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Trial registered on ANZCTR


Registration number
ACTRN12609000457246
Ethics application status
Not yet submitted
Date submitted
27/05/2009
Date registered
15/06/2009
Date last updated
16/09/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
Regular Exercise for Peripheral Arterial Ischaemia: a Randomised Intervention Trial
Scientific title
The effect of progressive resistance training on walking distance in peripheral arterial disease.
Universal Trial Number (UTN)
Trial acronym
REPAIR IT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Intermittent Claudication 4865 0
Peripheral Arterial Disease 236950 0
Condition category
Condition code
Cardiovascular 237217 237217 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Progressive resistance training (PRT) or weight lifting training is a common type of strength training for developing the strength and size of skeletal muscles. It uses the force of gravity or in our case compressed air resistance to oppose the force generated by muscle through concentric or eccentric contraction. Effectively stimulating and overloading the muscle to generate muscle adaptations such as improvements in strength, endurance and power. PRT is an anabolic form of exercise, differing substantially from aerobic exercise in its ability to induce muscle hypertrophy and associated metabolic and functional changes. It has been shown in randomised controlled trials (RCTs) of similar cohorts to improve insulin sensitivity, glucose homeostasis, blood pressure, dyslipidaemia, markers of inflammation and catabolism, and visceral obesity, thus addressing virtually all of the known risk factors associated with peripheral arterial disease (PAD). PRT also improves aerobic capacity, osteoarthritis pain and disability, depression, functional status, gait and balance impairments, bone density, and insomnia, thus addressing the spectrum of associated clinical disorders in older adults with PAD. Notably, high intensity PRT is feasible when robust aerobic exercise is impossible (as in our cohort) due to osteoarthritis or advanced peripheral arterial disease. PRT has also been shown to significantly improve walking ability when compared to control and/or baseline values in asymptomatic patients and those with mild to moderate claudication. In addition PRT has also been shown to improve functional status, quality of life and well-being scores in this same cohort. We will be comparing high intensity PRT to low intensity PRT and to a control condition.
Participants who receive high intensity resistance training will receive weight lifting exercises of 10 major muscle groups. Frequency of training will be 3 days per week under supervision using pneumatic resistance equipment. The exercises chosen include the large muscle groups of the arms, legs and trunk. More specifically we have chosen exercises that specifically focus on areas where claudication most commonly occurs, such as the calf or thigh. Exercises chosen include: calf plantar flexion, ankle dorsiflexion, knee extension, leg press, leg curl, hip extension, hip abduction, chest press, seated row and lat pulldown. These are symmetrical exercises and functionally relevant to activities of daily living, as well as gait performance, both of which are affected by intermittent claudication.
For each exercise participants will perform 3 sets of 8 repetitions, with controlled concentric and eccentric phases (4 seconds per repetition with 2 minutes rest between sets). Exercise to claudication pain was deemed unnecessary due to two recent aerobic exercise trials achieving improvements in walking distances based on a chosen exercise intensity that deliberately did not invoke claudication pain. In addition, in our experience of 25 years of working with persons with PAD, typical high intensity, low volume PRT has never caused the onset of claudication pain. However, if it does occur the participant will be encouraged to continue exercising to complete the set. If the pain becomes unbearable, they will be allowed to stop and rest until the pain dissipates enough for them to complete the set.
In addition this group will receive usual medical care advice on foot care, lifestyle change, such as quitting smoking, and maintaining a healthy weight. Advice on completing walking exercise will not be provided.
The initial intensity for the high intensity treatment group will be set at 50% of the most recently determined peak strength (1 repetition maximum or 1RM). Intensity will then be increased each session, over a 2 week period until 80% 1RM has been reached. Resistance used will be increased by about 3% per session or as tolerated using Borg scale rating of perceived exertion on a continuous basis throughout the 6 months. Repetition maximum testing will be repeated at 2 week intervals to ascertain progress and regulate intensity. All training will be fully supervised by skilled exercise physiologists to maintain proper intensity and progression, as well as to ensure correct technique. Supervision was deemed necessary for both groups as a recent meta-analysis demonstrated that supervised exercise therapy showed statistically significant and clinically relevant differences in improvements of maximal treadmill walking distance compared with non-supervised exercise regimens. Therefore both training groups will be exercising within a group of up to four participants per one exercise physiologist for approximately one hour, 3 days per week for an overall duration of 6 months.
The low intensity training protocol was designed with the intention of mimicking many current community resistance training intensities. Participants who receive low intensity resistance training will be trained by the same exercise physiologists in the same facility under the same training protocol. The one exception will be the change in intensity. The initial intensity for this treatment group will be set at 20% of the most recently determined peak strength (1 repetition maximum or 1RM). Intensity will then be increased each session, over a 1-2 week period, in 3% increments until 30% 1RM has been reached, and the load will be maintained at that level for the duration of the 6-month trial.
In addition, as with the high intensity group, this group will receive usual medical care advice on foot care, lifestyle change, such as quitting smoking, and maintaining a healthy weight. Advice on walking exercise will not be provided.
Intervention code [1] 236647 0
Treatment: Other
Comparator / control treatment
We will be comparing high intensity PRT (80% of 1 repition maximum (RM)) to low intensity PRT (30% 1RM) and to a third group known as the control condition who will be allocated to usual medical care which includes advice on completing regular aerobic walking exercise.
The control group will continue their usual medical care with the addition of standard lifestyle advice over a six month period, which according to the Society for Vascular Surgery, is defined as advice on walking exercise, foot care, lifestyle change such as quitting smoking, and maintaining a healthy weight. This information will be provided to them in a one-on-one session with an exercise physiologist at commencement of the trial and will be also delivered in writing in the form of a brochure. They will be instructed to walk as often as possible, unsupervised at home, to maximum pain levels tolerable, rest and repeat. They will remain blinded to the investigators’ hypotheses as to which are the experimental groups for the duration of the trial. No supervised exercise will be provided or recommended.
Control group
Active

Outcomes
Primary outcome [1] 238027 0
Initial claudication distance: The distance at which the participant first experiences claudication pain will be measured during a graded treadmill walking test.
Timepoint [1] 238027 0
Baseline prior to commencement of the treatment program and at 6 months after completion of the 6 month program.
Primary outcome [2] 238028 0
Absolute claudication distance: The distance at which a person can no longer ambulate due to intense claudication pain will be measured during a graded treadmill walking test.
Timepoint [2] 238028 0
Baseline prior to commencement of the treatment program and at 6 months after completion of the 6 month program.
Primary outcome [3] 238029 0
6 minute walk distance will be measured using a pedometer and stopwatch.
Timepoint [3] 238029 0
Baseline prior to commencement of the treatment program and at 6 months after completion of the 6 month program.
Secondary outcome [1] 242174 0
Muscle strength testing will be carried out using the 1 repetition maximum (1RM) test on the following equipment: seated leg press, seated chest press, seated knee extension, seated row and seated knee flexion using Keiser pneumatic resistance training equipment.
Timepoint [1] 242174 0
Baseline and every fortnight for six months in the high intensity group. Baseline and six months in control and low intensity group.
Secondary outcome [2] 242175 0
Lower Limb Brachial Indexes of the thigh, ankle and big toe will be measured using a manual sphygmomanometer and hand held ultrasound and photoplethysmographic doppler.
Timepoint [2] 242175 0
Indexes will be measured at baseline prior to commencement of the training program, midway through the program at 3 months and at 6 months upon completion of the program.
Secondary outcome [3] 242176 0
Muscle power and endurance will be measured using the Keiser pneumatic resistance training equipment. The participant will be asked to lift a set load as many times as they are able to consecutively. Muscle power will be measured also by asking the participent to lift a set load, however this time they will be asked to lift it as fast as they can whilst maintaining correct form.
Timepoint [3] 242176 0
Baseline prior to commencement of the treatment program and at 6 months after completion of the 6 month program.
Secondary outcome [4] 242177 0
Body composition including height, weight and waist circumference. Height will be measured using a wall mounted stadiometer and the participant will be barefoot. Body mass will be measured using a calibrated weighing scale. Waist circumference will be measured using a standard tape measure taken at the midpoint between the lower costal (rib) border and the iliac crest (measured and marked).
Timepoint [4] 242177 0
Baseline prior to commencement of the treatment program and at 6 months after completion of the 6 month program.
Secondary outcome [5] 242178 0
Short physical performance battery including walking speed, stair climbing, chair rising and balance
Timepoint [5] 242178 0
Baseline prior to commencement of the treatment program and at 6 months after completion of the 6 month program.
Secondary outcome [6] 242179 0
Arterial stiffness and heart rate variability measured via pulse wave velocity
Timepoint [6] 242179 0
Baseline prior to commencement of the treatment program and at 6 months after completion of the 6 month program.
Secondary outcome [7] 242180 0
High sensitivity c-reactive proteins (hs-cRP), total cholesterol, high density lipoproteins (HDL), low density lipoproteins (LDL), triglycerides (TG), insulin sensitivity, beta-cell function, blood glucose levels, glycated haemoglobin (HbA1c) in diabetics, cytokines, tumor necrosis factor (TNF)proteins and deoxyribonucleic acid (DNA) analysis will be assessed through blood analysis.
Timepoint [7] 242180 0
Baseline prior to commencement of the treatment program and at 6 months after completion of the 6 month program.
Secondary outcome [8] 242181 0
Calf muscle fiber area, intramuscular lipid content, mitochondrial function and local inflammatory factors measured via vastus lateralis muscle biopsy.
Timepoint [8] 242181 0
Baseline prior to commencement of the treatment program and at 6 months after completion of the 6 month program.
Secondary outcome [9] 242182 0
Psychosocial and Functionality questionnaires inlcluding the Geriatric Depression Scale (GDS), Ewart's Self Efficacy Scale, Physical Activity Scale for the Elderly (PASE) and Paffenberger's Physical Activity Index, the Quality of Life Medical Outcomes Survey (SF36v2), the peripheral arterial disease Walking Impairment Questionnaire (WIQ) and Pittsburgh Sleep Quality Index (PSIQ)
Timepoint [9] 242182 0
Baseline prior to commencement of the treatment program and at 6 months after completion of the 6 month program.

Eligibility
Key inclusion criteria
Men and women over the age of 50 who suffer from moderate to severe intermittent claudication from PAD as defined by lower extremity ultrasound in Professor Lord’s vascular laboratory will be recruited for this trial. Participants must be sedentary, ambulatory and community dwelling with no contra-indications to progressive resistance training. All participants must be clinically stable for 3 months prior to enrolment in the trial. Clinically stable will be defined as no significant change in claudication symptoms over a 3-month no treatment run-in period, as determined by the 6-minute walk test performed twice at baseline, 3-months apart.
We will preferentially recruit elderly (over the age of 70 years) and female participants, as these cohorts have been understudied in the past. Specifically, persons with diabetes, hypertension, coronary artery disease and/or a history of myocardial infarction will not be excluded. Persons who have had previous surgical intervention and/or who are on pharmaceutical treatment for symptoms of PAD will also not be excluded.
Minimum age
50 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusionary criteria include asymptomatic PAD, mild intermittent claudication (>200m initial claudication walking distance), ischaemic rest pain, tissue necrosis or gangrene, significant cognitive impairment, current alcohol or substance abuse, inability to comply with study requirements over the course of 6 months (including baseline and final assessments), those currently undertaking a resistance training or other regular (at least 3 days per week) moderate to high intensity exercise of any kind, and those confined to a nursing home or hostel or who are unable to perform PRT safely under supervision. Persons with specific contraindications to resistance training exercise such as unstable cardiovascular disease, aortic aneurysm, symptomatic hernias, proliferative diabetic retinopathy, retinal laser surgery within 6 weeks, uncontrolled hypertension or rapidly progressive or terminal illness will also be excluded. Persons who are currently actively awaiting surgical intervention for PAD will also be excluded.

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)
ENROLMENT PROCEDURE
The participant will be enrolled into the study after the informed consent process has been completed and the participant has met all inclusion criteria and none of the exclusion criteria. The participant will receive a study enrolment number and this will be documented in the participant’s medical record and on all study documents.

RANDOMISATION PROCEDURE
A concealed computer-generated sequence of randomly permuted blocks will be generated by a statistician not otherwise involved in the study (www.randomization.com). Sealed envelopes containing sequential treatment assignments based on this computer-generated randomisation scheme will be opened by the participant after completion of all baseline testing. Participants will be stratified by location of disease (proximal vs. distal), gender, current medication use and/or previous surgery for treatment of PAD.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation is at the level of the individual patient, and will be stratified by gender and age. Written informed consent will be required prior to any testing or randomisation. The list will be generated and maintained by a research assistant not otherwise involved in the study. Where randomisation occurs in person, assignments will be placed in sealed opaque envelopes and designated “Blue Group” for high intensity PRT, “Red Group” for low intensity PRT, “Yellow Group” for control. The sequential treatment assignments are based on a computer-generated randomisation scheme (by using the Web site www.randomization.com set up by Dr Gerard E. Dallal). The subject will open these envelopes after completion of all baseline testing. Subjects who dropout prior to completion of baseline testing will not be randomised.

Stratification by gender, age group (50-74 and 75+) and location of disease (proximal vs distal) will be planned, in anticipation of the greater prevalence of women in the targeted cohort, and potential age effects on underlying pathophysiology and adaptation to training. Participants will also be stratified based on current medication use for treatment of symptoms of the disease and/or previous surgery for treatment of PAD.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/07/2009
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
120
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 1732 0
2010

Funding & Sponsors
Funding source category [1] 5032 0
University
Name [1] 5032 0
University of Sydney
Country [1] 5032 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
75 East St
Lidcombe NSW 2141
Country
Australia
Secondary sponsor category [1] 4548 0
Individual
Name [1] 4548 0
Professor Maria Fiatarone Singh
Address [1] 4548 0
75 East St
Lidcombe NSW 2141
Country [1] 4548 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 239126 0
University of Sydney Human Research Ethics Committee (HREC)
Ethics committee address [1] 239126 0
Level 6, Jane Foss Russell Building,
G02 Maze Crescent
The University of Sydney
Camperdown, NSW 2006
Ethics committee country [1] 239126 0
Australia
Date submitted for ethics approval [1] 239126 0
22/06/2009
Approval date [1] 239126 0
Ethics approval number [1] 239126 0
Ethics committee name [2] 239127 0
St Vincent's HREC
Ethics committee address [2] 239127 0
390 Victoria St
Darlinghurst NSW 2010
Ethics committee country [2] 239127 0
Australia
Date submitted for ethics approval [2] 239127 0
25/05/2009
Approval date [2] 239127 0
Ethics approval number [2] 239127 0

Summary
Brief summary
120 participants with stable moderate to severe claudication from PAD as defined by lower extremity ultrasound, will be randomised to 6 months of supervised high intensity PRT, low intensity PRT or control which includes advice to do aerobic exercise. Our primary outcomes include absolute and initial claudication distances and 6-minute walk distance. Our secondary outcomes include resting arterial calf blood flow, resting brachial, hallux, ankle and distal thigh pressures and post exercise ankle, brachial pressures, change in clinical symptoms in relation to location of disease, dynamic muscle strength, power and endurance, vastus lateralis muscle biopsy to determine calf muscle fiber area, intramuscular lipid content, mitochondrial function and local inflammatory factors, arterial stiffness, blood lipids, systemic inflammatory factors, oxygen consumption, functional performance, self-efficacy, depressive symptoms and quality of life. Key outcomes will be measured at baseline and after the 6 month intervention and will be analysed by “intention to treat” with missing 6-month data imputed via the expectation maximisation algorithm.
Trial website
Trial related presentations / publications
International Association for Gerontology and Geriatrics 2009 Annual Scientific Meting, Paris. Presentation Tues 7th July
Public notes

Contacts
Principal investigator
Name 29655 0
Address 29655 0
Country 29655 0
Phone 29655 0
Fax 29655 0
Email 29655 0
Contact person for public queries
Name 12902 0
Belinda Parmenter
Address 12902 0
75 East St
Lidcombe NSW 2141
Country 12902 0
Australia
Phone 12902 0
+61 2 9351 9528
Fax 12902 0
+61 2 9351 9204
Email 12902 0
[email protected]
Contact person for scientific queries
Name 3830 0
Belinda Parmenter
Address 3830 0
75 East St
Lidcombe NSW 2141
Country 3830 0
Australia
Phone 3830 0
+61 2 9351 9528
Fax 3830 0
+61 2 9351 9204
Email 3830 0
[email protected]

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