Trial Review

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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] 294865 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
MERIT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Peripheral Artery Disease 307816 0
Condition category
Condition code
Cardiovascular 306863 306863 0 0
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] 301177 0
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] 305854 0
Maximum walking distance during a six minute walk test performed.
Timepoint [1] 305854 0
Baseline and 30 weeks.
Secondary outcome [1] 346797 0
Voluntary physical activity over 7 days assessed by ActiGraph
Timepoint [1] 346797 0
Baseline and 30 weeks
Secondary outcome [2] 346799 0
Plasma concentrations of vascular endothilial growth factor (VEGF).
Timepoint [2] 346799 0
Baseline and 30 weeks
Secondary outcome [3] 346803 0
Health-related quality of life measured by SF-36 Quality of Life Questionnaire
Timepoint [3] 346803 0
Baseline and 30 weeks
Secondary outcome [4] 346804 0
Lower Limb Blood Supply assessed by Ankle Brachial Pressure Index (ABPI)
Timepoint [4] 346804 0
Baseline and 30 weeks
Secondary outcome [5] 348298 0
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] 348298 0
baseline and 30 weeks
Secondary outcome [6] 349404 0
Quality of life using condition specific Intermittent Claudication Questionnaire.
Timepoint [6] 349404 0
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?
No
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] 14310 0
The Townsville Hospital - Douglas
Recruitment hospital [2] 14931 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [3] 14932 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 40157 0
2031 - Randwick
Recruitment postcode(s) [2] 28202 0
4029 - Herston
Recruitment postcode(s) [3] 28203 0
4102 - Woolloongabba
Recruitment postcode(s) [4] 27308 0
4814 - Douglas

Funding & Sponsors
Funding source category [1] 299452 0
University
Name [1] 299452 0
James Cook University
Country [1] 299452 0
Australia
Funding source category [2] 299844 0
Hospital
Name [2] 299844 0
The Townsville Hospital and Health Service
Country [2] 299844 0
Australia
Funding source category [3] 303386 0
Charities/Societies/Foundations
Name [3] 303386 0
National Heart Foundation of Australia
Country [3] 303386 0
Australia
Funding source category [4] 313684 0
Government body
Name [4] 313684 0
Medical Research Future Fund - Dementia, Ageing and Aged Care Mission
Country [4] 313684 0
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] 298748 0
None
Name [1] 298748 0
Address [1] 298748 0
Country [1] 298748 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300358 0
The Townsville Hospital & Health Service Human Research Ethics Committee
Ethics committee address [1] 300358 0
HREC Coordinator, The Townsville Hospital, IMB 52, PO Box 670, Townsville, QLD, 4810
Ethics committee country [1] 300358 0
Australia
Date submitted for ethics approval [1] 300358 0
21/06/2018
Approval date [1] 300358 0
02/08/2018
Ethics approval number [1] 300358 0
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 83390 0
Prof Jonathan Golledge
Address 83390 0
Queensland Research Centre for Peripheral Vascular Disease
College of Medicine & Dentistry
James Cook University, 1 James Cook Drive
Townsville QLD 4811
Country 83390 0
Australia
Phone 83390 0
+61 07 44331747
Fax 83390 0
Email 83390 0
jonathan.golledge@jcu.edu.au
Contact person for public queries
Name 83391 0
Dr Rene Jaeggi
Address 83391 0
Queensland Research Centre for Peripheral Vascular Disease
College of Medicine & Dentistry
James Cook University, 1 James Cook Drive
Townsville QLD 4811
Country 83391 0
Australia
Phone 83391 0
+61 07 47815449
Fax 83391 0
Email 83391 0
rene.jaeggi@jcu.edu.au
Contact person for scientific queries
Name 83392 0
Prof Jonathan Golledge
Address 83392 0
Queensland Research Centre for Peripheral Vascular Disease
College of Medicine & Dentistry
James Cook University, 1 James Cook Drive
Townsville QLD 4811
Country 83392 0
Australia
Phone 83392 0
+61 07 44331747
Fax 83392 0
Email 83392 0
jonathan.golledge@jcu.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
The study protocol does not involve the sharing of individual participant data to third parties.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
934Informed consent form https://www.jcu.edu.au/qrcpvd 
3432Study 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
SourceTitleYear of PublicationDOI
EmbasePathology, Progression, and Emerging Treatments of Peripheral Artery Disease-Related Limb Ischemia.2023https://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.