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Trial registered on ANZCTR


Registration number
ACTRN12620000180910
Ethics application status
Approved
Date submitted
3/02/2020
Date registered
17/02/2020
Date last updated
17/02/2020
Date data sharing statement initially provided
17/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Can Resveratrol Supplementation Mitigate Menstrual Migraine?
(Resveratrol for Menstrual Migraine - RESFORMM)
Scientific title
Can Resveratrol Supplementation Mitigate Menstrual Migraine?
Secondary ID [1] 300056 0
None
Universal Trial Number (UTN)
U1111-1245-2638
Trial acronym
RESFORMM Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Migraine 315587 0
Condition category
Condition code
Neurological 313873 313873 0 0
Other neurological disorders
Alternative and Complementary Medicine 314354 314354 0 0
Other alternative and complementary medicine
Reproductive Health and Childbirth 314471 314471 0 0
Menstruation and menopause

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised, double-blind, placebo-controlled, crossover study.

Participants will take either 150mg of resveratrol (75mg, twice daily) or matching placebo capsules for three menstrual cycles before crossing over to the other treatment arm for another three menstrual cycles. Capsules will be taken orally. There will be no washout period between treatments.

Participants will return their supplement container and study diary to check compliance at each visit following the dispensing of the supplement.
Intervention code [1] 316335 0
Prevention
Comparator / control treatment
Placebo (an inert filler consisting of calcium hydrogen phosphate, hydrated magnesium silicate, microcrystalline cellulose and prosolv 50).
Control group
Placebo

Outcomes
Primary outcome [1] 322261 0
Menstrual migraine burden (number of half-days with migraine per month) following resveratrol supplementation using data obtained from the study diary
Timepoint [1] 322261 0
Visit 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)

Due to the crossover nature of the study, half of the participants will complete the resveratrol supplementation at visit 2 and the other half at visit 3.
Secondary outcome [1] 377905 0
Mean blood flow velocity (MBFV) at the level of the middle cerebral artery (MCA) assessed using transcranial Doppler (TCD) ultrasound
Timepoint [1] 377905 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [2] 378408 0
Pulsatility index at the level of the MCA assessed using TCD ultrasound
Timepoint [2] 378408 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [3] 378409 0
MBFV at the level of the posterior cerebral artery (PCA) assessed using TCD ultrasound
Timepoint [3] 378409 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [4] 378410 0
Pulsatility index at the level of the PCA assessed using TCD ultrasound
Timepoint [4] 378410 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [5] 378411 0
Cerebrovascular responsiveness (CVR) to hypercapnia at the level of the MCA assessed using TCD ultrasound
Timepoint [5] 378411 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [6] 378412 0
CVR to hypercapnia at the level of the PCA assessed using TCD ultrasound
Timepoint [6] 378412 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [7] 378413 0
CVR to N-Back Task (neurovascular coupling) at the level of the MCA assessed using TCD ultrasound
Timepoint [7] 378413 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [8] 378415 0
CVR to Stroop Task (neurovascular coupling) at the level of the MCA assessed using TCD ultrasound
Timepoint [8] 378415 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [9] 378417 0
CVR to Computerised Multitasking Test Battery (neurovascular coupling) at the level of the MCA assessed using TCD ultrasound
Timepoint [9] 378417 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [10] 378431 0
Performance on N-Back Task to assess cognitive function (working memory)
Timepoint [10] 378431 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [11] 378512 0
Performance on Stroop Task to assess cognitive function (executive function)
Timepoint [11] 378512 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [12] 378513 0
Performance on Computerised Multitasking Test Battery to assess cognitive function
Timepoint [12] 378513 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [13] 378514 0
Clinic blood pressure assessed using Cardiovascular Profiler CR 2000
Timepoint [13] 378514 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [14] 378515 0
Large artery elasticity index assessed using Cardiovascular Profiler CR 2000
Timepoint [14] 378515 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [15] 378516 0
Small artery elasticity index assessed using Cardiovascular Profiler CR 2000
Timepoint [15] 378516 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [16] 378517 0
Migraine Disability Assessment (MIDAS)
Timepoint [16] 378517 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [17] 378518 0
Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQOL)
Timepoint [17] 378518 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [18] 378519 0
Headache Impact Test-6 (HIT-6)
Timepoint [18] 378519 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [19] 378520 0
Serum high sensitivity C-reactive protein (hs-CRP)
Timepoint [19] 378520 0
Visit 1 (at enrolment), 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [20] 378521 0
Gene expression of estrogen receptor 1 (ESR1) assessed by reverse transcription polymerase chain reaction (PCR)
Timepoint [20] 378521 0
Visit 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [21] 378522 0
Gene expression of progesterone receptor (PGR) assessed by reverse transcription PCR
Timepoint [21] 378522 0
Visit 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [22] 378523 0
Gene expression of tumour necrosis factor (TNF) assessed by reverse transcription polymerase chain reaction (PCR)
Timepoint [22] 378523 0
Visit 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [23] 378524 0
Gene expression of neuropilin-1 (NRP1) assessed by reverse transcription polymerase chain reaction (PCR)
Timepoint [23] 378524 0
Visit 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)
Secondary outcome [24] 378525 0
Gene expression of synaptic nuclear envelope protein-1 (SYNE1) assessed by reverse transcription polymerase chain reaction (PCR)
Timepoint [24] 378525 0
Visit 2 (12 weeks post-enrolment) and 3 (24 weeks post-enrolment)

Eligibility
Key inclusion criteria
Women aged between 18 - 50 years old who have a regular periods (menstrual cycle length between 21 and 35 days) and suffer from migraines that occur +/- 3 days from their period for at least three out of their previous six menstrual cycles
Minimum age
18 Years
Maximum age
50 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Amenorrhea (absence of period for > 3 months but not pregnant)

Currently consuming resveratrol containing supplements

Currently receiving In Vitro Fertilisation (IVF) therapy

Fibromyalgia

History of alcohol or drug abuse

History of using Botulinum toxin or neuromodulation devices or calcitonin gene-related peptide monoclonal antibody for treatment of migraine

Hysterectomy

Insulin-dependent diabetes

Liver or kidney disease

Malignant cancer

Neurological conditions including stroke, TIA, multiple sclerosis, epilepsy, Chiari malformation or Parkinson’s disease

Not fluent in reading and writing in English

Pregnant or breastfeeding

Polycystic ovarian syndrome or premature ovarian failure

Taking prophylactic migraine medications or migraine prevention therapies

Taking warfarin therapy or novel oral anticoagulants

Unmanaged or untreated major depression

Unwilling to provide a blood sample

Unwilling to refrain from consuming stimulants before each clinic visit

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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)
Safety/efficacy
Statistical methods / analysis
The treatment effect will be determined by comparing the within-individual mean differences between resveratrol and placebo using repeated measures ANOVA. False discovery rate estimations will be used for multiple comparisons for the secondary outcomes.

Changes in cerebrovascular function will be correlated with changes in hs-CRP concentrations, quality of life and migraine-related disability measures and gene expression levels. Associations between changes in cerebrovascular function, hs-CRP concentrations, quality of life and migraine-related disability measures and gene expression levels will be analysed using linear regression with false discovery rate estimations.

Data collected from participants who completed all study time points will be used for per-protocol analysis. An interim analysis using ANOVA will be performed at the end of the first stage of the crossover (after completion of three menstrual cycles) to determine the intra-individual treatment changes (pre-post supplementation) between placebo and resveratrol for relevant secondary outcomes.

Recruitment
Recruitment status
Not yet 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

Funding & Sponsors
Funding source category [1] 304509 0
Commercial sector/Industry
Name [1] 304509 0
Evolva SA
Address [1] 304509 0
Evolva SA
Duggingerstrasse 23, CH-4153
Reinach, Switzerland
Country [1] 304509 0
Switzerland
Primary sponsor type
University
Name
The University of Newcastle
Address
University of Newcastle
Faculty of Health and Medicine
School of Biomedical Sciences & Pharmacy
Clinical Nutrition Research Centre
Callaghan, New South Wales 2308
Australia
Country
Australia
Secondary sponsor category [1] 304777 0
None
Name [1] 304777 0
Address [1] 304777 0
Country [1] 304777 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304939 0
The University of Newcastle Human Research Ethics Committee
Ethics committee address [1] 304939 0
Chancellery
University of Newcastle
University Drive
Callaghan NSW 2308
Ethics committee country [1] 304939 0
Australia
Date submitted for ethics approval [1] 304939 0
29/11/2019
Approval date [1] 304939 0
31/01/2020
Ethics approval number [1] 304939 0
H-2019-0416

Summary
Brief summary
In our pilot observation, we found women who suffered from menstrual migraine to have poorer blood vessel function in the brain than women who did not suffer from migraine. Therefore, we hypothesise that improving and/or maintaining proper brain blood vessel function may potentially prevent the migraine from occurring.

We believe that supplementing with resveratrol (a natural ingredient found in grapes and berries that is known to improve our cardiovascular and brain health) throughout the menstrual cycle may improve blood vessel function and ultimately prevent the menstrual migraine and improve the quality of life in sufferers.

In this randomised, double-blind, placebo-controlled crossover trial, we will enrol 82 women aged between 18 and 50 who suffer from migraine +/- 3 days from their period for at least three out of their previous six menstrual cycles. Participants will take one 75mg resveratrol or one matching placebo capsule twice daily for three menstrual cycles before crossing over to the other treatment arm for another three menstrual cycles.
Trial website
https://www.newcastle.edu.au/research-and-innovation/centre/cnrc/volunteer
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98702 0
Dr Rachel Wong
Address 98702 0
Clinical Nutrition Research Centre, MS514
University of Newcastle
School of Biomedical Sciences & Pharmacy
Callaghan NSW 2308
Country 98702 0
Australia
Phone 98702 0
+61 249216408
Fax 98702 0
Email 98702 0
rachel.wong@newcastle.edu.au
Contact person for public queries
Name 98703 0
Miss Jemima Dzator
Address 98703 0
Clinical Nutrition Research Centre, MS514
University of Newcastle
School of Biomedical Sciences & Pharmacy
Callaghan NSW 2308
Country 98703 0
Australia
Phone 98703 0
+61 249218616
Fax 98703 0
Email 98703 0
cnrc@newcastle.edu.au
Contact person for scientific queries
Name 98704 0
Prof Peter Howe
Address 98704 0
Clinical Nutrition Research Centre, MS122a
University of Newcastle
School of Biomedical Sciences & Pharmacy
Callaghan NSW 2308
Country 98704 0
Australia
Phone 98704 0
+61 249217309
Fax 98704 0
Email 98704 0
peter.howe@newcastle.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results