Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001232426
Ethics application status
Approved
Date submitted
1/09/2016
Date registered
5/09/2016
Date last updated
9/08/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Post-operative exercise training for peripheral arterial disease
Scientific title
Targeting microvascular impairment in patients with peripheral arterial disease: efficacy of lower limb revascularisation combined with supervised exercise therapy
Secondary ID [1] 289657 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Peripheral arterial disease 299457 0
Condition category
Condition code
Cardiovascular 299436 299436 0 0
Diseases of the vasculature and circulation including the lymphatic system
Surgery 300044 300044 0 0
Other surgery
Physical Medicine / Rehabilitation 300045 300045 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Standard post-operative care plus supervised exercise therapy

The revascularisation intervention will be delivered by vascular surgeons at Nambour General Hospital. Revascularisation performed on the participant includes both open surgery and endovascular procedures. This will be personalised to each participant as considered necessary for optimal treatment by the vascular surgeon.
Following revascularisation, all patients will receive standard care that is based on international PAD management guidelines, including educational material with an emphasis on physical activity, smoking, and diet (Norgren et al. 2007). The vascular surgeon and the general practitioner of each participant will be sent a letter immediately after revascularisation and at 6-10 weeks after revascularisation, requesting that they adhere to clinical guidelines and targets (Norgren et al. 2007) (which will be outlined) so that all patients receive standardised care.
Patients allocated to the exercise intervention group will undergo an 8-week supervised exercise training program, commencing within six weeks after the revascularisation procedure (within two to six weeks post-revascularisation, depending on the vascular procedure completed and clearance to commence the study intervention by the patient’s vascular surgeon).
The exercise therapy intervention will be supervised by researchers (accredited physical therapists) at the University of the Sunshine Coast. Patients will attend group exercise sessions (3 sessions per week on non-consecutive days). Each session will include a combination of treadmill-walking and plantar-flexion exercise (both legs) as per recommended guidelines (Askew et al. 2014). Treadmill walking will consist of 20 min of intermittent walking that will be progressively increased in duration from 2.5 min in the first week, to 10 min in the last. Patients will walk at an intensity corresponding to the onset of mild-moderate claudication (e.g. 3-4 out of 5 in the claudication rating scale, where 0 = no pain and 5 = maximum pain). After the walking training, each patient will perform plantar flexion exercise using an isometric plantar flexion dynamometer. Participants will be seated with their hip and knee flexed, and with their foot resting on a foot-plate, and will perform three bouts of 5-min unilateral isometric contractions (2 s contraction: 3 s recovery) with each leg. Plantar-flexion exercise will be progressively increased in intensity from 40% of patient’s maximal force in the first week, to 70% of their maximal force in the last.
Adherence to the supervised exercise therapy will be recorded by the investigators responsible for the delivery as the total number of visits recorded. Efforts to improve exercise adherence include group exercise sessions. If participants are unable to complete a bout of exercise they will be offered a 30 second rest period and the opportunity to complete the bout after the rest. Patients will be required to attend at least 85% of sessions (=21 sessions) for successful completion of the supervised exercise program.
Intervention code [1] 295283 0
Treatment: Surgery
Intervention code [2] 295284 0
Rehabilitation
Comparator / control treatment
Standard post-operative care and monitoring (standard care)

The revascularisation intervention will be delivered by vascular surgeons at Nambour General Hospital. Revascularisation performed on the participant includes both open surgery and endovascular procedures. This will be personalised to each participant as considered necessary for optimal treatment by the vascular surgeon.
Following revascularisation, all patients will receive standard care that is based on international PAD management guidelines, including educational material with an emphasis on physical activity, smoking, and diet (Norgren et al. 2007). The vascular surgeon and the general practitioner of each participant will be sent a letter immediately after revascularisation and at 6-10 weeks after revascularisation, requesting that they adhere to clinical guidelines and targets (Norgren et al. 2007) (which will be outlined) so that all patients receive standardised care.
Control group
Active

Outcomes
Primary outcome [1] 298908 0
Walking capacity (6 minute walking distance)
Timepoint [1] 298908 0
Outcome measurements will be performed at baseline prior to revascularisation, then repeated following full recovery from revascularisation (2-6 weeks post-procedure), and then again at the completion of the 8 week post-operative intervention
Primary outcome [2] 298909 0
Calf muscle microvascular blood flow (using contrast-enhanced ultrasound [CEU])
Timepoint [2] 298909 0
Outcome measurements will be performed at baseline prior to revascularisation, then repeated following full recovery from revascularisation (2-6 weeks post-procedure), and then again at the completion of the 8 week post-operative intervention
Secondary outcome [1] 325628 0
Leg muscle function (plantar-flexion strength and fatigue) measured with an isometric plantar flexion dynamometer.
Timepoint [1] 325628 0
Outcome measurements will be performed at baseline prior to revascularisation, then repeated following full recovery from revascularisation (2-6 weeks post-procedure), and then again at the completion of the 8 week post-operative intervention
Secondary outcome [2] 325648 0
Ankle brachial index
Timepoint [2] 325648 0
Outcome measurements will be performed at baseline prior to revascularisation, then repeated following full recovery from revascularisation (2-6 weeks post-procedure), and then again at the completion of the 8 week post-operative intervention
Secondary outcome [3] 325649 0
Arterial stiffness (augumentation index and carotid-femoral pulse wave velocity) measured using the Sphygmocor XCEL system (Atcor, NSW, Australia).
Timepoint [3] 325649 0
Outcome measurements will be performed at baseline prior to revascularisation, then repeated following full recovery from revascularisation (2-6 weeks post-procedure), and then again at the completion of the 8 week post-operative intervention
Secondary outcome [4] 325650 0
Brachial and femoral artery function (flow mediated dilation)
Timepoint [4] 325650 0
Outcome measurements will be performed at baseline prior to revascularisation, then repeated following full recovery from revascularisation (2-6 weeks post-procedure), and then again at the completion of the 8 week post-operative intervention
Secondary outcome [5] 325651 0
Resting and exercise leg blood flow (using venous occlusion plethysmography [VOP])
Timepoint [5] 325651 0
Outcome measurements will be performed at baseline prior to revascularisation, then repeated following full recovery from revascularisation (2-6 weeks post-procedure), and then again at the completion of the 8 week post-operative intervention
Secondary outcome [6] 325654 0
Self reported walking impairment (Walking Impairment questionnaire)
Timepoint [6] 325654 0
Outcome measurements will be performed at baseline prior to revascularisation, then repeated following full recovery from revascularisation (2-6 weeks post-procedure), and then again at the completion of the 8 week post-operative intervention
Secondary outcome [7] 327432 0
Quality of Life (measured using SF-36 questionnaire)
Timepoint [7] 327432 0
Outcome measurements will be performed at baseline prior to revascularisation, then repeated following full recovery from revascularisation (2-6 weeks post-procedure), and then again at the completion of the 8 week post-operative intervention

Eligibility
Key inclusion criteria
1. Patients scheduled for lower limb revascularisation, including open surgery (e.g. bypass), an endovascular procedure, or a hybrid procedure (e.g. endarterectomy plus angioplasty);
2. Documented diagnosis of PAD based on symptoms (claudication or critical limb ischaemia), an ABI < 0.90, and imaging evidence of a significant (>50%) stenosis in at least one lower-limb arterial segment;
3. Stable medication and treatment regimen (>3 months);
4. Physician-assessed ability to undertake the intervention and exercise testing.
Minimum age
40 Years
Maximum age
90 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Not able to walk independently prior to revascularisation, or walking capacity is limited by symptoms not related to PAD (including neuropathy);
2. Have had or are undergoing a significant amputation (e.g. forefoot, leg) that is expected to limit ability to walk independently after surgery;
3. Exercise testing is contraindicated for reasons such as unstable angina, uncontrolled hypertension (>160/100), limiting venous disease or uncontrolled cardiac dysrhythmias;
4. Current or planned involvement in a supervised exercise rehabilitation program.

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)
A recruitment coordinator will oversee the screening, recruitment and blinded-randomisation of participants. Where possible, investigators and those collecting and analysing outcome data will be blinded to the treatment allocation at the time of randomisation and throughout the study. Participants will be stratified according to the type of intervention (endovascular or open surgery/hybrid). Randomisation will occur following revascularisation using a concealed envelope system.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation, using random block sizes will be used to ensure that group allocation at any point in time remains similar.
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
We hypothesise that participants will improve their 6-min walking distance by 50+/-50m with revascularisation (Stefanovic 2012), that there will be no further change with ongoing standard care, and a further 60+/-50m increase in the exercise-therapy group (effects size aprox. 1.2). This is similar to the effect we have observed with exercise following revascularisation in a previous study (Stefanovic 2012). We require 15 participants per group (power 90%, alpha 0.05, 1:1) to detect the hypothesised increase in walking capacity with post operative exercise therapy.
Assessment of combined therapy versus revascularisation outcomes (group x time interactions) will be determined using linear repeated measures mixed models. Covariates will be included as appropriate, including hypothesised confounders (e.g. age, gender, diabetes) and any outcomes where there is a significant group difference at baseline. Linear regression will be performed to determine the relationships between baseline values and changes in primary and secondary outcomes. Analysis of all outcomes will be undertaken on an intention-to-treat basis. In addition, for secondary variables, we will undertake per-treatment analysis using complete data-sets.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/10/2016
Actual
4/08/2017
Date of last participant enrolment
Anticipated
1/04/2018
Actual
Date of last data collection
Anticipated
30/06/2018
Actual
Sample size
Target
30
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 6154 0
Nambour General Hospital - Nambour
Recruitment hospital [2] 8753 0
Sunshine Coast University Hospital - Birtinya
Recruitment postcode(s) [1] 13594 0
4560 - Nambour
Recruitment postcode(s) [2] 16873 0
4575 - Birtinya

Funding & Sponsors
Funding source category [1] 294043 0
University
Name [1] 294043 0
University of the Sunshine Coast
Country [1] 294043 0
Australia
Primary sponsor type
University
Name
University of the Sunshine Coast
Address
90 Sippy Downs Dr, Sippy Downs QLD 4556
Country
Australia
Secondary sponsor category [1] 292869 0
None
Name [1] 292869 0
Address [1] 292869 0
Country [1] 292869 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295459 0
The Prince Charles Hospital
Ethics committee address [1] 295459 0
627 Rode Rd, Chermside QLD 4032


Ethics committee country [1] 295459 0
Australia
Date submitted for ethics approval [1] 295459 0
10/05/2016
Approval date [1] 295459 0
08/07/2016
Ethics approval number [1] 295459 0
HREC/16/QPCH/148

Summary
Brief summary
Peripheral Arterial Disease (PAD) is characterised by blockages in the large arteries of the lower limbs. Chronic reductions in leg blood flow leads to microvascular impairment, including a reduction in muscle capillary density. These macro and microvascular impairments are independently associated with a severe reduction in functional (walking) ability. Patients are limited during daily activities by leg muscle pain and discomfort (claudication), and many develop signs of severe critical ischaemia, including rest-pain, tissue ulceration and gangrene. Lower limb revascularization procedures improve claudication symptoms by improving limb blood flow, but do not address the microvascular impairment, and do not fully restore functional capacity. However, when revascularisation procedures are combined with exercise therapy, greater gains are made in functional capacity without further change in large-artery blood flow. Based on evidence that supervised exercise therapy induces skeletal muscle capillary growth, and gains in functional capacity are related to increased muscle capillarisation, we hypothesise that the combination of revascularization plus post-operative supervised exercise therapy will lead to further improvements in outcomes (e.g. exercise tolerance and skeletal muscle microcirculation) compared to revascularisation alone. Therefore, this study aims to compare the efficacy of lower limb revascularisation plus supervised exercise therapy, with revascularisation alone, for improvement of walking capacity and skeletal muscle blood flow in PAD patients. This study will be conducted at the University of Sunshine Coast and the Department of Cardiology at Nambour General Hospital. Patients with PAD and symptoms of intermittent claudication, who are scheduled to undergo lower limb revascularisation, will be randomly assigned to one of two interventions at study entry: (1) standard post-operative care and monitoring (standard care) or (2) standard post-operative care plus an 8-week supervised exercise therapy program. Primary outcome measures will include walking capacity (6 minute walking distance) and calf muscle microvascular blood flow (using contrast-enhanced ultrasound [CEU]). Secondary outcomes will include i) leg muscle function (plantar-flexion strength and fatigue), ii) ankle brachial index, iii) arterial stiffness (augumentation index and carotid-femoral pulse wave velocity), iv) brachial and femoral artery function (flow mediated dilation) and v) leg blood flow (using venous occlusion plethysmography [VOP]). All parameters will be assessed in the limb undergoing revascularisation. Outcome measurements will be performed at baseline prior to revascularisation, then repeated following full recovery from revascularisation (2-6 weeks post-procedure), and then again at the completion of the 8 week post-operative intervention.
Trial website
https://www.surveymonkey.com/r/vasoactive

http://www.usc.edu.au/explore/structure/faculty-of-science-health-education-and-engineering/staff/associate-professor-chris-askew
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67358 0
A/Prof Christopher Askew
Address 67358 0
University of the Sunshine Coast
90 Sippy Downs Dr, Sippy Downs QLD 4556
Country 67358 0
Australia
Phone 67358 0
+61 7 5456 5961
Fax 67358 0
Email 67358 0
[email protected]
Contact person for public queries
Name 67359 0
A/Prof Christopher Askew
Address 67359 0
University of the Sunshine Coast
90 Sippy Downs Dr, Sippy Downs QLD 4556
Country 67359 0
Australia
Phone 67359 0
+61 7 5456 5961
Fax 67359 0
Email 67359 0
[email protected]
Contact person for scientific queries
Name 67360 0
A/Prof Christopher Askew
Address 67360 0
University of the Sunshine Coast
90 Sippy Downs Dr, Sippy Downs QLD 4556
Country 67360 0
Australia
Phone 67360 0
+61 7 5456 5961
Fax 67360 0
Email 67360 0
[email protected]

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