Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000724673
Ethics application status
Approved
Date submitted
13/06/2023
Date registered
5/07/2023
Date last updated
5/07/2023
Date data sharing statement initially provided
5/07/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
The effects of exercise training on small blood vessel health in individuals with type 2 diabetes and in overweight and obese older participants.
Scientific title
The effect of exercise training on microvascular health and function in individuals with type 2 diabetes and overweight and obese older participants.
Secondary ID [1] 309652 0
None
Universal Trial Number (UTN)
Trial acronym
HeatEx
Linked study record

Health condition
Health condition(s) or problem(s) studied:
type 2 diabetes 329987 0
obesity 329988 0
Condition category
Condition code
Metabolic and Endocrine 326895 326895 0 0
Diabetes
Diet and Nutrition 326896 326896 0 0
Obesity

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Individuals will be randomised to one of four groups:
1. aerobic exercise training,
2. heat therapy,
3. aerobic exercise plus heat therapy, or
4. a control group who will be requested to maintain their usual lifestyle and activities, for a 12-week intervention period.

The aerobic exercise training involves 2 x 40-minute centre-based cycling, plus 1 x 40-minute home-based sessions (i.e. moderate-intensity aerobic training) per week for 12 weeks, with each session composed of 5 minutes of warmup, 30 minutes of aerobic exercise, and 5 minutes cooldown. Exercise intensity will change every 4 weeks, considering individuals adaptation to exercise and intensity. During the first 4 weeks, for familiarisation purposes, exercise intensity will be established at 60-65% of their maximum heart rate. For the following 4-week block, intensity will be established at 65-70% of their maximum heart rate. For the last 4-week block, exercise intensity will be established at 70-75% of their maximum heart rate. Five-minute warm-up period will be kept at 50-55% of individuals maximum heart rate throughout the whole exercise program. Regarding cool-down, individuals will maintain the exercise stimulus for 5 minutes in a very light intensity. Maximum heart rate will be determined via a maximal oxygen uptake (VO2max) exercise test. The exercise program will be individually prescribed by an Accredited Exercise Physiologist/Scientist, using individuals' maximal heart rate to match exercise intensity. Centre-based sessions will take place at The University of Western Australia (UWA) School of Human Sciences (Exercise and Sport Science) gymnasium and will be monitored by an experienced exercise physiologist/researcher. The centre-based exercise sessions will be provided in groups of five participants, whereas they will be constantly monitored by a physiologist/researcher. The home-based exercise sessions will consist of a fast-paced walking/jogging at the same heart rate zone as the centre-based exercise sessions. Individuals will be given a heart rate monitor in order to keep heart rate at the desired intensity. Adherence will be checked via session attendance checklist.

The two heat therapy groups will attend The University of Western Australia (UWA) School of Human Sciences (Exercise and Sport Science) every week for 12 weeks, for 3 x 40 minute sessions per week of heat therapy. The heat therapy will be via water immersion for 40 minutes in order to increase body core temperature and induce reflex blood flow changes in skin blood flow and sweating. Individuals will be immersed up to the shoulder level in a 40°C hot tub for 30 minutes. Sequentially, individuals will be positioned in a fashion that the water level reaches waist-level for another 10 minutes. Heat therapy sessions will be supervised by an exercise physiologist/researcher, and will be provided in small groups of five. Adherence will be monitored via session attendance checklist.

Individuals with type 2 diabetes and obesity will be enrolled, randomized and assessed together.
Intervention code [1] 326081 0
Treatment: Other
Intervention code [2] 326189 0
Prevention
Intervention code [3] 326310 0
Lifestyle
Comparator / control treatment
Individuals randomised to the control group will not be required to undertake exercise and/or heat therapy. They will be asked to maintain their regular daily activities throughout the duration of the experiment.
Control group
Active

Outcomes
Primary outcome [1] 334735 0
Indices of microvascular function derived from optical coherence tomography (OCT): microvascular density, diameter, blood speed and blood flow. They are a composite primary outcomes and will not be assessed independently.
Timepoint [1] 334735 0
12 weeks post-commencement of intervention
Secondary outcome [1] 422344 0
Endothelial function will be assessed in the brachial artery in response to application and release of an occlusive pressure cuff, and also in response to a single dose of glyceryl trinitrate (GTN), using non-invasive high resolution Duplex ultrasound. The dose of GTN is 400 µg, which is administered using a sub-lingual spray.
Timepoint [1] 422344 0
12 weeks post-commencement of intervention.
Secondary outcome [2] 422345 0
Cardiac structure, function, and mechanics will be assessed by means of echocardiography assessment, using a non-invasive ultrasound system with a crystal phased-array transducer. They are a composite primary outcomes and will not be assessed independently.
Timepoint [2] 422345 0
12 weeks post-commencement of intervention.
Secondary outcome [3] 422862 0
Arterial stiffness will be assessed using a tonometer simultaneously with a leg cuff to capture blood pressure waveforms at the carotid and femoral sites. The physical distance measurement form the carotid to the femoral site enables the quantification of the pulse wave velocity, the gold standard marker of arterial stiffness.
Timepoint [3] 422862 0
12 weeks post-commencement of intervention.
Secondary outcome [4] 422863 0
Whole body composition will be assessed using Dual Energy X-ray Absorptiometry.
Timepoint [4] 422863 0
12 weeks post commencement of intervention.
Secondary outcome [5] 422866 0
Lipid profile will be assessed after blood collection and analysis.
Timepoint [5] 422866 0
12 weeks post-commencement of intervention.
Secondary outcome [6] 422867 0
Cerebral blood flow velocity will be assessed by means of bilateral measures of middle cerebral artery flow velocity using the Transcranial Doppler (TCD) technique.
Timepoint [6] 422867 0
12 weeks post-commencement of intervention.
Secondary outcome [7] 422915 0
Adherence to exercise and heat therapy interventions will be recorded as number of sessions attended by each individual as a proportion of the total possible number of sessions.
Timepoint [7] 422915 0
Every exercise and/or heat therapy session (can reach up to 5 times per week for 12 weeks = 60 sessions per intervention).
Secondary outcome [8] 423273 0
Endothelial function will be assessed in the femoral artery in response to application and release of an occlusive pressure cuff, and also in response to a single dose of glyceryl trinitrate (GTN), using non-invasive high resolution Duplex ultrasound. The dose of GTN is 400 µg, which is administered using a sub-lingual spray.
Timepoint [8] 423273 0
12 weeks post intervention commencement

Eligibility
Key inclusion criteria
Age range between 45 and 70 years old;
BMI greater than 30 kg/m² or BMI 27-30 kg/m² with at least one established weight-related cardiometabolic co-morbidity, or type 2 diabetes diagnosis >1 year.
Minimum age
45 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Type 2 diabetes diagnosis <1 year
Insulin and/or sulphonylurea medication
Glycated haemoglobin >8.5
Advanced microvessel complications including ulceration, decrease kidney function and/or eye complications which require treatment
Macrovascular complications including a history of unregulated high blood pressure, myocardial infarction and/or cerebrovascular disease.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealed. Central randomization will be performed by using an internet-based dedicated tool for randomization. The number of individuals for block randomization will be previously defined and will respect the randomization pattern further generated.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation will be used for participant allocation in order to ensure similar numbers and sex-matching of participants between groups. A bespoke ‘ralloc’ package will be used (Stata software V13, StataCorp, College Station, TX): blocks of 4 or 8 will be randomly selected and sex-matched randomisation within blocks performed.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
Data will be analysed on an intention to treat basis by a professional statistician who is independent of the study. Linear mixed models will be used to investigate the relationship between exercise, heat therapy, and time, while accounting for age and interactions. We will also conduct a completers analysis to confirm our LMM findings. For all analyses, interactions and main effects will be calculated.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
20/07/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
80
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 313843 0
University
Name [1] 313843 0
University of Western Australia
Country [1] 313843 0
Australia
Primary sponsor type
University
Name
The University of Western Australia
Address
35 Stirling Highway, Crawley, 6009, Perth, WA, Australia.
Country
Australia
Secondary sponsor category [1] 315670 0
None
Name [1] 315670 0
Address [1] 315670 0
Country [1] 315670 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312993 0
Human Research Ethics Committee - University of Western Australia
Ethics committee address [1] 312993 0
35 Stirling Highway, Crawley, 6009, Perth, WA, Australia.
Ethics committee country [1] 312993 0
Australia
Date submitted for ethics approval [1] 312993 0
Approval date [1] 312993 0
14/03/2023
Ethics approval number [1] 312993 0
2022/ET000738

Summary
Brief summary
Microvessels are the smallest type of blood vessels inside every organ of the human body. They are approximately the size of a human hair, or smaller. There are approximately 100,000 km of these microvessels in humans and they are crucial for human health and wellbeing, as they are responsible for maintaining tissue nutrition including the delivery and exchange of oxygen.

Microvessels are capable of undergoing structural and functional change during growth and development and they respond and/or adapt to stimuli including heating and exercise. Microvessels may become dysfunctional, causing symptoms that affect the skin, kidneys, eyes, muscles, nerves, heart and brain. These microvessel diseases are particularly common in people with cardiovascular diseases, obesity and diabetes. However, at present, we know very little about microvessel function and health in humans due to the lack of direct and reliable imaging methods.


The aim of this study is to use optical coherence tomography (OCT) techniques to quantify and compare the effect of exercise training and repeated body heating on the health and function of skin microvessels in individuals with T2D, and in older overweight and obese persons. We will also measure artery function in large arteries in the limbs and the brain, alongside heart function, to determine which of these factors impact on microvessel function.

The exercise training will consist of 3x per week aerobic training (i.e. cycling/fast-paced walking) for 40 minutes during 12 weeks. There will be two centre-based and one home-based exercise session per week. Centre-based sessions will consist of cycling at range from 60 to 75% of individuals' maximum heart rate, depending on the exercise block, with less intense warm-up and cool down periods. Home-based sessions will consist of a fast-paced walking also meeting the desired heart rate training zone (60-75% of maximum hear rate).

The heat therapy will be fully centre-based and will consist of 3 session per week, with a duration of 40 minutes each session, for 12 weeks. Individuals will remain in a hot tube at 40°C for 40 minutes.

Trial website
Trial related presentations / publications
Public notes
The skin possesses a complex and dense network of small blood vessels which may provide an accessible window for assessing systemic microvascular health. We recently developed a new technique, called optical coherence tomography (OCT), that can visualise skin microvessels in humans. It is non-invasive, has a very high resolution, and can quantify skin microvessel parameters such as their diameter and density as well as blood flow speed and flow rate. However, OCT has not been used to determine whether exercise training modifies skin microvascular function or structure in subjects with cardiovascular diseases such as diabetes or in healthy older individuals with risk factors such as overweight and obesity.

Contacts
Principal investigator
Name 126614 0
Prof Daniel J Green
Address 126614 0
The University of Western Australia, 35 Stirling Highway, Crawley, 6009, WA, Australia
Country 126614 0
Australia
Phone 126614 0
+61 864882361
Fax 126614 0
Email 126614 0
danny.green@uwa.edu.au
Contact person for public queries
Name 126615 0
Prof Daniel J Green
Address 126615 0
The University of Western Australia, 35 Stirling Highway, Crawley, 6009, WA, Australia
Country 126615 0
Australia
Phone 126615 0
+61 864882361
Fax 126615 0
Email 126615 0
danny.green@uwa.edu.au
Contact person for scientific queries
Name 126616 0
Prof Daniel J Green
Address 126616 0
The University of Western Australia, 35 Stirling Highway, Crawley, 6009, WA, Australia
Country 126616 0
Australia
Phone 126616 0
+61 864882361
Fax 126616 0
Email 126616 0
danny.green@uwa.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
Individual participant data will remain confidential and will be used strictly for research purposes.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.