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Trial registered on ANZCTR

Registration number

ACTRN12621001476820

Ethics application status

Approved

Date submitted

4/08/2021

Date registered

28/10/2021

Date last updated

7/10/2022

Date data sharing statement initially provided

28/10/2021

Type of registration

Retrospectively registered

Titles & IDs

Public title

Measuring the effects of L-arginine and aged garlic extract on migraine in Australian adults

Scientific title

Investigating the effects of L-arginine and aged garlic extract on frequency and severity of migraine in adults

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1268-1117

Trial acronym

L-Arginine and Garlic Extract trial (the LARGE-trial)

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Migraine

Condition category

Condition code

Neurological

Other neurological disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

We compare L-arginine and aged garlic extract (AGE) as separate systemic vasodilating agents to see which (if either) is more effective in preventing migraines. We assess whether any of these comparators have differing efficacies in different aspects of the headache, such as frequency, duration or severity. Each subject will self-administer the treatments as follows: 2500 mg/day placebo as oral capsules for the first 2 weeks, then their allocated treatment (placebo oral capsules, 1500 mg/day L-arginine oral capsules, 1000 mg/day AGE oral capsules, or both as oral capsules) for the next 12 weeks. Participants are required to return the initial capsule bottle (placebo capsules provided at week 1) at the baseline visit (week 3). Eighty percent compliance is required to continue in the study to ensure compliance during treatment. Participants are also contacted one week following commencement of treatment to discuss any potential adverse events and treatment compliance. Participants are required to return their treatment capsule bottle(s) at the end of week 14 (post-intervention) visit to monitor adherence.

Intervention code [1]

Treatment: Other

Comparator / control treatment

We include a placebo control to see whether the two compounds do have a significant effect on migraines. The placebo treatment is comprised of microcellulose capsules

Control group

Placebo

Outcomes

Primary outcome [1]

To measure the effects of 1500 mg/day L-arginine and/or 1000 mg/day aged garlic extract (AGE) on migraine frequency in migraineurs, over 14 weeks
Measured via daily headache diaries

Timepoint [1]

Daily over the 14 weeks

Primary outcome [2]

To measure the effects of 1500 mg/day L-arginine and/or 1000 mg/day aged garlic extract (AGE) on photosensitivity in migraineurs, over 14 weeks
Measured via photosensitivity test

Timepoint [2]

At Weeks 3 (baseline) and 14 (immediate post-intervention)

Primary outcome [3]

To measure the effects of 1500 mg/day L-arginine and/or 1000 mg/day aged garlic extract (AGE) on quality of life in migraineurs, over 14 weeks
Measured via Migraine-Specific Quality-of-Life Questionnaire (MSQ)

Timepoint [3]

At Weeks 1 (pre-baseline) and 14 (immediate post-intervention)

Secondary outcome [1]

To measure the effects of 1500 mg/day L-arginine and/or 1000 mg/day aged garlic extract (AGE) on retinal vascular diameter in migraineurs, over 12 weeks
Measured via optical coherence tomography angiography (OCTA) scans of left and right eyes

Timepoint [1]

At Weeks 3 (baseline) and 14 (immediate post-intervention)

Secondary outcome [2]

To examine the adverse effects of 1500 mg/day L-arginine and/or 1000 mg/day aged garlic extract (AGE) on the body in migraineurs, over 14 weeks
Examined via reporting of quantity and quality of adverse effects by participants and graded according to the NCI-CTCAE v5 (or higher)

Timepoint [2]

Daily reporting throughout 14-week duration of trial

Secondary outcome [3]

Primary outcome: To measure the effects of 1500 mg/day L-arginine and/or 1000 mg/day aged garlic extract (AGE) on migraine severity in migraineurs, over 14 weeks
Measured using the Short-Form McGill Pain Questionnaire (SF-MPQ)

Timepoint [3]

At Weeks 1 (pre-baseline), 14 (immediate post-intervention) and weekly over the 14 weeks.

Secondary outcome [4]

Primary outcome: To measure the effects of 1500 mg/day L-arginine and/or 1000 mg/day aged garlic extract (AGE) on photosensitivity in migraineurs, over 14 weeks using the Visual Light Sensitivity Questionnaire – 8 (VLSQ-8)

Timepoint [4]

At weeks 1 (pre-baseline) and 14 (immediate post-intervention)

Secondary outcome [5]

Primary outcome: To measure the effects of 1500 mg/day L-arginine and/or 1000 mg/day aged garlic extract (AGE) on photosensitivity in migraineurs, over 14 weeks as measured by the Leiden Visual Sensitivity Scale (L-VISS)

Timepoint [5]

At weeks 1 (pre-baseline) and 14 (immediate post-intervention)

Secondary outcome [6]

Primary outcome: To measure the effects of 1500 mg/day L-arginine and/or 1000 mg/day aged garlic extract (AGE) on migraine severity in migraineurs, over 14 weeks
Measured via daily headache diaries

Timepoint [6]

Daily over the 14 weeks

Secondary outcome [7]

To measure the effects of 1500 mg/day L-arginine and/or 1000 mg/day aged garlic extract (AGE) on blood biomarkers of vascular tone in migraineurs, over 12 weeks
Measured via enzyme-linked immunological assay (ELISA) for asymmetric dimethylarginine (ADMA)

Timepoint [7]

Fasted blood samples collected at Weeks 3 (baseline) and 14 (immediate post-intervention) will be analysed

Secondary outcome [8]

To measure the effects of 1500 mg/day L-arginine and/or 1000 mg/day aged garlic extract (AGE) on blood biomarkers of vascular tone in migraineurs, over 12 weeks
Measured via enzyme-linked immunological (ELISA) assay for symmetric dimethylarginine (SDMA)

Timepoint [8]

Fasted blood samples collected at Weeks 3 (baseline) and 14 (immediate post-intervention) will be analysed

Secondary outcome [9]

Timepoint [9]

Fasted blood samples collected at Weeks 3 (baseline) and 14 (immediate post-intervention) will be analysed

Secondary outcome [10]

Timepoint [10]

Fasted blood samples collected at Weeks 3 (baseline) and 14 (immediate post-intervention) will be analysed

Eligibility

Key inclusion criteria

1. Migraine (with or without aura) diagnosed at least 1 year ago
2. Migraine onset occurred before 50 years of age
3. 2-6 migraine episodes and fewer than 6 'other' headache types per month, over the last 3 months
4. Able to distinguish between migraine and 'other' headache types
5. Able to complete a daily diary about migraine experience
6. Able to commit to taking the 5 capsules a day for 14 weeks

Minimum age

18 Years

Maximum age

80 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Taking medications/drugs affecting vascular tone or blood pressure
2. Taking nitrate drugs or isoproterenol (often prescribed for angina or heart failure)
3. Taking more than two migraine-prevention drugs
4. Taking antidepressants or diuretics, herbs, supplements
5. Taking Sildafenil, Cialis, Spedra and any other PGE-5 inhibitor drugs
6. Taking drugs with potential blood-vessel effects (analgesics, decongestants, or antihistamines)
7. Already taking L-arginine or garlic supplements for 3 months before the study
8. Having headaches causing fainting or another medical emergency
9. Having chronic daily headaches, medication-overuse headaches and/or other secondary headache disorders
10. Having diagnoses other than migraine as the primary cause of headache
11. A change in migraine treatment in the 3 months prior to or during the study
12. Clinical reports of renal or liver dysfunction
13. Clinical risks associated with bleeding or coagulopathy or currently on blood-thinning medications such as warfarin/heparin therapy
14. Having any cardiovascular or neoplastic diseases
15. Having major chronic metabolic or neurologic disorders, or receiving current therapy for them
16. Being diagnosed with psychosis or bipolar affective disorder
17. Diagnosis of cancer
18. Substance abuse/dependence/addiction in the 3 months prior to or during the study
19. Having an history of diabetes, hypertension, collagen vascular disease, vasculitis, or renal disease/failure
20. Having any low-blood-pressure-related issues or Type-1 or -2 diabetes
21. Having the possibility of pregnancy or lactation
22. Being allergic to garlic or its constituents
23. Having gastric disturbances such as bloating, stomach pain, heartburn, diarrhoea, constipation, nausea or vomiting
24. Are a smoker
25. Having an history of eye pathology, surface disorder, surgery (except cataract extraction), injury
26. Not being able to see clearly (with glasses, if need be)
27. Having disorders of the optic nerve (including glaucoma) or retina
28. The significant possibility of our not being able to see the inside of your eye clearly
29. Having poor image perception due to cataract or unstable fixation

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)

The statistician will allocate an identification number to each participant, as per the IHS guidelines. They will do this after the investigator enters the participants into the REsearch Data Capture (REDCap) tool, whereby the statistician will then have access to the list and be able to assign identification numbers that the investigators will not be privy to.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

We are using block randomisation: eligible subjects will be computer-randomised in blocks of 8, to one of the 4 treatment groups (placebo control, L-arginine, aged garlic extract (AGE), and L-arginine + AGE). As migraine is taken to be specifically affected by hormonal cyclical changes, we aim to control for menstruation effects in our statistical analysis. We will randomise by participant ID, as this should preclude group allocation by order of study entry.

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

Not Applicable

Type of endpoint/s

Efficacy

Statistical methods / analysis

We will analyse the results at the completion of the trial, using IBM SPSS® Statistics for Windows, Version 24.0 (IBM Corp., Armonk NY, USA). We will analyse data on an intention-to-treat basis if at least two months of the headache diary are completed. If data from the final (third) trial month is missing, we will substitute in data from the second month. We will report results as a group mean ± standard deviation (SD). We will analyse differences in outcome measures within the groups using Wilcoxon’s matched-pairs signed-ranks test, and we will analyse outcome differences between the groups using the Mann-Whitney U test. We will use the Chi-Square test for demographic data. The criterion for statistical significance will be p < 0.05. We will organise the 4 randomised treatment groups as sex-by-treatment as a 2x2 factorial. We will analyse data from continuous variable outcomes using a General Linear Model, with the baseline values as covariates. We will conduct a post-hoc comparison of means if the interaction between sex and treatment is statistically significant. We will express differences between treatment groups as mean differences with associated 95% confidence intervals. We will analyse data from categorical variable outcomes using a Multivariable Logistic Regression Model, again with the baseline values as covariates. We will express treatment group effects as odds ratios with associated 95% confidence intervals. We will examine residuals from the analyses.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

Actual

27/05/2021

Date of last participant enrolment

Anticipated

30/06/2023

Actual

Date of last data collection

Anticipated

6/10/2023

Actual

Sample size

Target

240

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Multiple Sclerosis WA (MSWA)

Address [1]

29 Parkhill Way, Wilson WA 6107

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

The McCusker Charitable Foundation

Address [2]

46 Stanley Street, Nedlands, WA 6009

Country [2]

Australia

Primary sponsor type

University

Name

Curtin University

Address

Kent Street, Bentley WA 6102

Country

Australia

Secondary sponsor category [1]

None

Name [1]

None

Address [1]

None

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Curtin University Human Research Ethics Committee (HREC)

Ethics committee address [1]

Kent St, Bentley WA 6102

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

19/04/2021

Ethics approval number [1]

HRE2020-0466

Summary

Brief summary

The study hypothesis is that migraines are caused by the constriction of small blood vessels (capillaries) in the brain and that the use of natural, vessel-widening supplements will cause these small blood vessels to dilate and therefore reduce the frequency and severity of migraines. The aim of this study is to investigate whether oral treatment with L-arginine and/or aged garlic extract prevents/decreases migraines in Australian adults. The trial is specifically designed to provide evidence that treatment with these nutraceuticals dilates the small vessels of the brain, thereby improving blood flow and preventing the onset of migraines.  This is a double-blind trial, meaning the participant and investigator will not be aware which group the participant has been randomised to. Approximately 240 men and women who have been diagnosed with migraines, will receive 1500 mg/day L-arginine and/or 1000 mg/day aged garlic extract and/or placebo for 14 weeks. Each participant will be required to take 5 capsules a day over the 14 weeks, and will be asked to monitor their migraine frequency and severity. 
At visit 1, participants will complete a series of daily diaries and questionnaires that will capture information about their pain experience, light-sensitivity and quality of life. We also complete anthropometric measurements. Participants will also receive a 2-week supply of study capsules and two weeks of migraine diaries to be completed daily.
At visit 2 (2 weeks after visit 1), participants will provide a blood sample, complete a light-sensitivity test, and an OCTA (optical coherence tomography angiography) scan. Participants will then receive a 12-week supply of the study capsules and migraine diaries to be completed daily.
At visit 3 (12 weeks after visit 2), participants will recomplete the questionnaires from visit 1, and will recomplete the measures from visit 2, After the 14 weeks (visits 1-3), we will compare each participant’s baseline (visits 1 & 2) and post-intervention (visit 3) results to examine the impact of L-arginine and aged garlic extract on migraine symptoms, and whether this corresponds with dilation of the small cerebral blood vessels.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof John Mamo

Address

Curtin University, Kent Street, Bentley WA 6102

Country

Australia

Phone

+61 08 9266 7232

Fax

j.mamo@curtin.edu.au

Contact person for public queries

Name

John Mamo

Address

Curtin University, Kent Street, Bentley WA 6102

Country

Australia

Phone

+61 08 9266 7232

Fax

j.mamo@curtin.edu.au

Contact person for scientific queries

Name

John Mamo

Address

Curtin University, Kent Street, Bentley WA 6102

Country

Australia

Phone

+61 08 9266 7232

Fax

j.mamo@curtin.edu.au

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

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	L-arginine and aged garlic extract for the prevention of migraine: a study protocol for a randomised, double-blind, placebo-controlled, phase-II trial (LARGE trial).	2023	https://dx.doi.org/10.1186/s12883-023-03149-y

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

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