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Trial registered on ANZCTR


Registration number
ACTRN12620000243910
Ethics application status
Approved
Date submitted
22/01/2020
Date registered
26/02/2020
Date last updated
26/02/2020
Date data sharing statement initially provided
26/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of home-based exercise training on muscle microvascular dysfunction in type 2 diabetes.
Scientific title
Is skeletal muscle microvascular dysfunction a key determinant of exercise intolerance and impaired glycaemic control in patients with type 2 diabetes?
Secondary ID [1] 300334 0
APP1157930
Universal Trial Number (UTN)
U1111-1247-0752
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metabolic and endocrine 315946 0
Condition category
Condition code
Metabolic and Endocrine 314214 314214 0 0
Diabetes
Physical Medicine / Rehabilitation 314647 314647 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a single-site two-armed, parallel, randomized controlled trial comparing the effect of 3 months of home-based exercise training to usual care.

Clinical chemistries and anthropometrics: Fasting clinical chemistries (glucose, insulin, lipid profile, HbA1c, lactate) and body composition (height, weight, hip and waist circumferences and lean/fat mass by DEXA) will be measured. A medical, lifestyle and dietary questionnaire will be used to assess overall health, physical activity and dietary habits.

Vascular function and metabolic responses to both exercise stress testing and mixed nutrient meal ingestion will be performed before and after a 3-month intervention (home-based exercise training or usual care).

Exercise Doppler-echocardiogram: Graded exercise testing will be performed on an exercise bike using standard cardiopulmonary stress equipment and symptom limited graded exercise test protocol. Resting and post-exercise echocardiographic assessment will be performed using a commercial ultrasound machine at rest and during exercise testing.

Microvascular responses in skeletal muscle during exercise and after mixed nutrient meal ingestion: Microvascular blood flow responses will be tested via contrast enhanced ultrasound imaging of thigh muscle at rest, at the end of the exercise stress tests, and during and after ingesting a mixed nutrient meal.

Large artery function and central haemodynamics: Femoral artery blood flow will be assessed using 2D and Doppler imaging at rest, at the end of the exercise stress tests, and during and after ingesting a mixed nutrient meal.

Mixed nutrient meal: Participants will be provided a mixed nutrient meal to consume within 5 minutes. The mixed meal contains an UP&GO™ shake combined with 26.02 g BULK protein powder (Musashi) and 2.29 g Lean Whey protein isolate (Musashi) constituting 1256 kJ of total energy (approximately 21.6 g protein, 4.9 g fat, 40 g carbohydrate).

Muscle capillary density/biochemistry: A vastus lateralis muscle biopsy will be performed before and after mixed nutrient meal ingestion. The number of capillaries per mm2 and per muscle fibre will be determined by histology. Oxidative enzyme capacity (e.g. citrate synthase) and cell signalling linked to muscle function and exercise adaptation will be performed via western blot.

3-month Intervention:
Following baseline testing, participants will be randomised to either i) usual care or ii) home-based (remote) exercise training for 3 months. Groups will be matched for age, BMI, sex and LV filling pressure (assessed as E/e’ by echo). Randomisation will be in accordance with CONSORT guidelines for non-pharmacological trials, and all researchers performing outcome measures will be blinded to group allocation.
i) Remote home based exercise training:
Participants will be asked to undergo three 35 minute exercise sessions per week, for 3 months. Exercise intensity will be prescribed based of heart rate reserve (HRR; Intensity * (HR peak - HR rest) + HR rest], and can include any type of exercise that elicits the target heart rate (e.g., fast pace walking, jogging, running, walking uphill, cycling). The exercise protocol will include four 4-minute walking/jogging intervals of high-intensity exercise at 80-85% HRR, with each interval separated by 3 minutes of low-intensity exercise at 50% HRR. All exercise sessions will include a 5-minute warm-up and 5-minute cool-down at 50% of HRR.

The exercise program will be administered and supervised remotely using a wearable fitness sensor, bespoke smartphone and web apps, and custom middleware. The sensor provides information on heart and respiratory rates, single lead ECG and accelerometry. Participants will use the bespoke telerehabilitation platform to connect with a remotely-located accredited exercise physiologist. Participants will receive real-time coaching, feedback, and support from exercise physiologists, delivered as audio notifications via the bespoke smartphone app. All intervention group participants will complete a bespoke training module, receive an illustrated user guide, and have access to technical support via email and/or telephone if required.

Participants can be monitored in any environment with an active Wi-Fi or 3G/4G broadband connection, and the platform supports simultaneous monitoring of multiple participants. Exercise physiologists will receive comprehensive training to deliver these intervention components. This will include 3 hours of face-to-face training and induction on-site (Deakin University) and the provision of contact details for a trained research member who can provide real-time assistance when a session is in place, further training, and the answering of any questions.

ii) Usual care:
Those participants randomised to this group will be instructed to maintain their normal lifestyle habits, while following usual care (but refrain from increasing physical activity levels).

Exercise training adherence and compliance will be measured via session output data (e.g., Heart Rate and Sessions completed) that is logged and provided by the fitness session and phone application.
Intervention code [1] 316613 0
Rehabilitation
Intervention code [2] 316614 0
Treatment: Devices
Comparator / control treatment
A usual care group will be included whom do not undergo the home-based exercise intervention. Participants randomised to this group will be instructed to maintain their normal lifestyle habits, physical activity levels (whether low, moderate or high), and current treatment/medication as instructed and recommended by their GP/Health Specialist. Participants in this group will however be asked to refrain from increasing their physical activity level above from what they are currently undergoing.
Control group
Active

Outcomes
Primary outcome [1] 322600 0
Change in peak post-exercise microvascular blood flow (Arbitrary units) measured by contrast enhanced ultrasound after the 3-month intervention.
Timepoint [1] 322600 0
Peak post-exercise microvascular blood flow measured immediately before and after the 3-month intervention.
Primary outcome [2] 322601 0
Change in peak meal induced microvascular blood flow (Arbitrary units) measured by contrast enhanced ultrasound after the 3-month intervention.
Timepoint [2] 322601 0
Peak meal-induced microvascular blood flow measured immediately before and after the 3-month intervention.
Secondary outcome [1] 379020 0
Change in exercise capacity (peak volume of oxygen utilisation) assessed by metabolic cart and oxygen analyser during the graded exercise test..
Timepoint [1] 379020 0
Exercise capacity (peak volume of oxygen utilisation) measured during the graded exercise test both before and after the 3-month intervention.

Eligibility
Key inclusion criteria
Inclusion criteria:
1. Aged 40–80 years.
2. Clinical diagnosis of T2D
Controlled diabetes through diet or medication (excluding insulin) for at least 8 weeks.
3. Have given signed informed consent to participate in the study.
Minimum age
40 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:
1. Age <40 years or > 80 years.
2. Patients using insulin to control blood sugar levels.
3. Pulmonary hypertension.
4. Atrial fibrillation.
5. Cardiovascular disease including coronary artery disease or heart valve disease.
6. Poor ejection fraction (<50%) or elevated left ventricle filling pressure (E/e’ >15).
7. Critical limb ischemia including peripheral artery disease or previous revascularisation or other surgical treatment for peripheral artery disease.
8. History of malignancy within past 5 years (except for non-melanoma skin cancers).
9. Identification of any medical condition requiring immediate therapeutic intervention.
10. Uncontrolled hypertension (resting brachial blood pressure greater than or equal to 160/100 mmHg).
11. Other non-cardiovascular barriers to exercise
12. Current or previous smoker with past 12 months.
13. Participation or intention to participate in a structured and/or supervised physical activity program during the study period.
14. History of severe liver disease.
15. Elective major surgery during the course of the study.
16. Pregnancy/lactation.

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation (first 4 randomisation envelopes will contain 2 usual care and 2 exercise intervention).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Data will be checked for normality and analysed using Predictive Analytics Software (PASW v20, SPSS Inc.). Comparison of means between groups will be compared using analysis of variance (ANOVA) and multivariable linear regression where appropriate. Comparison of multiple means will be analysed using a two-factor repeated measures ANOVA with time (before and after exercise tests, before and after mixed meal ingestion, and before and after the intervention) as the within-subjects factor and group (exercise tolerant T2D, exercise intolerant T2D (untrained/usual care), and exercise intolerant T2D (trained) as the between-subjects factor. Significant interaction and main effects will be explored post-hoc with corrections for multiple comparisons. All data will be reported as mean ± standard deviation and all statistical analysis will be conducted at the 95% level of significance (p = 0.05). Where possible, data analysis will be conducted in a blind fashion (e.g., blood sample and muscle analysis will be re-identifiable and coded to remove bias during analysis).

Recruitment
Recruitment status
Not yet recruiting
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 in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 304760 0
Commercial sector/Industry
Name [1] 304760 0
National Heart Foundation of Australia
Address [1] 304760 0
2/850 Collins St, Melbourne VIC 3008
Country [1] 304760 0
Australia
Funding source category [2] 304762 0
Government body
Name [2] 304762 0
National Health and Medical Research Council
Address [2] 304762 0
414 La Trobe St, Melbourne VIC 3000
Country [2] 304762 0
Australia
Primary sponsor type
University
Name
Deakin University
Address
221 Burwood Hwy, Burwood VIC 3125
Country
Australia
Secondary sponsor category [1] 305076 0
None
Name [1] 305076 0
Address [1] 305076 0
Country [1] 305076 0
Other collaborator category [1] 281142 0
Other
Name [1] 281142 0
Baker Heart and Diabetes Institute
Address [1] 281142 0
75 Commercial Rd, Melbourne VIC 3004
Country [1] 281142 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305177 0
Alfred Health
Ethics committee address [1] 305177 0
75 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 305177 0
Australia
Date submitted for ethics approval [1] 305177 0
26/09/2019
Approval date [1] 305177 0
30/09/2019
Ethics approval number [1] 305177 0
513/19
Ethics committee name [2] 305180 0
Deakin University Human Ethics Committee
Ethics committee address [2] 305180 0
221 Burwood Highway, VIC, 3125
Ethics committee country [2] 305180 0
Australia
Date submitted for ethics approval [2] 305180 0
20/11/2019
Approval date [2] 305180 0
09/12/2019
Ethics approval number [2] 305180 0
2019-426

Summary
Brief summary
Many patients with type 2 diabetes exhibit exercise intolerance (decreased capacity to exercise) and this is often associated with poorer insulin and glucose (glycaemic) control, accelerated disease progression, reduced quality of life, and decreased longevity and survival. However, the primary causes behind exercise intolerance and poor glycaemic control in these patients are not well understood. Using modern biochemical and ultrasound imaging techniques this project aims to determine whether skeletal muscle microvascular dysfunction (impaired blood flow through small blood vessels), is the main underlying cause behind exercise intolerance and poor glycaemic control. Furthermore, this study will investigate whether a 3-month home-based exercise program can improve muscle microvascular function, glycaemic control and exercise tolerance in patients with T2D.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 99502 0
Dr Lewan Parker
Address 99502 0
Deakin University
221 Burwood Highway, VIC, 3125
Country 99502 0
Australia
Phone 99502 0
+61 3 9246 8740
Fax 99502 0
Email 99502 0
lewan.parker@deakin.edu.au
Contact person for public queries
Name 99503 0
Dr Lewan Parker
Address 99503 0
Deakin University
221 Burwood Highway, VIC, 3125
Country 99503 0
Australia
Phone 99503 0
+61 3 9246 8740
Fax 99503 0
Email 99503 0
lewan.parker@deakin.edu.au
Contact person for scientific queries
Name 99504 0
Dr Lewan Parker
Address 99504 0
Deakin University
221 Burwood Highway, VIC, 3125
Country 99504 0
Australia
Phone 99504 0
+61 3 9246 8740
Fax 99504 0
Email 99504 0
lewan.parker@deakin.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
What supporting documents are/will be available?
No other documents available
Summary results
No Results