Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000337774
Ethics application status
Approved
Date submitted
7/05/2021
Date registered
24/02/2022
Date last updated
24/02/2022
Date data sharing statement initially provided
24/02/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
The wellderly study, where bone-muscle-fat interact: effects of exercise in middle-aged and older adults populations.
Scientific title
The wellderly study: effects of exercise on bone remodelling markers in middle-aged and older adults populations
Secondary ID [1] 304139 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sarcopenia 321831 0
Condition category
Condition code
Musculoskeletal 319563 319563 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study involves three main parts. 1) screening and baseline assessments related to bone, muscle and body composition health, 2) acute high intensity exercise and 3) chronic exercise training (4-weeks).
For all acute HIE and exercise training visits, participants will be supervised by Accredited Exercise Physiologists in a 1:1 or 1:2 format. All the assessments and exercise training will be conducted face-to-face.
EFFECTS OF ACUTE EXERCISE
We will examine the effects of acute high intensity interval exercise (HIIE) on markers of bone, muscle and fat metabolism as well as changes in markers of metabolic and CV risk (glucose, lipids, inflammation etc). This (identical) acute HIIE session will also be performed following 4-weeks of HIIE training. Blood sampling will be taken before exercise, immediately following exercise, and up to 180 min post-exercise. Urine samples will be taken before and following exercise. Participants can elect to have none, one (at rest) or four (1 at rest and 1 following each acute exercise session) muscle and adipose tissue biopsies. Muscle will be analysed for protein degradation and protein synthesis pathways. Other novel markers associated with muscle, bone and fat health may also be assessed.
Twenty-four hours prior to the acute HIIE session participants will be asked to refrain from any formal exercise, consume their normal diet and not take caffeine or alcohol. Participants will arrive to our lab between 7-8am after an overnight fast. At the start of each visit, a cannula will be inserted into the antecubital vein. At each testing visit we will take six blood samples (~20 to 25 ml each), one at rest before you exercise, and one immediately when you finish then at 30, 60, 120 and 180 mins post-exercise. The total blood volume taken in one visit is around 140ml. The acute HIIE session incudes 4 sets x 4 minutes of cycling (on a cycle ergometer) at 80-90% of HRR with 2 minutes of active recovery between sets).
Participant will be able to consume water, however, they will be unable to eat until the end of the visit. Participants will also be asked to complete some simple short questionnaires. The Feelings scale and The subjective exercise experience scale (SEES).
EFFECTS OF 4-WEEKS HIIT EXERCISE TRAINING
Following the acute exercise, participants will be randomised (using block randomisation, sealed envelope) to receive either 4 weeks of exercise training, or 4 weeks of standard clinical care (control). Training will be 3 sessions per week. The format of these sessions will be the same as the acute HIIE session 4 sets x 4 minutes of cycling (on a cycle ergometer) at 80-90% of HRR with 2 minutes of active recovery between sets). Blood pressure and heart rate will be monitored before and after exercise. Both before and after the chronic training period we will administer the third version of Behavioral Regulation in Exercise Questionnaire (BREQ 3) to assess baseline exercise motivation and determine if the applied intervention positively impacts internal or external motivation for exercise participation. The study coordinator will be in close contact with the participant to arrange all training sessions, and will maintain a session attendance checklist to monitor adherence to the intervention.
Following the 4 week intervention (exercise training and control) and between 48 to 72 hours after their final visit, participants will attend VU for final assessments which will be a repeat of the baseline testing and acute exercise.
Intervention code [1] 320482 0
Lifestyle
Comparator / control treatment
Participants who will be randomized to the control group (no exercise) will continue with their normal daily routine/or standard clinical care for 4 weeks. If randomised to control, participants will be asked to maintain their normal habitual behaviours and diet. For those randomised to control, following their final testing day, as a courtesy for their participation in the study, we will offer them 4 weeks of exercise training.
Control group
Active

Outcomes
Primary outcome [1] 327427 0
change in bone remodelling markers, such as. osteocalcin, C-terminal telopeptide of type 1 collagenand lipocalin 2, following acute exercise and chronic exercise assessed via blood sampling.
Timepoint [1] 327427 0
Baseline and immediately following the 30min acute HIE session 0mins, 30mins, 60mins, 120mins (primary endpoint) and 180 mins post exercise and for the chronic training the timepoints are baseline and 4 weeks post exercise training
Primary outcome [2] 327428 0
change in cardiometabolic health markers (i.e. insulin, glucose, HOMA-IR) following acute exercise and chronic exercise assessed via blood sampling
Timepoint [2] 327428 0
Baseline and immediately following the 30min acute HIE session 0mins, 30mins, 60mins, 120mins (primary endpoint) and 180 mins post exercise, and for the chronic training the timepoints are baseline and 4 weeks post exercise training
Primary outcome [3] 327429 0
Expression of proteins associated with muscle hypertrophy/degradation. Will be assessed via muscle sampling, Western Blots (i.e mTOR, Akt, ERK1/2,)
Timepoint [3] 327429 0
Baseline and post 1 h of exercise (acute) and 4 weeks of training (chronic)
Secondary outcome [1] 395105 0
Genetic analysis from blood and muscle sampling. Exploratory outcome
Timepoint [1] 395105 0
baseline and 4 weeks post chronic exercise training
Secondary outcome [2] 395106 0
Vascular stiffness, assessed via applanation tonometry (sphygmocor)
Timepoint [2] 395106 0
baseline and 4 weeks post chronic exercise training
Secondary outcome [3] 395107 0
Body composition assessed via DXA
Timepoint [3] 395107 0
baseline and 4 weeks post chronic exercise training
Secondary outcome [4] 397796 0
change in physical performance test score (combined score including performance in timed up and go, gait velocity, stair climbing, stair descending) from baseline to after chronic exercise training
Timepoint [4] 397796 0
baseline and following 4 weeks chronic exercise training
Secondary outcome [5] 397797 0
change in aerobic capacity (VO2Peak) from baseline to after chronic exercise training
Timepoint [5] 397797 0
baseline and following 4 weeks chronic exercise training

Eligibility
Key inclusion criteria
Males and females aged >45years or older. Postmenopausal Females will be required to be a minimum of 12 months post menopause.
Minimum age
45 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Potential participants will be excluded from the study if they:

have been recently diagnosed (less than 14 days) with COVID-19, have been identified as a close-contact of someone with COVID-19, or have signs or symptoms suggestive of COVID-19. Once the individual has been cleared of COVID-19, they will be allowed to participate in the study. This is to be determined by your medical doctor, and a letter of approval will need to be provided. All participants will be phone screened for these criteria 24 hours prior to each of their in-person visits (see appendix 4). They will also complete the form again on arrival.
have had any fractures in the previous 3 months, or have commenced antiresorptive medication or any other new osteoporotic treatment within the last three months.
have diabetes mellitus or are taking hypoglycaemic medications
have any blood or marrow disorders
have any bone malignancies or tumours
are taking warfarin or vitamin K supplementation or restriction
have a body mass index equal to or greater than 40kg/m2
are professionally active (compete at a high level: national or international sporting competitions)
are a current smoker, or have ceased smoking in the last 12 months
have begun any new medications, new physical activity or dietary regimens (food intake) in the last 3 months
are known to have a high blood pressure (more than 160/100 mmHg) or have been diagnosed with coronary artery disease or chronic heart failure.
are taking hormone replacement therapy (HRT)
If you are taking glucocorticoids or other medications that alter bone metabolism


Additional criteria include:

are unable to give informed consent independently, we will not include any persons who are unable to give independent informed consent for safety reasons, particularly as we take some invasive measures.
pregnancy, the effects of maximal exercise whilst during pregnancy remain unclear. For safety precautions we will not include pregnant women.
unable to understand English, this could potentially be a safety concern if unable to communicate during some of the maximal exertion testing visits, and for the acute exercise bout.

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)
The person responsible for the randomisation, will not be involved in the project. Randomisation will be stratified by age group (middle aged and older adults) and by sex (female and male) to ensure similar number of males and females in each group (training or control)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation. Similar number of notes for training and control will be inserted into concealed envelop Four notes from each will be used to ensure similar number in each group every 8 participants.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
SCREENING AND BASELINE ASSESSMENTS.
The following assessments will be performed as part of the screening and baseline testing:
• Height will be measured with the participant standing barefoot on a stadiometer and weight will be measured with participants wearing just light clothes whilst standing on a calibrated scale.
• Dual energy x-ray absorptiometry (DXA): Body composition and bone mineral density (BMD) will be assessed using a DXA scanner (Hologic, Horizon A, software version 5.6.0.4). Total BMD as well as the neck of femur and lumbar spine BMD will be assessed. In addition, lean body mass and fat mass will be assessed.
• Bone microarchitecture and fat infiltration: Peripheral Quantitative Computer Tomography (pQCT; Stratec XCT3000, Stratec Medizintechnik GmbH, Pforzheim, Germany) will be used to quantify muscle and bone mass, density and adipose infiltration at the nondominant forearm and foreleg. Calf intra-muscular adipose tissue (IMAT) cross-sectional area (CSA; cm2) will be quantified. Trabecular and cortical bone densities and structure will be assessed at the relevant regions of interest.
• Grip strength and gait velocity: Grip strength will be measured using a hand dynamometer; a result of <20 kg for females and <30 kgs for males will identify low muscle strength. For Gait velocity we will measure using 3 different protocols with reduced physical function determined as <80 cm/sec. Both the grip strength and gait velocity thresholds noted are accepted as a measurement of sarcopenia and will form the definition in this study. For measurement of gait velocity, a normal paced walking speed test will be assessed using three protocols; 1) using a 4-meter walk test where participants will be timed from word go, instructed to walk at their normal comfortable pace to the 4-meter mark where time is then recorded; 2) using a 4-meter walk test to calculate normal walking speed within an 8 m course where the participant will be instructed to walk normally, the stopwatch will begin once the foot crosses the acceleration phase (2-meter mark), walk 4m, then time stopped once foot lands in the deceleration phase (6-meter mark); and lastly 3) we will also measure a fast paced walk test for the calculation of maximum speed using the exact same protocol described in (2) above however, participants will be asked to walk as fast as they can, without running. For all 3 gait speed trials, participants will have 3 attempts, and the average calculated and described in m/s.
• Lower limb maximal strength and leg muscle quality: Participants will perform a one maximal repetition (1RM) test on a leg press. This will be performed twice with the first visit serving as familiarisation. Leg muscle quality (LMQ), an estimate of specific force, has been shown to decrease with age is described as the amount of force a muscle group can produce per unit of muscle mass. We will calculate leg muscle quality as:
LMQ = leg strength (kg) /(left leg lean mass (kg) + right leg lean mass (kg)) (61)
Leg strength will be defined as the participants 1RM, and leg lean mass will be obtained from the DXA assessment.
• Physical performance test: Participants will complete a Physical Performance Test (PPT), adapted from Levinger et al. and will include four functional mobility tasks; (1) a gait velocity assessment (described earlier), (2) timed up and go test, (3) stair climbing power (SCP) and (4) stair descending. All tests will be scored in time (seconds).
The timed up and go test is a simple performance-based assessment, requiring minimal equipment including; standard arm chair, 3-meter walkway with floor mark and stopwatch (time, seconds). It is performed as time (seconds) taken to rise from a seated position, walk 3 meters, turn, walk back to the chair and then sit. The SCP will consist of a rapid ascent of 10 stairs, where;
SCP = body weight (kg) x 9.8ms-2 x step height (m) x number of steps x time -1 (s-1)
The stair descent will be time to safely descend 10 stairs. The rest between the ascent and descent will be 45 s. Participants will undergo four attempts on each task and the best time recorded for each. The PPT score will be the sum of the fastest times recorded for each test.
• Aerobic capacity and vascular health: Participants will complete three graded exercise tests (GXTs), one at each baseline visit and one during post assessments for the determination of peak oxygen consumption (VO2Peak). VO2Peak will be assessed on a cycle ergometer with the initial intensity beginning at 10-30 Watts (W) and increasing by 10-30W×min-1 according to participant ability. Participants will be monitored by 12-lead electrocardiogram (ECG; Mortara, X-Scribe II, Milwaukee, WI). VO2 for each 15-s interval will be measured by gas exchange analysis (BreezeEx, version 3.02, Medical Graphics Corp.)
• Vascular stiffness will be assessed by non-invasive measures of pulse wave velocity (simultaneous comparison of carotid and femoral arterial pulses) and pulse wave analysis (pulsations recorded at the brachial artery to produce central aortic pressure waveforms) using applanation tonometry (SphygmoCor EXCEL system V1, AtCor Medical, New South Wales, Australia) (66).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
13/05/2021
Date of last participant enrolment
Anticipated
1/06/2023
Actual
Date of last data collection
Anticipated
1/08/2023
Actual
Sample size
Target
40
Accrual to date
4
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 308516 0
Charities/Societies/Foundations
Name [1] 308516 0
Defence Science Institute
Country [1] 308516 0
Australia
Funding source category [2] 310715 0
University
Name [2] 310715 0
Victoria University
Country [2] 310715 0
Australia
Primary sponsor type
University
Name
Victoria University
Address
Victoria University,
PO Box 14428,
Melbourne, VIC 8001
Australia
Country
Australia
Secondary sponsor category [1] 309398 0
None
Name [1] 309398 0
N/A
Address [1] 309398 0
N/A
Country [1] 309398 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308473 0
Victoria University Human Research Ethics Committee
Ethics committee address [1] 308473 0
Ethics committee country [1] 308473 0
Australia
Date submitted for ethics approval [1] 308473 0
Approval date [1] 308473 0
03/08/2020
Ethics approval number [1] 308473 0
HRE20-105

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110814 0
Prof Itamar Levinger
Address 110814 0
Institute for Health and Sport (IHES)
Victoria University,
PO Box 14428,
Melbourne, VIC 8001
Australia
Country 110814 0
Australia
Phone 110814 0
+61399195343
Fax 110814 0
Email 110814 0
[email protected]
Contact person for public queries
Name 110815 0
Itamar Levinger
Address 110815 0
Institute for Health and Sport (IHES)
Victoria University,
PO Box 14428,
Melbourne, VIC 8001
Australia
Country 110815 0
Australia
Phone 110815 0
+61399195343
Fax 110815 0
Email 110815 0
[email protected]
Contact person for scientific queries
Name 110816 0
Itamar Levinger
Address 110816 0
Institute for Health and Sport (IHES)
Victoria University,
PO Box 14428,
Melbourne, VIC 8001
Australia
Country 110816 0
Australia
Phone 110816 0
+61399195343
Fax 110816 0
Email 110816 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All coded data will be shared with an approval from the relevant ethics committee and consent from individuals.
When will data be available (start and end dates)?
Up to 5 years post data collection (1 Jan 2023- 24 Dec 2027)
Available to whom?
Universities and research institutes recognized by the NHMRC
Available for what types of analyses?
To increase sample size of other studies conducted in related areas.
How or where can data be obtained?
The data can be obtained by approaching CI Levinger ([email protected]).


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11609Study protocol  [email protected]
11610Statistical analysis plan  [email protected]
11611Informed consent form  [email protected]
11612Ethical approval  [email protected]



Results publications and other study-related documents

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