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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
8/10/2019
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
Gender
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
We estimate that at 6 months the mean (±SD) maximum walking distance during a six minute walk test will be 368±93m in patients receiving placebo and 433±109m in those allocated metformin. The outcome estimate for the control group was based on findings in our current trial in 122 PAD patients. We will test a difference of 65m between the intervention and placebo groups since previous research suggests that a minimum clinically meaningful difference in maximum walking distance during a six minute walk test is between 30m and 167m or ~65m (mean of six previous studies 30, 37, 45, 45, 48, 167= 62m). We have assumed that the mean will differ in line with the SD. Based on these estimates we require 52 patients per group (power 90%, a = 0.05, continuity correction included) to detect the hypothesised difference. Allowing for a 10% drop-out rate and rounding up we will recruit 116 patients in total.

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
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)
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] 28202 0
4029 - Herston
Recruitment postcode(s) [2] 28203 0
4102 - Woolloongabba
Recruitment postcode(s) [3] 27308 0
4814 - Douglas

Funding & Sponsors
Funding source category [1] 299452 0
University
Name [1] 299452 0
James Cook University
Address [1] 299452 0
James Cook University, 1 James Cook Drive, Townsville QLD 4811 AUSTRALIA
Country [1] 299452 0
Australia
Funding source category [2] 299844 0
Hospital
Name [2] 299844 0
The Townsville Hospital and Health Service
Address [2] 299844 0
100 Angus Smith Drive, Douglas, QLD, 4814
Country [2] 299844 0
Australia
Funding source category [3] 303386 0
Charities/Societies/Foundations
Name [3] 303386 0
National Heart Foundation of Australia
Address [3] 303386 0
Level 2, 850 Collins Street, Docklands VIC 3008
Country [3] 303386 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, 116 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
Mrs Jenna Pinchbeck
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
jenna.pinchbeck@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?
Study protocol
Informed consent form
How or where can supporting documents be obtained?
Type [1] 934 0
Informed consent form
Citation [1] 934 0
Link [1] 934 0
Email [1] 934 0
Other [1] 934 0
Attachment [1] 934 0
Type [2] 3432 0
Study protocol
Citation [2] 3432 0
Link [2] 3432 0
Email [2] 3432 0
Other [2] 3432 0
It is anticipated that the study protocol will be published in a peer review journal.
Attachment [2] 3432 0
Summary results
No Results