Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000250235
Ethics application status
Approved
Date submitted
22/01/2018
Date registered
16/02/2018
Date last updated
16/02/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
(M)ultifactorial (I)ntervention in Patients with (P)eripheral (A)rterial (D)isease - A Randomised Controlled Trial
Scientific title
MIPAD: A randomised controlled trial of a multifactorial intervention targeting functional status, cardiovascular risk factors and quality of life in patients with. peripheral arterial disease
Secondary ID [1] 292687 0
None
Universal Trial Number (UTN)
U1111-1200-9791
Trial acronym
MIPAD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Peripheral arterial disease 304437 0
Condition category
Condition code
Cardiovascular 303770 303770 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The aim of this study is to investigate the effects of a multifactorial intervention compared with standard treatment in patients with peripheral arterial disease. Patients with peripheral arterial disease are also at risk of coronary artery disease and cerebrovascular disease. Studies have shown that patients with peripheral arterial disease have suboptimal control of many cardiovascular risk factors.

This study is a prospective, local multi-centre randomised controlled trial. A total of 150 participants will be randomised in a 1:1 ratio to an intervention arm (group A) and a control arm (group B). The total followup is 12 months.

Group A (Intervention arm)
Group A will undergo a multifactorial intervention with comprehensive lifestyle and medical program designed to manage cardiovascular risk factors. Intervention in group A is intended to complement standard practice. Multifactorial intervention will occur in the medical clinic setting and can include:
Frequent review in a medical clinic
Review of blood pressure, cholesterol and diabetes with introduction of medications to treat these conditions
Smoking cessation program
Structured exercise program
Weight loss program
Obstructive sleep apnoea screening and treatment

Procedure Specifics:
Medical history and medication review
Review by medical physician. Details include: symptoms, past medical history, social history, medication history, and drug allergies and intolerances. If any clinically significant adverse event occurs, in the judgement of the investigator, it will be reported on the adverse event form. It is intended that group A participants are seen mainly by a single medical physician during the study period, to provide continuity of care.

Blood pressure management
Blood pressure will be measured during clinic review or using a home-based automated monitor. Group A participants with home-based monitoring will record values in a journal. Hypertension will be treated with target resting BP less than 130/80 mmHg at least 80% of the time. Participants with hypertension will be monitored with echocardiography to assess for left ventricular hypertrophy progression/ regression. An echocardiogram will be performed at baseline and upon study completion.
Lifestyle modification for treatment of hypertension will include dietary salt restriction and/or weight loss program. Pharmacotherapy will be initiated in a stepwise fashion with a preference for angiotensin-converting enzyme inhibitors or angiotensin 2 receptor antagonists as first line treatment of choice.

Lipid Management
Serum lipid testing will be performed throughout the study. All participants will be commenced on statin medication, where tolerated. Lipid targets include: LDL less than 1.8 mmol/L and Non-HDL cholesterol less than 2.6 mmol/L. Treatment of dyslipidaemia will include dietary guidance and escalation of statin therapy to maximum tolerated dose. Additional therapy such as ezetimibe or fibrates may be introduced, where targets are not being met.

Weight Management
Where a group A participant has a BMI greater than or equal to 27kg/m2, they will be offered a weight management program. The goal will be for a BMI less than 27kg/m2 or at least 10% weight loss. The weight management program will emulate methodology executed in a previous cardiovascular risk factor modification study. Participants will have a structured motivational and goal-directed program with physician-led counselling. Meal plans will consist of a calorie-restricted diet with foods high in protein and a low glycaemic index. In addition, participants will commence a structured exercise program as described below. These participants will be encouraged to maintain a lifestyle journal with documentation of a nutritional intake and physical activities during the week. Weight management will be a priority throughout the duration of the study. Investigators will provide regular feedback and advice to participants via clinic follow-up and/or email contact. Frequency of contact at discretion of the treating physician.

Exercise Therapy
Group A participants will be offered an optional structured exercise program that is developed in consultation with an exercise physiologist. This plan is personalised and will consider the motivation and physical limitations of the individual. The program will begin with directly-supervised exercise therapy, and then a structured home-based exercise program thereafter. For example: An initial supervised exercise program occurs in an outpatient facility. Subsequently, the participant is counselled and given instructions for home-based exercise therapy, such as walking, cycling and/or lower limb training. The participant is encouraged to exercise until moderate-maximum claudication, alternating with periods of rest. The goal is to gradually increase the duration and/or intensity of prescribed activities. The participant logs an activity diary and keeps in regular contact with the healthcare provider (via regular email, and clinic). Clinic review will occur every 6-8 weeks with the exercise physiologist.

Glycaemic Control
Diagnosis of diabetes may be made with a fasting blood glucose test and/or HbA1c. Management of glycaemia could involve lifestyle modification and/or pharmacotherapy. Participants will be instructed about symptoms and management of hypoglcaemia. To reach target HbA1c less than 7%, group A participants may be referred to a specialised diabetes clinic.

Smoking Cessation
Group A participants will be encouraged to stop smoking. Smoking abstinence may be achieved by counselling and/ or pharmacotherapy. Medications such as nicotine replacement therapy, bupropion and/or varenicline may be commenced.

Sleep-Disordered Breathing Management
Participants in the intervention arm (group A) will undergo Berlin Questionnaire and home sleep testing (Apnea Link) screening at baseline. The results of these investigations will be made available to their usual treating clinicians. Participants with suspected obstructive sleep apnoea will be referred for review by a dedicated sleep disorder unit. The diagnosis can be confirmed with an overnight polysomnography test. Group A participants with an elevated apnoea-hypopnoea index (at least 30/hour) will be offered continuous positive airway pressure (CPAP) therapy.
Intervention code [1] 298922 0
Lifestyle
Intervention code [2] 298923 0
Treatment: Drugs
Intervention code [3] 300297 0
Treatment: Other
Comparator / control treatment
Group B (Control arm)
Group B (control) participants will undergo study investigations at baseline, 6months and 12 months.

It is common for patients with PAD to have serial follow-up with a vascular surgeon and/or general practitioner. Group B participants will continue with standard care. Standard care will be defined as the treatment received by their usual treating clinicians. They will be offered the option of multifactorial intervention after completion of the study at 12 months.
Control group
Active

Outcomes
Primary outcome [1] 303136 0
The maximum walking distance (MWD) at 12-months, as defined as the distance the patient can walk on a treadmill (fixed at 2.4km/hour with a 6-degree incline; up to 15 mins) before they have to stop due to any reason.
Timepoint [1] 303136 0
Assessed at baseline, 6months and 12 months
12 months is the primary time-point
Secondary outcome [1] 337995 0
Composite secondary outcome of number of risk factors under "control" (total of 7).
Assessment of each risk factor is dichotomous and will be categorised as under “control” if they are meeting specified targets: (1) Systolic BP less than 130mmHg and diastolic BP less than 80mmHg. Blood pressure measured using sphygmomanometer (2) Glycated haemoglobin less than 7.0%. Glycated haemoglobin measured using plasma assay. (3) LDL less than 1.8mmol/L. Low density lipoprotein measured using serum assay (4) Non-HDL cholesterol less than 2.6 mmol/L. Non high density lipoprotein cholesterol measured using serum assay (5) hsCRP less than 2 mg/L. High sensitivity C-reactive protein measured by serum assay. (6) Smoking abstinence for previous 3 months. Smoking abstinence will be assessed via participant self-reporting. (7) Body mass index (BMI) less than 27kg/m2 or at least 10% weight loss. Body mass index calculated from height and weight.
Timepoint [1] 337995 0
Assessed at baseline, 6months and 12 months.
Secondary outcome [2] 337997 0
Quality of life score (as measured by the Peripheral Artery Questionnaire)
Timepoint [2] 337997 0
Baseline, 6months and 12 months
Secondary outcome [3] 337998 0
Composite secondary outcome of "adherence" (total of 5) to guideline-based therapy:
(1) Use of angiotensin-converting enzyme inhibitor or angiotensin 2 receptor antagonist. Participant is taking medication, ascertained from history.

(2) Use of statin.
Participant is taking medication, ascertained from history.

(3) Smoking abstinence for previous 3 months
Participant has abstained from smoking, as ascertained from medical history.

(4) Use of antithrombotic medication
Participant is taking medication, ascertained from history.

(5) Participation in a structured exercise program.
Participation and review of exercise regimen within the last 3 months. Ascertained from history. The exercise program includes review in hospital or outpatient setting (within the last 3 months). There is guidance from a qualified healthcare provider specifically regarding exercise rehabilitation.
Timepoint [3] 337998 0
Baseline, 6months and 12 months
Secondary outcome [4] 337999 0
Initial claudication distance (ICD), which is defined as the distance the patient can walk on the treadmill before onset of claudication
Timepoint [4] 337999 0
Baseline, 6months and 12 months
Secondary outcome [5] 338001 0
Berlin Questionnaire score snoring and sleep quality
Timepoint [5] 338001 0
Baseline, 6months and 12 months
Secondary outcome [6] 338002 0
Change in markers of inflammation and endothelial function (including hsCRP, TNF, IL-6, IL-1B, s-VCAM, MPO, neutrophil counts, lymphocyte/neutrophil ratio, Endothelin-1 and other exploratory biomarkers). These markers will be measured using serum assay.
Timepoint [6] 338002 0
Baseline, 6months and 12 months
Secondary outcome [7] 338005 0
Number of hospitalisations during the study period. This will be identified from study-specific questionnaire and/or consultation with medical records.
Timepoint [7] 338005 0
Baseline, 6months and 12 months
Secondary outcome [8] 338006 0
Number of revascularisation procedures during the study period. This will be identified from study-specific questionnaire and/or consultation with medical records.
Timepoint [8] 338006 0
Baseline, 6months and 12 months
Secondary outcome [9] 338007 0
Composite secondary endpoint of major adverse cardiovascular events (MACE) during study period. This includes non-fatal myocardial infarction, non-fatal stroke and cardiovascular-mortality. This will be identified from study-specific questionnaire and/or consultation with medical records.
Timepoint [9] 338007 0
Baseline, 6months and 12 months
Secondary outcome [10] 338008 0
Composite secondary endpoint of major adverse limb events (MALE) during study period. This includes acute limb ischemia and/or limb amputation. This will be identified from study-specific questionnaire and/or consultation with medical records.
Timepoint [10] 338008 0
Baseline, 6months and 12 months
Secondary outcome [11] 338009 0
Mortality during study period
Timepoint [11] 338009 0
Baseline, 6months and 12 months
Secondary outcome [12] 338010 0
Composite outcome of MACE, MALE, cardiovascular mortality, revascularisations, and hospitalisations. This will be identified from study-specific questionnaire and/or consultation with medical records.
Timepoint [12] 338010 0
Baseline, 6months and 12 months
Secondary outcome [13] 342955 0
Blood pressure measured using sphygmomanometer.
The outcome will be continuous (specific blood pressure measure) and dichotomous (target met: yes/no). Target systolic blood pressure less than 130mmHg and diastolic blood pressure less than 80 mmHg.
Timepoint [13] 342955 0
Baseline, 6months and 12 months
Secondary outcome [14] 342956 0
Glycated haemoglobin measured using a plasma assay.
The outcome will be continuous (specific glycated haemoglobin measurement) and dichotomous (target met: yes/no). Target glycated haemoglobin less than 7.0%.
Timepoint [14] 342956 0
Baseline, 6months and 12 months
Secondary outcome [15] 342957 0
Low density lipoprotein measured using serum assay. The outcome will be continuous (specific LDL measurement) and dichotomous (target met: yes/no). Target LDL less than 1.8mmol/L.
Timepoint [15] 342957 0
Baseline, 6months and 12 months
Secondary outcome [16] 342958 0
Non high density lipoprotein cholesterol measured using serum assay. The outcome will be continuous (specific non-HDL cholesterol measurement) and dichotomous (target met: yes/no). Target non-HDL cholesterol less than 2.6 mmol/L.
Timepoint [16] 342958 0
Baseline, 6months and 12 months
Secondary outcome [17] 342959 0
High sensitivity C-reactive protein measured by serum assay. The outcome will be continuous (specific high sensitivity measure) and dichotomous (target met: yes/no). Target high sensitivity C-reactive protein of less than 2mg/L.
Timepoint [17] 342959 0
Baseline, 6months, 12 months
Secondary outcome [18] 342960 0
Smoking abstinence for previous 3 months. The outcome will be dichotomous (target met: yes/no). Smoking abstinence will be assessed via participant self-reporting.
Timepoint [18] 342960 0
Baseline, 6months and 12 months
Secondary outcome [19] 342961 0
Body mass index calculated from height and weight. The outcome will be continuous (specific BMI measurement) and dichotomous (target met: yes/no). Target body mass index (BMI) less than 27kg/m2 or at least 10% weight loss (where baseline BMI greater than or equal to 27kg/m2).
Timepoint [19] 342961 0
Baseline, 6months and 12 months

Eligibility
Key inclusion criteria
1. Established symptomatic peripheral arterial disease with diagnosis confirmed by either:
- Ankle brachial index (ABI) less than or equal to 0.9
OR
- Specialist review
OR
- Documented history of a previous lower limb revascularisation procedure

2. Aged between 18 and 80 at the time of enrolment
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known to a physician specifically for optimisation of atherosclerotic risk factors
2. Acute coronary syndrome and/or invasive coronary intervention (such as coronary artery bypass graft surgery or percutaneous coronary intervention) within 12-months prior to screening.
3. Planned lower limb revascularisation procedure within 3 months of screening
4. Presence of congestive heart failure (CHF)
5. Transient ischaemic attack (TIA) or stroke within 12-months prior to screening.
6. Other clinically significant cardiovascular, pulmonary, renal, endocrine, hepatic, neurological, psychiatric, immunological, gastrointestinal, haematological or metabolic disease that is, in the opinion of the investigator, not stabilised or may otherwise confound the results of the study.
7. Other co-morbidities which would, in the investigator’s judgement, prevent the participant from successfully completing protocol requirements. These include (but are not limited to): unstable critical limb ischemia, lower limb ulceration and/or amputation(s), severe respiratory disease; neurological dementia; end-stage renal disease with estimated glomerular filtration rate (EGFR<30 mL/min) or undergoing haemodialysis; thrombocytopenia as defined by a platelet count <100 x 10^9; active malignancy; active autoimmune or systemic inflammatory disease; severe hepatic failure
8. Estimated life expectancy less than 24 months
9. Not willing to attend regular follow-up
10. Female participants cannot be pregnant or breastfeeding
11. Participants whom, in the investigator’s judgement, cannot provide adequate informed consent

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)
Allocation concealment. Central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


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
Sample Size Calculation
This study will be adequately powered to assess the primary outcome of maximum walk distance (MWD) at 12 months. Exercise training will be a particularly relevant factor, as it is recognised as the most important non-invasive intervention to improve walk distance and claudication in PAD. MWD will be affected less predictably by other multifactorial interventions. We suspect that patients in the standard therapy arm (group B) will have limited participation in exercise therapy. We believe that the interventional arm (group A) will benefit with an increased adherence to a structured exercise program. According to a Cochrane meta-analysis, supervised exercise therapy increased MWD by 60% (compared with non-supervised exercise therapy) after 12 months in symptomatic PAD. However, in predicting the treatment effect, there are many factors including compliance, symptom burden and the confounding impact of revascularisation during the study period. We have used published data on the treadmill protocol testing, estimating a mean MWD 204 metres for group B (standard deviation 116 metres). We will power the study to detect a net mean increase in MWD by 30% for group A. Therefore, a sample size of 150 participants (1:1 randomisation) allows for an approximate 20% drop out, and will have 80% power to detect a difference of MWD at a 0.05 significance level.
Other endpoints include the: total number of risk factors categorised as under “control”; quality of life score (as measured by Peripheral Artery Questionnaire); total adherence to guideline-based therapies; and other listed secondary outcomes. There will be analysis of the rate of hospitalisations, revascularisations, Major Adverse Cardiovascular Events (MACE), Major Adverse Limb Events (MALE) and mortality. However, this study will not be powered to assess the impact of intervention on these clinical outcomes.

Statistical Analysis
Normally distributed data will be expressed as mean +/- standard deviation. Count data will be expressed as a count and percentage. Differences between groups will be analysed using unpaired t-tests for continuous data or Fisher’s exact test for count data.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
19/02/2018
Actual
Date of last participant enrolment
Anticipated
2/02/2019
Actual
Date of last data collection
Anticipated
8/02/2020
Actual
Sample size
Target
150
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 8830 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 8831 0
The Queen Elizabeth Hospital - Woodville
Recruitment postcode(s) [1] 16958 0
5000 - Adelaide
Recruitment postcode(s) [2] 16959 0
5011 - Woodville

Funding & Sponsors
Funding source category [1] 297328 0
Other
Name [1] 297328 0
South Australian Health and Medical Research Institute (SAHMRI)
Country [1] 297328 0
Australia
Primary sponsor type
Other
Name
South Australian Health and Medical Research Institute (SAHMRI)
Address
South Australian Health and Medical Research Institute
North Terrace, Adelaide, South Australia 5000
Country
Australia
Secondary sponsor category [1] 296301 0
University
Name [1] 296301 0
University of Adelaide
Address [1] 296301 0
University of Adelaide
North Terrace, Adelaide, SA 5000
Country [1] 296301 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298430 0
Royal Adelaide Hospital Human Research Ethics Committee
Ethics committee address [1] 298430 0
Level 4, Women’s Health Centre Royal Adelaide Hospital
North Terrace Adelaide, South Australia, 5000
Ethics committee country [1] 298430 0
Australia
Date submitted for ethics approval [1] 298430 0
Approval date [1] 298430 0
11/08/2017
Ethics approval number [1] 298430 0
R20170316

Summary
Brief summary
There are clinical trials that have examined the benefits of supervised exercise training in addition to “optimal medical care” in peripheral arterial disease (PAD). However, aggressive risk factor modification was not the focus, as it has been in other (non-PAD) cardiovascular studies. This randomised controlled trial will evaluate the impact of a systematic physician-led approach to aggressive risk factor modification in PAD.

Hypothesis:
A multifactorial intervention in patients with PAD, compared to standard practice, will lead to improved functional status (as assessed by maximum walking distance [MWD]), cardiovascular risk factor control, and quality of life (as measured by Peripheral Artery Questionnaire). This systematic physician-led program will increase adherence to guideline-based therapies. There will be beneficial effects on the atherosclerotic disease process (as measured by exploratory biomarkers of inflammation).

TRIAL DESIGN
This is an investigator initiated, local, multicentre, randomised controlled trial in South Australia. A total of 150 participants will be randomised into two groups. The intervention arm (group A) will undergo multifactorial intervention under a physician-led program of behaviour modification with stepwise introduction of pharmacologic therapy. This group will have follow-up over a 12-month study period. The follow-up frequency will be up to the discretion of the study physician. The standard therapy arm (group B) will have conventional treatment (e.g. follow-up with general practitioner and/or vascular surgeon) for the length of the 12-month study period. These patients will be offered multifactorial intervention after completion of the protocol. The clinic reviews and investigations in this study are intended to complement standard practice. All participants will continue to see their usual treating clinicians throughout the study period.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77058 0
Prof Stephen Nicholls
Address 77058 0
South Australian Health and Medical Research Institute
North Terrace, Adelaide, SA 5000
Country 77058 0
Australia
Phone 77058 0
61 8 8128 4510
Fax 77058 0
Email 77058 0
[email protected]
Contact person for public queries
Name 77059 0
Dr Saman Parvar
Address 77059 0
South Australian Health and Medical Research Institute
North Terrace, Adelaide, SA 5000
Country 77059 0
Australia
Phone 77059 0
61 8 8128 4510
Fax 77059 0
Email 77059 0
[email protected]
Contact person for scientific queries
Name 77060 0
Dr Saman Parvar
Address 77060 0
South Australian Health and Medical Research Institute
North Terrace, Adelaide, SA 5000
Country 77060 0
Australia
Phone 77060 0
61 8 8128 4510
Fax 77060 0
Email 77060 0
[email protected]

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No Supporting Document Provided



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