and 14 weeks (visit 2).
Secondary outcome [9] 313637 0
To assess the sustained effects of resveratrol supplementation on:

Menopausal symptoms (Menopause Rating Scale).

The Menopause Rating Scale (MRS) has been shown to be effective in measuring treatment effects on quality of life across the full range of severity of complaints in ageing women. Volunteers will indicate either none, mild, moderate, severe or very severe for each of the 11 items that they have been experiencing in the questionnaire.
Timepoint [9] 313637 0
Baseline and 14 weeks (visit 2).
Secondary outcome [10] 313638 0
To assess the sustained effects of resveratrol supplementation on:

Safety: number of adverse events (AE) and serious adverse events (SAE)

Medical assistance is readily available on site in the unlikely event of AEs and SAEs. The study coordinator will inform the Principal Investigator of all AEs and SAEs in the first instance, who will then follow the CNRC’s Emergency Unblinding Procedures, if necessary, and notify the relevant bodies. Depending on the nature of AEs or SAEs, it may be necessary for treatment to cease and/or for the participant to be withdrawn from the study. Any participants experiencing AEs or SAEs on site will be referred to the consulting physician immediately for further medical evaluation. The Principal Investigator will follow-up with the consulting physician to determine the relationship of the AE or SAE to the study product.

All SAE, including pregnancy that may be related or unrelated to the investigational product will be documented in the SAE Forms and in the Case Report Form. There are no known AE or SAE reported for the use of resveratrol at the dose that we are giving to the volunteers. An AE) is any symptom, sign, illness or experience that develops or worsens in severity in a subject involved in a biomedical research project administered an investigational product whether or not considered related to this product or study-related procedure and reported by the subject or observed by the investigator. A SAE is any AE that is:

- fatal (results in death)
(note: death is an outcome, not an event)
- life-threatening
(note: the term “life-threatening” refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event which could hypothetically have caused death had it been more severe)
- requires or prolongs hospital stay
(note: “in-patient hospitalisation” refers to an unplanned, overnight hospitalisation)
- results in persistent or significant disability or incapacity
(note: the term means substantial disruption of one’s ability to conduct normal life function)
- a congenital anomaly or birth defect
(note: congenital anomaly/birth defect in offspring of subject taking the product regardless of time to diagnosis)
- an important medical event
(note: Important medical events are those that may not be immediately life threatening, but are clearly of major clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the other serious outcomes noted above. For example, a seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would typically be considered serious.)
Timepoint [10] 313638 0
Baseline and 14 weeks (visit 2).

Eligibility
Key inclusion criteria
Post-menopausal (self-reported cessation of menses for > 6 months).
Clinic BP <160/100mmHg (determined at screening).
No change in medication type or dose for 3 months before the intervention.
Unlikely to change pre-existing medication/supplements during the intervention.
Minimum age
40 Years
Maximum age
90 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 6 months)
Suspected dementia (3MS score of < 78/100 determined at screening)
History of breast or cervical cancer or mastectomy or hysterectomy
Smokers or currently on nicotine therapy
Neurological conditions
Kidney/liver disease
Warfarin therapy
Insulin therapy
Regularly consuming more than 4 standard alcoholic drinks per day
Major depression as diagnosed by a health care professional
Illiterate
Physical difficulty that will impede on motor and locomotive performance.
Unable to walk without assistance from people (walking aids ok)
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)
Participants will return the completed Questionnaire along with a signed consent from the volunteer to allow the study investigators to use demographic and lifestyle details to help determine their suitability before visiting the CNRC for a screening/baseline visit.

Allocation to either treatment phase is based on the minimisation method (age and BMI) to ensure well-balanced groups.

Active and placebo treatments will be encapsulated and matched for colour. Capsules will be packaged in sealed HD-PE bottles and assigned numbers which will be randomly allocated to the volunteers upon enrolment.
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 (Altman & Bland, BMJ 2005;330;843), where age and body mass index will be the primary determinant. The initial allocation of the first participant will be determined by a coin toss.
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
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Seventy four women in a parallel design will give 80% power to detect an effect size difference of 1.0 in cognitive performance at alpha = 0.05, based on a 1.5 SD. To allow for dropouts we will recruit 80 participants.

Baseline measures will be used as covariates. Age and years since cessation of menses and other potentially confounding variables such as years of education, BMI may be added as covariates if they are significantly correlated with the outcome measures.

Correlations between years since cessation of menses and CVR to hypercapnia (anterior and posterior circulation) and cognitive function will be determined.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
10/04/2015
Actual
4/05/2015
Date of last participant enrolment
Anticipated
Actual
24/06/2015
Date of last data collection
Anticipated
Actual
29/09/2015
Sample size
Target
80
Accrual to date
Final
80
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 290430 0
Charities/Societies/Foundations
Name [1] 290430 0
Hunter Medical Research Institute
Country [1] 290430 0
Australia
Primary sponsor type
University
Name
University of Newcastle
Address
University Drive
Callaghan NSW 2308
Country
Australia
Secondary sponsor category [1] 289142 0
None
Name [1] 289142 0
Address [1] 289142 0
Country [1] 289142 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292112 0
University of Newcastle Human Research Ethics Committee
Ethics committee address [1] 292112 0
Ethics committee country [1] 292112 0
Australia
Date submitted for ethics approval [1] 292112 0
13/12/2014
Approval date [1] 292112 0
13/03/2015
Ethics approval number [1] 292112 0
H-2015-0002

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 353 353 0 0
/AnzctrAttachments/367629-BC04 Expedited Approval.pdf

Contacts
Principal investigator
Name 53574 0
Prof Peter Howe
Address 53574 0
Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
Medical Sciences Building, MS 514
University of Newcastle
University Drive
Callaghan NSW 2308
Country 53574 0
Australia
Phone 53574 0
+61 02 4921 7309
Fax 53574 0
+61 02 4921 2028
Email 53574 0
Peter.Howe@newcastle.edu.au
Contact person for public queries
Name 53575 0
Rachel Wong
Address 53575 0
Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
Medical Sciences Building, MS 514
University of Newcastle
University Drive
Callaghan NSW 2308
Country 53575 0
Australia
Phone 53575 0
+61 02 4921 6408
Fax 53575 0
Email 53575 0
Rachel.Wong@newcastle.edu.au
Contact person for scientific queries
Name 53576 0
Peter Howe
Address 53576 0
Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
Medical Sciences Building, MS 514
University of Newcastle
University Drive
Callaghan NSW 2308
Country 53576 0
Australia
Phone 53576 0
+61 02 4921 7309
Fax 53576 0
+61 02 4921 2028
Email 53576 0
Peter.Howe@newcastle.edu.au

No information has been provided regarding IPD availability


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
SourceTitleYear of PublicationDOI
EmbaseClinical evaluation of effects of chronic resveratrol supplementation on cerebrovascular function, cognition, mood, physical function and general well-being in postmenopausal women-rationale and study design.2016https://dx.doi.org/10.3390/nu8030150
EmbaseEffects of resveratrol on cognitive performance, mood and cerebrovascular function in post-menopausal women; a 14-week randomised placebo-controlled intervention trial.2017https://dx.doi.org/10.3390/nu9010027
EmbaseResveratrol supplementation reduces pain experience by postmenopausal women.2017https://dx.doi.org/10.1097/GME.0000000000000861
N.B. These documents automatically identified may not have been verified by the study sponsor.