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Trial registered on ANZCTR


Registration number
ACTRN12616001049460
Ethics application status
Approved
Date submitted
3/08/2016
Date registered
5/08/2016
Date last updated
12/02/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Does heat conditioning improve health in peripheral arterial disease?
Scientific title
Randomised controlled trial of the effects of heat conditioning compared with supervised exercise on cardiovascular health and functional capacity in peripheral arterial disease
Secondary ID [1] 289699 0
None
Universal Trial Number (UTN)
U1111-1185-1258
Trial acronym
None
Linked study record

Health condition
Health condition(s) or problem(s) studied:
peripheral arterial disease 299514 0
Condition category
Condition code
Cardiovascular 299491 299491 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Heat conditioning:
Location: School of Physical Education, Sport and Exercise Sciences aquatic facility (University of Otago, Dunedin, NZ). Heat sessions will be supervised by the PI and/or a research fellow, both first aid trained. Attendance will be recorded at each session by the supervising researcher.
Exposure: Participants will be seated in a spa bath at ~38 degrees C for progressive duration (see below). Following the spa bath, heat stress will be maintained for 15-30 min using long-sleeved/legged clothing with gentle callisthenic exercise (3 days/week) or seated rest in clothing for other 2 days/week. Callisthenics will be performed in temperate environment (~21 degrees C) using an elastic resistance band incorporating a range of exercises utilising all muscle groups. Contractions will be performed for 1 min followed by 1 min rest (seated or standing). Callisthenics will be performed at an average rate of perceived exertion of 16/20 (Borg scale).

Exposure time will progress as follows, if tolerable to increase:
Week 1: 15 min spa + 30 min callisthenics 3 days/week (3 exposures)
Week 2: 20 min spa + 30 min callisthenics 3 days/week and 20 min spa + 30 min warm rest 1 day/week (4 exposures)
Week 3-6: 25 min spa + 30 min callisthenics 3 days/week and 25 min spa + 30 min warm rest 2 days/week (5 exposures)

Dosage: After six weeks, if the primary outcome is achieved (>=100% increase in 6 min walking distance), participants will be randomised to either continue this dosage or reduce frequency to 3 days/week. If the primary outcome is not achieved at 6 weeks, the dosage will continue at 5 days/week as described for weeks 3-6 above.

Duration: 3 months
Intervention code [1] 295328 0
Treatment: Other
Comparator / control treatment
Control:
Location: Dunedin Public Hospital (Dunedin, NZ).
Exposure: Participants will be encouraged to join a supervised exercise group that runs at the hospital. Exercise is supervised by a physiotherapist and consists of 30 min self-paced walking on a marked course in hospital corridors followed by 20-30 min self-selected circuit exercises in the hospital gym.
Dosage: 2 d/w
Duration: 3 months
Control group
Active

Outcomes
Primary outcome [1] 298973 0
6-minute walking distance, performed on a treadmill.
Timepoint [1] 298973 0
Baseline, 6 weeks and 12 weeks
Secondary outcome [1] 325784 0
Cardiorespiratory capacity during a cardiac stress test using a step incremental protocol on a cycle ergometer.
Timepoint [1] 325784 0
Baseline and 12 weeks
Secondary outcome [2] 325785 0
Ankle-brachial index at rest and following a standardised 3-min treadmill exercise test (3 min, 3 kph, 10% gradient).
Timepoint [2] 325785 0
Baseline and 12 weeks
Secondary outcome [3] 325786 0
Peripheral vascular function will be assessed as brachial artery flow-mediated dilation using duplex ultrasound.
Timepoint [3] 325786 0
Baseline, 4 weeks and 12 weeks
Secondary outcome [4] 325848 0
Blood volume will be measured using carbon monoxide dilution rebreathing.
Timepoint [4] 325848 0
Baseline, 6 weeks and 12 weeks
Secondary outcome [5] 325849 0
Plasma samples will be taken by venipuncture for measurement of haemoglobin.
Timepoint [5] 325849 0
Baseline, 6 weeks and 12 weeks
Secondary outcome [6] 326406 0
Heart rate during 6-min walking test will be measured using ECG.
Timepoint [6] 326406 0
Baseline, 6 and 12 weeks
Secondary outcome [7] 326407 0
Heart rate variability at rest and during the 6-min walking test will be measured using ECG.
Timepoint [7] 326407 0
Baseline, 6 and 12 weeks
Secondary outcome [8] 326408 0
Blood pressure at rest and during the 6-min walking test will be measured using finger photoplethysmography and the auscultatory method.
Timepoint [8] 326408 0
Baseline, 6 and 12 weeks
Secondary outcome [9] 326409 0
Tissue oxygenation will be measured during the 6-min walking test on the calf muscle using near-infrared spectroscopy.
Timepoint [9] 326409 0
Baseline, 6 and 12 weeks
Secondary outcome [10] 326410 0
Claudication pain will be measured during the 6-min walking test using a visual analog scale.
Timepoint [10] 326410 0
Baseline, 6 and 12 weeks
Secondary outcome [11] 326411 0
Blood pressure will be measured during the cardiac stress test using the auscultatory method.
Timepoint [11] 326411 0
Baseline and 12 weeks
Secondary outcome [12] 326412 0
Heart rate will be measured during the cardiac stress test using ECG.
Timepoint [12] 326412 0
Baseline and 12 weeks
Secondary outcome [13] 326413 0
Claudication pain will be measured during the cardiac stress test using a visual analog scale.
Timepoint [13] 326413 0
Baseline and 12 weeks.
Secondary outcome [14] 326414 0
Expired gases (O2 and CO2) will be measured during the cardiac stress test using a gas analyser.
Timepoint [14] 326414 0
Baseline and 12 weeks
Secondary outcome [15] 326415 0
Peripheral vascular will be assessed as popliteal flow-mediated dilation using duplex ultrasound.
Timepoint [15] 326415 0
Baseline, 4 and 12 weeks
Secondary outcome [16] 326416 0
Central pulse wave velocity will be measured as carotid-femoral pulse wave velocity using ECG and applanation tonometry
Timepoint [16] 326416 0
Baseline, 4 and 12 weeks
Secondary outcome [17] 326417 0
Peripheral pulse wave velocity will be measured as carotid-radial pulse wave velocity using ECG and a applanation tonometry
Timepoint [17] 326417 0
Baseline, 4 and 12 weeks
Secondary outcome [18] 326418 0
Plasma samples will be taken by venipuncture for measurement of oxidative stress markers including NFK-B, superoxide, urate, CRP, TNF-a, and NO metabolites.
Timepoint [18] 326418 0
Baseline, 6 and 12 weeks
Secondary outcome [19] 326419 0
Plasma samples will be taken by venipuncture for measurement of vascular adaptation markers including endothelin-1 and VEGF.
Timepoint [19] 326419 0
Baseline, 6 and 12 weeks
Secondary outcome [20] 326420 0
Plasma samples will be taken by venipuncture for measurement of metabolic markers (HbA1C).
Timepoint [20] 326420 0
Baseline, 6 and 12 weeks
Secondary outcome [21] 326421 0
Plasma samples will be taken by venipuncture for measurement of stress response markers (heat shock proteins).
Timepoint [21] 326421 0
Baseline, 6 and 12 weeks
Secondary outcome [22] 326422 0
Plasma samples will be taken by venipuncture for measurement of gut permeability (iFABP).
Timepoint [22] 326422 0
Baseline, 6 and 12 weeks

Eligibility
Key inclusion criteria
1) PAD confirmed by ankle-brachial index in at least one leg of <=0.8 at rest and/or a reduction following exercise;
2) Mild to moderate claudication described, corresponding to Fontaine stage IIa to IIb;
3) > 45 years old;
4) Females must be post-menopausal and not taking hormone replacement therapy;
5) Able to comply with study requirements including repeat visits to the laboratory.
Minimum age
45 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Functioning bypass graft in-situ;
2) Isolated disease in aorta / iliac vessels;
3) Type 1 diabetes;
4) Previous occurence of heat intolerance;
5) Unstable angina or myocardial infarction in the past 12 months;
6) Evidence of clinically significant ischaemic heart disease present in the cardiac stress test, and deemed so by the cardiologist.

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 will be performed by a colleague independent of the study using sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
An independent colleague not involved in the study will allocate randomisation using a computer-generated list involving block randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The sample size is based on a previous intervention study of heating in PAD (Tei C, JACC 2007). A power analysis using these study results would indicate 8-9 participants need to complete intervention and control arms to achieve an 80% probability of detecting a mean doubling of walking distance over 3 months if the type I error rate is controlled at 5%. The increased sample size allows for dropout and a more conservative estimation of the magnitude of treatment effect.
The two heat conditioning groups will be compared at 12 weeks to determine the effect of conditioning dose (5 vs 3 d/w). If they are equivalent then the heat conditioning groups will be combined and compared against the control group at 12 weeks, but if they are different then peak responses will be compared against control.

Recruitment
Recruitment status
Completed
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 outside Australia
Country [1] 8039 0
New Zealand
State/province [1] 8039 0
Otago

Funding & Sponsors
Funding source category [1] 294083 0
Charities/Societies/Foundations
Name [1] 294083 0
Lottery Health Council
Address [1] 294083 0
National Office
The Department of Internal Affairs
46 Waring Taylor Street
WELLINGTON 6011
Country [1] 294083 0
New Zealand
Primary sponsor type
Individual
Name
Associate Prof. Jim Cotter
Address
School of Physical Education, Sport and Exercise Sciences
University of Otago
46 Union St West
PO Box 56
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 292913 0
Individual
Name [1] 292913 0
Kate Thomas
Address [1] 292913 0
Department of Surgical Sciences
Dunedin School of Medicine
PO Box 913
Dunedin 9054
Country [1] 292913 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295499 0
Health and Disability Ethics Committee
Ethics committee address [1] 295499 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington 6011
Ethics committee country [1] 295499 0
New Zealand
Date submitted for ethics approval [1] 295499 0
07/07/2016
Approval date [1] 295499 0
02/08/2016
Ethics approval number [1] 295499 0
16/CEN/90

Summary
Brief summary
Significant numbers of people are unable to engage in exercise for cardiovascular benefit due to their physical disability. However heat conditioning may be an alternative for people who face such barriers to exercise, but for whom its cardiovascular effects would be particularly beneficial. Patients with peripheral arterial disease (PAD) are one such group to which this applies. Our aim is to determine whether our prior work on the benefits of heat conditioning can be translated to clinical benefit for people with this common condition. This will be tested in a randomised controlled trial of people with PAD, who will undergo either 3-months of heat-stressful health conditioning, or receive advice to undertake supervised exercise as best able. The primary determinant of benefit will be at least a doubling of pain-free walking capacity (primary outcome), along with improvements in blood flow to the affected leg(s), improved cardiorespiratory capacity, quality of life (QOL) and metabolic health. If benefits are seen in this population, we anticipate transferability to people with other cardiovascular and musculoskeletal conditions, and therefore similar obstacles to traditional exercise.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67238 0
Prof Jim Cotter
Address 67238 0
School of Physical Education, Sport and Exercise Sciences
University of Otago
46 Union St West
PO Box 56
Dunedin 9016
Country 67238 0
New Zealand
Phone 67238 0
+64 34799109
Fax 67238 0
Email 67238 0
jim.cotter@otago.ac.nz
Contact person for public queries
Name 67239 0
A/Prof Jim Cotter
Address 67239 0
School of Physical Education, Sport and Exercise Sciences
University of Otago
46 Union St West
PO Box 56
Dunedin 9016
Country 67239 0
New Zealand
Phone 67239 0
+64 34799109
Fax 67239 0
Email 67239 0
jim.cotter@otago.ac.nz
Contact person for scientific queries
Name 67240 0
A/Prof Jim Cotter
Address 67240 0
School of Physical Education, Sport and Exercise Sciences
University of Otago
46 Union St West
PO Box 56
Dunedin 9016
Country 67240 0
New Zealand
Phone 67240 0
+64 34799109
Fax 67240 0
Email 67240 0
jim.cotter@otago.ac.nz

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary