Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000072112
Ethics application status
Approved
Date submitted
14/01/2019
Date registered
18/01/2019
Date last updated
25/02/2019
Date data sharing statement initially provided
18/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessing the impact of exercise timing on glycaemic control
Scientific title
Role of diurnal exercise timing on glycaemic control in individuals with Type 2 diabetes mellitus: A randomised controlled trial
Secondary ID [1] 297058 0
NIL
Universal Trial Number (UTN)
U1111-1226-6930
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes Mellitus 311061 0
Condition category
Condition code
Metabolic and Endocrine 309697 309697 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study Design:
Potential participants will be initially be screened by the study coordinator. Participants will then be invited to attend the Exercise Physiology Clinic at Murdoch University for the collection of preliminary measurements and baseline data following attainment of written informed consent. Following baseline assessments, participants will be randomly assigned into their intervention groups (POSTam and POSTpm) to begin their 12-week exercise training intervention. Mid-intervention assessments will occur during Week 6 to assess: (i) glycaemic control and; (ii) aerobic fitness. At least 24 hours after the last training session in Week 12, but no more than 96 hours after the last training session, participants will then complete their final assessment of glycaemic control and aerobic fitness.

Procedures:
Participants will continue their medications at the usual dose, frequency and time while participating in this study. Baseline testing will include body anthropometrics (dual energy X-ray absorptiometry [DXA], height, weight and waist circumference), aerobic fitness assessment (VO2 peak test; modified Bruce treadmill test protocol), diet history (24h dietary recall conducted on 5 separate occasions representing different days), 14-day sleep and physical activity monitoring (Actigraph and diary), 24 h skin temperature (iButton, data logger) and an appetite questionnaire.

Additionally, participants will attend the laboratory (study day) for assessment of postprandial glucose changes (in response to a oral glucose tolerance test; OGTT) and changes in fasting glucose and insulin along with measures of peripheral insulin sensitivity derived during the OGTT (Cederholm index). The OGTT (75g) will be performed in the morning, following an overnight fast. One blood sample will be taken prior to the ingestion of the glucose solution (Trutol) for measures of glycaemic control (HbA1c; 1,5-anhydroglucitol [1,5-AG]). Thereafter, samples will be taken every 15min via a venous canula for the duration of the 2-h OGTT for changes in postprandial glucose response. A prior evening meal will be standardised (Lite and Easy) and provided to the participants.

Following baseline assessments, participants will be randomly assigned into their respective intervention groups (POSTam and POSTpm). Randomisation and allocation will be performed on unique study I.D.’s by an independent investigator using randomly permutated blocks (each block n = 4-6; http://www.randomisation.com) with males and females counterbalanced (separate allocation sequences generated) across groups. This list will then be forwarded back to the study researcher. Participants from both intervention groups will undertake three supervised 55-65 min exercise-training sessions per week (165-190min supervised per week) for a total of 12-weeks. The exercise training sessions will be performed by the participants under the supervision of a trained exercise physiologist. The testing battery for the baseline (pre-) and post-intervention assessments will be identical. A mid-intervention assessment during Week 6, will include 1,5-AG, fasting glucose and VO2
peak test only. The 1,5-AG will enable short-term (~2 week) changes in glycaemic control to be assessed.

The supervised exercise intervention will consist of a progressive resistance (2-3 sets x 10/12
repetitions; 4 exercises (i.e. bench press, military press, lat-pulldown and leg press) performed in a circuit style) and brisk walking (at ~60% of VO2 peak for 35-45min). The intensity and volume of both the aerobic and resistance exercises are prescribed in accordance to the American Heart Association scientific statement. The exact exercises and repetitions performed for the resistance exercises will be determined by the supervising exercise physiologist at every training session depending on the participant's fitness levels. Additionally, for the resistance exercises, once the participants are able to complete 12 repetitions for each set of exercises on 2 consecutive sessions (2-by-2 rule), the prescribed intensity of each exercise will increase. This process will be overseen by the exercise physiologist during the training sessions. The POSTam will be performed in the morning (0530-0930h) i.e. post-breakfast) while POSTpm will be performed 30-120min after the final meal in the evening (evening meal considered >633 calories; based of an average total daily (3 meals) intake of 2000 calories). Participants in the POSTpm group will be consistently asked whether they have adhered to the diet program (i.e. no consumption of food after each exercise training session). This will be completed via over the phone reminders and a questionnaire that will be completed after each training session. As for the POSTam group, they will be asked to consume a breakfast meal at least 30 minutes prior to the start each training session for duration of the intervention. The design of the exercise intervention is such that it requires minimal equipment and can be conducted at the participant’s home following a similar model to that successfully completed previously (NCT01283854). The training workload (volume and intensity) will be monitored closely by the exercise physiologist at every session. All exercise sessions will be recorded in a logbook with attendance taken as well as sessional RPE for each individual training session over the 12-week period. Additional Physical activity advise will be focussed on increasing physical activity levels to >220min per week (i.e., additional 30 to 50 min per week), with the focus being to conduct that physical activity at the same time-period as their supervised session (but not a requirement). Dietary advise will be individualised and based on diet preference and diet history so as to align with Australian Diabetes recommendations (energy-intake; macronutrient profile only).

Blood analysis:
A total of 11 blood samples [baseline blood sample (6ml); and 10 venous blood samples (3ml)] will be collected via the antecubital vein during the study days for the analysis of metabolites (glucose, lactate, lipids and haematocrit). The blood samples will be transferred into EDTA-coated tubes pre-treated with 30 micro-litres of dipeptidyl peptidase IV inhibitor and aprotinin (Millipore) for later determination of metabolites via the COBAS 6000 chemistry analyzer. Our group has previously published using these techniques and all facilities are available. Baseline samples from each study day will also be assessed for HbA1c and 1,5-AG (Western Diagnostics Laboratories).
Intervention code [1] 313333 0
Treatment: Other
Comparator / control treatment
Comparison between two intervention groups (i.e. POSTam vs. POSTpm) with POSTam being the comparator.
Control group
Active

Outcomes
Primary outcome [1] 318663 0
The primary outcome will be glycaemic control as done through the analysis of composite measures that include: glycosylated haemoglobin (HbA1c),fasting glucose and 1,5-anhydroglucitol (1,5-AG) levels. Blood samples will be sent to an external provider (Western Diagnostic) for the analysis of HbA1c and 1,5-AG. Additionally,blood samples will be analysed in-house using a COBAS 6000 chemistry analyzer for fasting glucose levels.
Timepoint [1] 318663 0
Glycosylated haemoglobin, fasting glucose and 1,5-AG levels will be done prior to the start of the 12-week training intervention during baseline assessment (study day) and at least 24 hours after the last training session in week 12, but no more than 96 hours after the last training session (post-intervention study day). In addition, fasting glucose and 1,5-AG levels will be done during the mid-intervention assessments which will occur in week 6.
Secondary outcome [1] 365617 0
The secondary outcome will be the changes in postprandial responses to a 2-h OGTT as analysed using composite measures of postprandial glucose (PPG) and postprandial insulin (PPI) concentrations. All blood samples will be analysed in-house using a COBAS 6000 chemistry analyzer for both PPG and PPI concentrations.
Timepoint [1] 365617 0
Postprandial glucose and insulin concentrations will be done prior to the start of the 12-week training intervention during baseline assessment (study day) and at least 24 hours after the last training session in week 12, but no more than 96 hours after the last training session (post-intervention study day) during the 2-h OGTT.
Secondary outcome [2] 365623 0
Changes in body anthropometrics would be analysed using composite measures of body mass index (calculated with height (stadiometer) and weight (digital weighing scale) , waist circumference (tape measure) and body fat percentage (DXA scan).
Timepoint [2] 365623 0
Prior to the start of the 12-week training intervention during baseline assessment (pre-intervention), mid-intervention assessment (week 6) and at least 24 hours after the last training session in week 12, but no more than 96 hours after the last training session (post-intervention).
Secondary outcome [3] 365624 0
Changes in cardiovascular fitness levels as measured by maximal oxygen consumption (VO2max) during a modified Bruce treadmill testing protocol.
Timepoint [3] 365624 0
Prior to the start of the 12-week training intervention during baseline assessment (pre-intervention), mid-intervention assessment (week 6) and at least 24 hours after the last training session in week 12, but no more than 96 hours after the last training session (post-intervention).
Secondary outcome [4] 365844 0
Dietary history will be analysed using a 24h dietary recall that will be completed online using the NIH Automated Self-Administered 24h-Hour Dietary Tool (ASA24-2016).
Timepoint [4] 365844 0
Prior to the start of the 12-week training intervention during baseline assessment (pre-intervention) and at least 24 hours after the last training session in week 12, but no more than 96 hours after the last training session (post-intervention). For both pre-intervention and post-intervention, a total of 10 24h dietary recalls (5 occasions over a period of 2 weeks for each time point) will be completed.
Secondary outcome [5] 365845 0
Changes in sleeping patterns will be analysed using composite measures of sleep monitoring (Actigraph monitor) and a 14-day sleep diary (which will be used to sync with the raw data extracted from the Actigraph monitor)
Timepoint [5] 365845 0
Prior to the start of the 12-week training intervention during baseline assessment (pre-intervention) and at least 24 hours after the last training session in week 12, but no more than 96 hours after the last training session (post-intervention). For both pre-intervention and post-intervention, individuals will have the Actigraph monitors on for a duration of 2 weeks.
Secondary outcome [6] 365846 0
Changes in physical activity will be analysed using composite measures of activity monitoring (Actigraph monitor) and a 14-day physical activity diary (which will be used to sync with the raw data extracted from the Actigraph monitor)
Timepoint [6] 365846 0
Prior to the start of the 12-week training intervention during baseline assessment (pre-intervention) and at least 24 hours after the last training session in week 12, but no more than 96 hours after the last training session (post-intervention). For both pre-intervention and post-intervention, individuals will have the Actigraph monitors on for a duration of 2 weeks.
Secondary outcome [7] 365847 0
24h skin temperature will be measured using a temperature logger (Thermochron iButton)
Timepoint [7] 365847 0
Prior to the start of the 12-week training intervention during baseline assessment (pre-intervention) and at least 24 hours after the last training session in week 12, but no more than 96 hours after the last training session (post-intervention). For both pre-intervention and post-intervention, individuals will have the temperature loggers on for a duration of 2 weeks.
Secondary outcome [8] 365848 0
Changes in appetite will be analysed using a Three Factor Eating Questionnaire (TFEQ)
Timepoint [8] 365848 0
Prior to the start of the 12-week training intervention during baseline assessment (pre-intervention) and at least 24 hours after the last training session in week 12, but no more than 96 hours after the last training session (post-intervention)

Eligibility
Key inclusion criteria
Non-smoking, sedentary (defined as the accrual of less than 150 min of exercise per week) individuals who are overweight (body mass index more than or equal to 27 kg/m2) and have an existing diagnosis of Type 2 diabetes mellitus
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will not be eligible if: (i) they are unable to complete exercise or have a condition which is known to be aggravated by exercise (assessed using the Exercise and Sports Science Australia pre-exercise screening tool); (ii) they are on insulin; (iii) have had surgery for weight loss; (iv) they had prior history of heart, lung, kidney, endocrine or liver disease; (v) experienced recent weight loss (4 kg or more) in previous month.

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)
Following baseline assessments, participants will be randomly assigned into their intervention groups (POSTam and POSTpm). Randomisation and allocation will be performed on unique study I.D.’s by an independent investigator (A/Prof Kym Guelfi) using randomly permutated blocks (each block n = 4-6; http://www.randomisation.com) with males and females counterbalanced (separate allocation sequences generated) across groups. The allocation of participants to their respective groups are sealed in opaque envelopes and will be open prior to the participant's first training session by the study researcher.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permutated block randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
NA
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Given the expected drop-out and non-compliance rate to be approximately 10-15%, data analysis will include both intent-to-treat analysis of randomized participants at last observation, and efficacy analysis of treated-only participants over the study intervention.

Treatment effects will be estimated using linear mixed models (LMM) to assess for any changes over time (pre- and post-exercise intervention). The hypothesis of interest is the group by time interaction (modelled as fixed effects), using a random intercept which accounts for baseline differences. These will be examined with pairwise comparisons of the estimated marginal means. Main effects of time (but not group) will be assessed using the pairwise comparisons. Secondary analysis will be compared using group-based comparisons on change-scores (e.g. independent t-test). All data will be analysed using SPSS statistical software (V.18, Chicago, IL, USA) with a priori statistical significance set at p < 0.05. All results/data will be presented as means ± standard deviation (SD).

Using the effect size from the primary outcome of interest (glycosylated haemoglobin; HbA1c) (r-squared = 0.11) in a previous study (ACTRN12616001172493) of 10 participants per group (using the T2DM individuals only), will provide 80% power to detect a significant (a-error probability set at 0.05) interaction effect (2 observations). To account for the attrition rate during the course of the project, we have added an additional 20% to the calculated sample size, bringing the total sample size to 24 (12 per group) participants.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/02/2019
Actual
Date of last participant enrolment
Anticipated
15/09/2019
Actual
Date of last data collection
Anticipated
15/12/2019
Actual
Sample size
Target
24
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 301629 0
Charities/Societies/Foundations
Name [1] 301629 0
Diabetes Australia
Country [1] 301629 0
Australia
Primary sponsor type
University
Name
Murdoch University
Address
90 South Street, Murdoch, Perth Western Australia 6150
Country
Australia
Secondary sponsor category [1] 301338 0
None
Name [1] 301338 0
Address [1] 301338 0
Country [1] 301338 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302353 0
Murdoch University Human Research Ethics Committee
Ethics committee address [1] 302353 0
Ethics committee country [1] 302353 0
Australia
Date submitted for ethics approval [1] 302353 0
22/11/2018
Approval date [1] 302353 0
20/02/2019
Ethics approval number [1] 302353 0

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

Contacts
Principal investigator
Name 89930 0
A/Prof Timothy Fairchild
Address 89930 0
School of Psychology and Exercise Science
Murdoch University
90 South Street, Murdoch WA 6150
Country 89930 0
Australia
Phone 89930 0
+61 8 9360 2959
Fax 89930 0
Email 89930 0
[email protected]
Contact person for public queries
Name 89931 0
Shaun Teo
Address 89931 0
School of Psychology and Exercise Science
Murdoch University
90 South Street, Murdoch WA 6150
Country 89931 0
Australia
Phone 89931 0
+61 423 716 780
Fax 89931 0
Email 89931 0
[email protected]
Contact person for scientific queries
Name 89932 0
Shaun Teo
Address 89932 0
School of Psychology and Exercise Science
Murdoch University
90 South Street, Murdoch WA 6150
Country 89932 0
Australia
Phone 89932 0
+61 423 716 780
Fax 89932 0
Email 89932 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.