Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614000891628
Ethics application status
Approved
Date submitted
12/08/2014
Date registered
21/08/2014
Date last updated
30/08/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Dose response evaluation of resveratrol supplementation on cerebrovascular function, mood and cognitive performance in type 2 diabetes mellitus (T2DM).
Scientific title
Acute randomised, double blind, placebo controlled crossover dietary intervention trial. A dose response evaluation of resveratrol supplementation on cerebrovascular function, mood and cognitive performance in type 2 diabetes mellitus.
Secondary ID [1] 284962 0
Nil
Universal Trial Number (UTN)
U1111-1159-1283
Trial acronym
resDiaCog cerebrovascular dose-response study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetes 292455 0
Condition category
Condition code
Metabolic and Endocrine 292771 292771 0 0
Diabetes
Mental Health 292772 292772 0 0
Studies of normal psychology, cognitive function and behaviour

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Enrolled participants will be required to consume 4 capsules, each containing varying doses of resveratrol, as follows:
1) Placebo: 4 capsules
2) Resvida 'Trademark' dietary supplement 75 mg: 1 cap @75 mg + 3 placebo cap
2) Resvida 'Trademark' dietary supplement 150 mg: 2 cap @75 mg + 2 placebo cap
3) Resvida 'Trademark' dietary supplement 300 mg: 4 cap @75 mg
Capsules will be taken orally with water, during weekly visits for four weeks. Particpants will take a single dose on 4 occasions at weekly intervals (one week washout between doses).
Participants will be required to attend the Clinical Nutrition Research Centre (CNCR) 5 times over 5 weeks.
Participants will arrive at the CNRC following a 4hr fast (no food/beverage, except water) for further screening to determine study eligibility. Anthropometric measurements of height, weight and waist circumference will be obtained before clinic Blood Pressure (BP) and Arterial Compliance (AC) measurements are assessed. Those with clinic BP not within the study inclusion range will be excluded.

The dementia status of the participants will be determined using the Australian Version of the Modified Mini Mental State Examination (3MS). Participants scoring below 78/100 (considered an indicator of suspected dementia) will be excluded from this study.

Participants will then be fitted with a headpiece supporting an ultrasound probe on each temporal region. An investigator will adjust the probes until a measurable blood flow signal is obtained in each middle cerebral artery (MCA). If the investigator is unable to obtain a blood flow signal in both MCAs, the participant will be excluded from the study. Otherwise, blood flow velocity changes (CVR) to hypercapnia in the MCA will be assessed. The investigator will adjust 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 posterior cerebral artery will be located. Studies have confirmed that the PCA and BA responsiveness to hypercapnia is similar and therefore can be used as its own surrogate (Skow RJ, MacKay CM, Tymko MM, Willie CK, Smith KJ, Ainslie PN, et al. Differential cerebrovascular carbon dioxide (CO2) reactivity in anterior and posterior cerebral circulations. Resp Physiol Neurobi. 2013 Oct 1;189(1):76-86). Once a suitable blood flow signal is located, CVR to hypercapnia in the posterior arteries will be assessed. Participants will not be excluded if blood flow signals from the posterior arteries are not found.

To minimize learning effects and to control cognitive test duration in the latter visits, participants will be familiarized with the computerized cognitive test battery at this visit. Here, participants will be given instructions for each cognitive test and a couple of practice trials. Participants will have the opportunity to break fast before undergoing the practice session. This gives the study investigators and the participants the opportunity to clarify test instructions. The anticipated duration for this visit including the practice test is estimated for 2.5 hr.

Eligible participants will then be given a blood request form for a blood sample analysis of fasting glucose, insulin and glycated hemoglobin (HbA1C) at the Hunter Area Pathology Service (HAPS) Centre at the end of the initial visit. Participants will have to visit their nearest HAPS Centre the following day or any day before their scheduled visit 2, after an overnight fast of 8 hr.

Visits 2 to 5: Participants will arrive at the CNRC after a 4hr fast. Assessment of clinic BP will be obtained. A blood sample will be taken and assessment of AC and CVR to hypercapnia in the MCA and PCA/BA will be obtained. Participants will then consume their assigned resveratrol dose capsules on site with water in the presence of the study investigator. The order of treatment for each subject will be determined by a Latin Square design. During the 45 minute absorption phase, participants will be reminded of the computerized multi-tasking test battery instructions and if necessary have a few trial practices. Pharmacokinetics studies of single dose consumption of resveratrol showed that plasma resveratrol peaks around 36-48mins for older adults (Nunes T, Almeida L, Rocha JF, Falcao A, Fernandes-Lopes C, Loureiro AI, et al. Pharmacokinetics of trans-resveratrol following repeated administration in healthy elderly and young subjects. J Clin Pharmacol. 2009 Dec;49(12):1477-82). Therefore, post-consumption CVR to hypercapnia in the MCA will be obtained at 45min post-consumption and CVR to neuropsychological test battery will commence at the 55min post-consumption time point. Continuous recordings of changes in mean blood flow velocities in the MCA during the neuropsychological test battery will be obtained. Time taken to complete the neuropsyschological tests is 30min. CVR to hypercapnia in the posterior arteries will be assessed in participants who have successful blood flow signal in the PCA/BA. A second blood sample will be taken at the conclusion of each visit. This protocol is repeated at weekly intervals with different resveratrol doses. Duration of each visit may last up to 3hr 30min. Light refreshments will be served at the conclusion of each visit.
Intervention code [1] 289791 0
Treatment: Drugs
Comparator / control treatment
Placebo (corn oil)
Mode – taken orally with water
Frequency – Particpants will take a single dose on 4 occasions at weekly intervals.
Duration – 4 oral capsules of placebo (corn oil) one day for 1 week, 3 oral capsules of placebo (corn oil) one day for 1 week, 2 oral capsules of placebo (corn oil) one day for 1 week.
Control group
Placebo

Outcomes
Primary outcome [1] 292621 0
Use of Transcranial Doppler (TCD) ultrasound to determine the most efficacious dose of resveratrol to improve cerebral vasodilator responsiveness (CVR) to hypercapnia in the anterior circulation (MCA) in adults with T2DM.
Timepoint [1] 292621 0
Weeks 1 to 4.
Secondary outcome [1] 309350 0
Clinic BP and arterial compliance (AC)
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 and tonometer (for pulse wave analysis) positioned perpendicularly over right radial artery to assess elasticity of large and small arteries. After resting quietly in a seated position for 10 min, four consecutive BP, heart rate and AC readings will be taken at 5 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] 309350 0
Baseline at week 0 and at weeks 1 to 4.
Secondary outcome [2] 309351 0
CVR to hypercapnia, measured with TCD ultrasound
Increases in blood flow velocity in the MCA and PCA/B.A 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 triplicates with a resting interval of at least 2min between each recording.
Timepoint [2] 309351 0
Baseline at week 0 and at weeks 1 to 4.
Secondary outcome [3] 309352 0
CVR to neuropsychological tests, measured with TCD ultrasound.
Changes in mean blood flow velocity in the MCA during cognitive assessments will be recorded continuously using the TCD device. The computerised multi-tasking test battery (Purple Framework, UK) will consist of non-verbal tasks (to minimise potential artefacts from speaking) that assess attention, concentration, processing speed and executive function. We have recently identified the cognitive domains and the neuropsychological tests most sensitive to deficits in high functioning, dementia-free adults with T2DM. Domains most susceptible to decline are executive and attentional function, working memory and psychomotor speed. CVR will be assessed only in the non-verbal tasks of the cognitive battery, i.e. all except the dual-task conditions. The multi-tasking test battery will comprise of the Stroop Colour-Word test (executive function), N-back task (working memory), Visual Warning (reaction time) and High Number Tap (attention). Participants will be assessed on each individual task separately for 3 min set at a level of high difficulty to ascertain their performance. Then, the participants will attempt to complete all four tasks simultaneously for 5 min set at a level of moderate difficulty to obtain an overall performance score on their dual-tasking abilities.
Timepoint [3] 309352 0
Baseline at week 0 and at weeks 1 to 4.
Secondary outcome [4] 309353 0
Blood sample collection and analysis.
Blood samples will be collected and analysed off-site by licensed professionals at the Hunter Area Pathology Services (HAPS) Centre in the Hunter region of NSW.
Once eligible for the study, participants will be given a blood request form for a fasting (8hr) blood sample analysis of glucose, insulin and HbA1c levels. Participants will visit a HAPS-specific collection centre of their choice. HAPS will mail the results of the analyses to the study investigators.
Timepoint [4] 309353 0
Following Baseline visit at week 0
Secondary outcome [5] 309354 0
Blood sample collection and analysis of plasma resveratrol concentration.
Blood samples will be collected by qualified study personnel at the Clinical Nutrition Research Centre Clinic and analysed on-site by co-investigators at the Nutraceuticals Research Group Laboratory.
Timepoint [5] 309354 0
At weeks 1 to 4.

Eligibility
Key inclusion criteria
Non-insulin-dependent type 2 diabetes mellitus adults; non-smoking; women must be postmenopausal; dementia-free, Clinic SBP between 130-160mmHg ; BMI less than 40kg/m2; computer literate; have measurable ultrasound signal on both sides of the head; unlikely to change medication/supplements during the intervention.
Minimum age
40 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Suspected dementia (3MS score of less than 78/100 determined at screening); Smokers or currently on nicotine therapy; Neurological conditions; Kidney/liver disease; Insulin therapy ; Major depression as diagnosed by a health care professional; Visual problems including the inability to distinguish the colours of red, green, blue and yellow; Illiterate; Physical difficulty in both hands that will impede on motor performance of the hand/arm; Unable to obtain a measurable signal in the MCA; Unwilling to provide two blood samples at each visit; Unwilling to maintain pre-enrolment physical activity levels and dietary habits for the duration of the trial.; Unwilling to fast for 4hr; Currently consuming resveratrol or other grape extract supplements.

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 receive and return a completed health and lifestyle questionnaire and consent form,
Participants will then attend the research clinic for their screening/baseline visit
Participants will be provided with each dose on one occasion. This dose will be consumed in the research clinic. Capsules will be packaged by a research assistant not involved in data collection and labeled as supplement A-D and will be provided to the volunteers in random order. The doses that these letters correspond to will not be revealed to the investigators until after the data has been analysed. The code will be held by a member of the research clinic staff who is not involved in the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be allocated their initial treatment accordingly to the randomisation by minimisation process (Altman & Bland BMJ 2005;330;843), where gender 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
Crossover
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Baseline measures will be used as covariates. Age and gender and other potentially confounding variables such as years of education, duration of diabetes, Homeostasis Model Assessment (HOMA) and HbA1c levels may be added as covariates if they are significantly correlated with the outcome measures.
Correlations between biomarkers of diabetes (glucose, HOMA and HbA1c) and CVR to hypercapnia (anterior and posterior circulation) will be determined.
Data of CVR to hypercapnia collected at baseline and at the pre-capsules consumption during visits 2-5 will be averaged and used to determine intra-class correlation coefficient (two-way mixed model).
Thirty five participants in a crossover design will give 80% power to detect a 5% change in CVR to hypercapnia at alpha equal to 0.05, based on a 10% SD observed in our recent assessments. To allow for dropouts we will recruit 40 participants aged 40-80 years with a diagnosis of T2DM.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/10/2014
Actual
30/09/2014
Date of last participant enrolment
Anticipated
Actual
17/04/2015
Date of last data collection
Anticipated
Actual
22/05/2015
Sample size
Target
40
Accrual to date
Final
39
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 289585 0
Charities/Societies/Foundations
Name [1] 289585 0
Dementia Collaborative Research Centre
Country [1] 289585 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Dementia Collaborative Research Centre
Address
Centre for Research on Ageing,
Health and Wellbeing (CRAHW)
Bdg 62A cnr Eggleston/Mills Rd
Australian National University
Canberra ACT 0200
Country
Australia
Secondary sponsor category [1] 288269 0
Commercial sector/Industry
Name [1] 288269 0
DSM Nutritional Products
Address [1] 288269 0
P.O. Box 2676, Bldg. 241/419
CH-4002 Basel, Switzerland
Country [1] 288269 0
Switzerland

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291333 0
Human Research Ethics Committee
Ethics committee address [1] 291333 0
Ethics committee country [1] 291333 0
Australia
Date submitted for ethics approval [1] 291333 0
31/07/2014
Approval date [1] 291333 0
10/09/2014
Ethics approval number [1] 291333 0
H-2014-0265

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 49862 0
Prof Peter Howe
Address 49862 0
Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
Medical Sciences Building, MS 514
University of Newcastle
University Drive
Callaghan, NSW 2308
Country 49862 0
Australia
Phone 49862 0
+61 02 4921 7309
Fax 49862 0
+61 02 4921 2028
Email 49862 0
[email protected]
Contact person for public queries
Name 49863 0
Rachel Wong
Address 49863 0
Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
Medical Sciences Building, MS 514
University of Newcastle
University Drive
Callaghan, NSW 2308
Country 49863 0
Australia
Phone 49863 0
+61 02 4921 6408
Fax 49863 0
Email 49863 0
[email protected]
Contact person for scientific queries
Name 49864 0
Peter Howe
Address 49864 0
Clinical Nutrition Research Centre
School of Biomedical Sciences & Pharmacy
Medical Sciences Building, MS 514
University of Newcastle
University Drive
Callaghan, NSW 2308
Country 49864 0
Australia
Phone 49864 0
+61 02 4921 7309
Fax 49864 0
Email 49864 0
[email protected]

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
EmbaseAcute resveratrol consumption improves neurovascular coupling capacity in adults with type 2 diabetes mellitus.2016https://dx.doi.org/10.3390/nu8070425
EmbaseLow dose resveratrol improves cerebrovascular function in type 2 diabetes mellitus.2016https://dx.doi.org/10.1016/j.numecd.2016.03.003
N.B. These documents automatically identified may not have been verified by the study sponsor.