Trial Review

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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
17/02/2023
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.

Pre-intervention testing:
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. Medical, lifestyle, quality of life, and dietary questionnaires will be used to assess overall health, physical activity, quality of life, and dietary habits. A 6-minute walk test and a 2-minute step test will be conducted to assess functional exercise capacity.

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/treadmill 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 nutrient meal constitutes approximately 21.6 g protein, 4.9 g fat, and 40 g carbohydrate with 1256 kJ of total energy.

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) 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 first week of the home-based exercise training program (three complete exercise sessions) will be conducted at the research facility and will be supervised by an exercise physiologist to help familiarise the participant with this type of exercise and help answer any questions about adapting the exercise for home use/outside the clinic (e.g., using plastic aerobic steps in the house or in their local park, or incorporating other types of aerobic exercise to elicit the target heart rate intensity). Participants will complete the remainder of the training program at home/outside the clinic (i.e., under free living conditions). Research staff will check-in with participants (email, phone, and/or text message) after each training day for the first two weeks of home-based exercise training, and then once a week for the remainder of the training program.

Heart rate data after each exercise session will be recorded and uploaded to the commercial Polar Flow online servers using a wearable heart rate strap provided to participants which will be connected to a smart phone (either participant owned or a loaned smartphone). The researchers will then access this server to download the heart rate data to confirm that the prescribed workload (heart rate intensity) was achieved, and to confirm the number of sessions completed over the course of the exercise program (compliance). An android phone will be loaned to participants in the event participants do not have a mobile phone, or would prefer not to use their personal phone for the research study.

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).

Mid-intervention exercise tolerance testing (after 6 weeks):
After 6 weeks of the exercise program or usual care, participants will be asked to attend a single session at the research facility to undergo a 6-minute walk test, 2-minute step test, and a maximal exercise test on a gym bike/treadmill. No ultrasound measures or blood will be taken during this visit. Aerobic capacity (exercise tolerance) will be measured via a face-mask during the maximal exercise test.

Post-intervention mixed meal challenge and Cardiopulmonary Exercise Tests:
Participants will repeat the same mixed meal challenge and exercise tests as performed in the pre-intervention visits. These visits will be conducted a minimum of 48 hours after the final training session to eliminate the effects of acute exercise. Medical, lifestyle, quality of life, and dietary questionnaires will be completed after the intervention to assess overall health, physical activity, quality of life, and dietary habits.
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.
Secondary outcome [2] 407314 0
Change in functional exercise capacity (distance walked) assessed by the 6-minute walk test.
Timepoint [2] 407314 0
Functional exercise capacity (distance walked) measured after the 6-minute walk test both before and after the 3-month intervention.
Secondary outcome [3] 407315 0
Change in functional exercise capacity (number of steps taken) assessed by the 2-minute step test.
Timepoint [3] 407315 0
Functional exercise capacity (number of steps taken) measured during the 2-minute step test both before and after the 3-month intervention.

Eligibility
Key inclusion criteria
Inclusion criteria:
1. Aged 40–80 years.
2. Clinical diagnosis of pre-diabetes (HbA1C = 5.7%) or T2D (HbA1C = 6.5%)
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
Sex
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 Graphpad Prism statistical analysis package. 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 (usual care versus exercise trained group) as the between-subjects factor. Sub-group secondary analysis of the effects of exercise tolerance on all outcomes will be investigated (exercise tolerance will be added to the statistical model as a between subjects factor) using the pre-defined definition of exercise tolerance. 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
Recruiting
Date of first participant enrolment
Anticipated
14/03/2022
Actual
Date of last participant enrolment
Anticipated
30/06/2023
Actual
Date of last data collection
Anticipated
30/09/2023
Actual
Sample size
Target
56
Accrual to date
0
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
Country [1] 304760 0
Australia
Funding source category [2] 304762 0
Government body
Name [2] 304762 0
National Health and Medical Research Council
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
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
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
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
[email protected]
Contact person for public queries
Name 99503 0
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
[email protected]
Contact person for scientific queries
Name 99504 0
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
[email protected]

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 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.