ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12618001186246

Ethics application status

Approved

Date submitted

31/05/2018

Date registered

17/07/2018

Date last updated

7/04/2024

Date data sharing statement initially provided

25/07/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

Metformin for treating peripheral artery disease-related walking impairment

Scientific title

Metformin for treating peripheral artery disease-related walking impairment

Secondary ID [1]

Nil Known

Universal Trial Number (UTN)

Trial acronym

MERIT

Linked study record

Health condition

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

Peripheral Artery Disease

Condition category

Condition code

Cardiovascular

Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Study Design: Parallel group, blinded, placebo-controlled randomised clinical trial.

Intervention - metformin: up to one 500mg capsule three times per day (1500mg/day).

Titration (1-6 weeks): Participants in both arms will have their medications up titrated over 6 weeks to tolerance based on symptoms.
Week 1 & 2: one 500mg capsule once per day with food (~500mg/day).
Week 3 & 4: one 500mg capsule twice per day with food (~1000mg/day).
Week 5 & 6: one 500mg capsule three times per day with food (~1500mg/day).

Follow-up (24 weeks post titration period): participants will continue to take the maximum tolerated dose of drug up to 1500mg/day for 24 weeks.
Week 7-30: one 500mg capsule three times per day with food (~1500mg/day).

Participants will be given a calendar diary to keep track of the dose to be taken each week and to record the number and time of day the capsules are taken. The purpose of the diary is to assist the participant in taking the right amount of drug at the right time and day.

Participants will be asked to return any empty bottles and remaining capsules to the study coordinator for a pill count in order to assess adherence.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Study Design: Parallel group, blinded, placebo-controlled randomised clinical trial.

Placebo - an inert cellulose powder: up to one 500mg capsule three times per day (1500mg/day).

Titration (1-6 weeks): Participants in both arms will have their medications up titrated over 6 weeks to tolerance based on symptoms.
Week 1 & 2: one 500mg capsule once per day with food (~500mg/day).
Week 3 & 4: one 500mg capsule twice per day with food (~1000mg/day).
Week 5 & 6: one 500mg capsule three times per day with food (~1500mg/day).

Follow-up (24 weeks post titration period): participants will continue to take the maximum tolerated dose of drug up to 1500mg/day for 24 weeks.
Week 7-30: one 500mg capsule three times per day with food (~1500mg/day).

Participants will be given a calendar diary to keep track of the dose to be taken each week and to record the number and time of day the capsules are taken. The purpose of the diary is to assist the participant in taking the right amount of drug at the right time and day.

Participants will be asked to return any empty bottles and remaining capsules to the study coordinator for a pill count in order to assess adherence.

Control group

Placebo

Outcomes

Primary outcome [1]

Maximum walking distance during a six minute walk test performed.

Timepoint [1]

Baseline and 30 weeks.

Secondary outcome [1]

Voluntary physical activity over 7 days assessed by ActiGraph

Timepoint [1]

Baseline and 30 weeks

Secondary outcome [2]

Plasma concentrations of vascular endothilial growth factor (VEGF).

Timepoint [2]

Baseline and 30 weeks

Secondary outcome [3]

Health-related quality of life measured by SF-36 Quality of Life Questionnaire

Timepoint [3]

Baseline and 30 weeks

Secondary outcome [4]

Lower Limb Blood Supply assessed by Ankle Brachial Pressure Index (ABPI)

Timepoint [4]

Baseline and 30 weeks

Secondary outcome [5]

Occurrence of cardiovascular events (myocardial infarction, stroke, death) and interventions (open or endovascular peripheral revascularization and cardiac procedures). This data will be collected from the patient during follow-up phone calls and their medical records.

Timepoint [5]

baseline and 30 weeks

Secondary outcome [6]

Quality of life using condition specific Intermittent Claudication Questionnaire.

Timepoint [6]

Baseline and 30 weeks

Eligibility

Key inclusion criteria

1. PAD diagnosed by a vascular specialist based on current guidelines including PAD symptoms and absence of lower limb pulses or resting ABPI <0.9 or >1.4, or imaging evidence of lower limb arterial stenosis or occlusion;

2. Able to walk independently, with or without walking aids, but walking limited by intermittent claudication based on history and assessment by experienced observer during a six minute walk test;

3. No currently planned peripheral vascular intervention;

4. No contraindications to metformin, including renal impairment (defined as estimated glomerular filtration rate <45ml/min/1.73m2) and severe heart failure requiring in-patient treatment within the last 12 months or leading to shortness of breath at rest.

Minimum age

40 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Asymptomatic PAD;
2. Patients currently involved in an exercise program for treating PAD;
3. Patients with severe PAD, such as rest pain or gangrene requiring urgent vascular intervention;
4. Previous major lower limb amputation;
5. Diabetes defined by Haemoglobin A1C (HbA1c) equal or greater than 6.5%.
6. Terminal illness making it unlikely the patient will survive 6 months;
7. Involvement in any other drug trial;
8. Clinical concern from the treating physician that the patient is not suitable for the trial.

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)

independent online minimisation randomisation program where allocation will be sent to local pharmacist who will dispense medication in concealed medication bottles.

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

independent online minimisation randomisation program which will ensure equal balance of important determinants of between treatment groups (MWD on a six minute walk test, ABI category i.e. <0.5, 0.5-0.9 and >1.4, age, sex and center). A random element will be included such that the probability of being allocated that treatment determined by the minimization algorithm is 90%.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Phase 4

Type of endpoint/s

Efficacy

Statistical methods / analysis

A prior study examined what a meaningful change in 6MWT distance was in 777 PAD patients. Participants were asked to rate their walking impairment on a Likert scale from 0 (inability to walk) to 4 (no difficulty). Participants who reported a 2-point improvement in walking ability had a mean increase in 6MWT distance of ~30 metres. This 30m difference in 6MWT distance equated to an increase in SF-36 PCS score of ~45% and a 12% reduction in the risk of major cardiovascular events. In past trials, the SD of 6MWT distance was between 60 and 80m. In order to test a 30m (SD 80m) difference in 6MWT at six months (i.e. effect size of 0.4) as the primary hypothesis, using a linear mixed effects model where the primary coefficient of interest is the interaction term between time and group (power 90%, two-sided a=0.05 and correlation over time of 0.7) we require 112 participants per group. We have conservatively increased the sample size by 10% to account for potential drop-out (e.g. inability to tolerate drug) meaning that a total of 250 participants (n=125 per group) are required. Based on our prior studies in PAD patients, this sample size will be very well powered to test the key secondary outcome of HRQOL.

Data will be monitored using a risk-based approach where data relating to primary and secondary outcomes will be checked in real time for completeness, accuracy and validity by an experienced central study coordinator. In instances where there are errors in the data the study coordinator will contact the site coordinator for clarification as soon as reasonably possible.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

4/02/2019

Actual

21/06/2019

Date of last participant enrolment

Anticipated

30/06/2025

Actual

Date of last data collection

Anticipated

31/12/2025

Actual

Sample size

Target

250

Accrual to date

158

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD

Recruitment hospital [1]

The Townsville Hospital - Douglas

Recruitment hospital [2]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [3]

Princess Alexandra Hospital - Woolloongabba

Recruitment postcode(s) [1]

4814 - Douglas

Recruitment postcode(s) [2]

4029 - Herston

Recruitment postcode(s) [3]

4102 - Woolloongabba

Recruitment postcode(s) [4]

2031 - Randwick

Funding & Sponsors

Funding source category [1]

University

Name [1]

James Cook University

Address [1]

James Cook University, 1 James Cook Drive, Townsville QLD 4811 AUSTRALIA

Country [1]

Australia

Funding source category [2]

Hospital

Name [2]

The Townsville Hospital and Health Service

Address [2]

100 Angus Smith Drive, Douglas, QLD, 4814

Country [2]

Australia

Funding source category [3]

Charities/Societies/Foundations

Name [3]

National Heart Foundation of Australia

Address [3]

Level 2, 850 Collins Street, Docklands VIC 3008

Country [3]

Australia

Funding source category [4]

Government body

Name [4]

Medical Research Future Fund - Dementia, Ageing and Aged Care Mission

Address [4]

National Health and Medical research Council
16 Marcus Clarke St
Canberra ACT 2601

Country [4]

Australia

Primary sponsor type

University

Name

James Cook University

Address

James Cook University, 1 James Cook Drive, Townsville QLD 4811 AUSTRALIA

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Townsville Hospital & Health Service Human Research Ethics Committee

Ethics committee address [1]

HREC Coordinator, The Townsville Hospital, IMB 52, PO Box 670, Townsville, QLD, 4810

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

21/06/2018

Approval date [1]

02/08/2018

Ethics approval number [1]

HREC/18/QTHS/158

Summary

Brief summary

This parallel group, blinded, placebo-controlled randomised trial will determine whether 1500mg/day of metformin administered for 6 months improves walking ability in PAD patients. Based on sample size calculations focused on the minimal clinically important difference, 250 PAD patients that do not have diabetes, renal or cardiac failure will be included. The trial will employ an independently run minimisation randomisation system and identical appearance, weight and packaging of drug and placebo to ensure blinding of investigations, patients and assessors, along with balancing of important determinants of outcome. The primary outcome measure will be the 6-month maximum walking distance during a six minute walk test. Secondary outcomes will include physical activity assessed over 7 days with an accelerometer, health-related quality of life, leg blood supply assessed with ankle-brachial pressure index and circulating concentrations of key markers of angiogenesis. Adverse events will be monitored by an independent data monitoring committee. Previous trials indicate metformin is safe for patients without diabetes.

Trial website

https://www.jcu.edu.au/qrcpvd

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Jonathan Golledge

Address

Queensland Research Centre for Peripheral Vascular Disease
College of Medicine & Dentistry
James Cook University, 1 James Cook Drive
Townsville QLD 4811

Country

Australia

Phone

+61 07 44331747

Fax

[email protected]

Contact person for public queries

Name

Rene Jaeggi

Address

Queensland Research Centre for Peripheral Vascular Disease
College of Medicine & Dentistry
James Cook University, 1 James Cook Drive
Townsville QLD 4811

Country

Australia

Phone

+61 07 47815449

Fax

[email protected]

Contact person for scientific queries

Name

Jonathan Golledge

Address

Queensland Research Centre for Peripheral Vascular Disease
College of Medicine & Dentistry
James Cook University, 1 James Cook Drive
Townsville QLD 4811

Country

Australia

Phone

+61 07 44331747

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

The study protocol does not involve the sharing of individual participant data to third parties.

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
934	Informed consent form		https://www.jcu.edu.au/qrcpvd
3432	Study protocol				It is anticipated that the study protocol will be ... [More Details]

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	Pathology, Progression, and Emerging Treatments of Peripheral Artery Disease-Related Limb Ischemia.	2023	https://dx.doi.org/10.1016/j.clinthera.2023.09.005

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

Trial Review

Documents added manually

Documents added automatically