Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000280202
Ethics application status
Approved
Date submitted
17/02/2018
Date registered
22/02/2018
Date last updated
27/02/2020
Date data sharing statement initially provided
25/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
An exploratory study to determine if exercise can impact the gut microbiota composition of men receiving androgen deprivation therapy for prostate cancer.
Scientific title
An exploratory study to determine if exercise can impact the gut microbiota composition of men receiving androgen deprivation therapy for prostate cancer.
Secondary ID [1] 293938 0
None
Universal Trial Number (UTN)
U1111-1208-8095
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prostate Cancer 306425 0
Bowel Function 306426 0
Condition category
Condition code
Cancer 305513 305513 0 0
Prostate
Physical Medicine / Rehabilitation 305514 305514 0 0
Other physical medicine / rehabilitation
Oral and Gastrointestinal 305799 305799 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Men with prostate cancer receiving androgen deprivation therapy will attend three clinic-based supervised exercise sessions each week, for 12 weeks (3 months), consisting of moderate-to-high intensity resistance and aerobic exercise (interval and continuous). Each session will take approximately 60 minutes, including warm-up and cool-down, and will be supervised by accredited exercise physiologists (AEP; Exercise and Sport Science Australia, Brisbane, Australia), face-to-face (in groups of up to 8 people per session). The exercise program is designed to provide optimal stimulus to the cardiorespiratory and neuromuscular systems while maximising safety, compliance and retention, thus will be tailored, progressive, periodised and autoregulated in collaboration with the patient (i.e. adjusted based on the patient’s presentation at each session).

Resistance exercise will be prescribed using repetition maximums (RM), where patients will be required to perform 6-8 different resistance exercises using major muscle groups, at 6-12 RM (the maximal weight that can be lifted 6 to 12 times each set, equivalent to ~60-85% of 1RM) for 3-4 sets per exercise to achieve moderate-to-high intensity and volume. Aerobic exercise will include 20 to 30 minutes of moderate-to-vigorous intensity activity (equating to ~60-85% of estimated maximum heart rate; or a rating of perceived exertion (RPE) between 6-9 using the BORG-10 scale) involving a variety of modes including walking, jogging, cycling or rowing, using treadmills and/or stationary ergometers respectively. Aerobic intensity will be monitored using heart rate monitors (Polar M400, H10 Sensor, Polar Electro, NSW, Australia) and an RPE chart for assessment. Patients will also be encouraged to perform additional aerobic exercise outside of their supervised exercise clinic visits, such as brisk walking, with the goal of achieving at least 150 minutes of moderate-to-vigorous intensity aerobic exercise each week (i.e. a further ~60-90 minutes self-managed). Flexibility exercises for all joints considered important for function and for all muscles engaged during the session will be provided during the cool-down phase of each exercise session.

The exercise program will be periodised, progressive and autoregulated, to allow for transient changes in patient presentation to exercise sessions in accordance with their cancer therapy or treatment cycles. All exercise sessions will be fully supervised by an accredited exercise physiologist (AEP; Exercise and Sport Science Australia). All exercise sessions will take place at one of four exercise clinic locations: 1) Edith Cowan University (Joondalup), Vario Health Clinic; 2) Edith Cowan University (Mt Lawley), Gymnasium; 3) University of Western Australia; or 4) Fiona Stanley Hospital (Murdoch).

Exercise program adherence and compliance will be assessed through the use of attendance rates to supervised clinic sessions; and percent of exercise session completed; specifically using exercise record sheets with prescribed programming variables; with actual versus completed components recorded.
Intervention code [1] 300202 0
Lifestyle
Intervention code [2] 300203 0
Rehabilitation
Intervention code [3] 300384 0
Treatment: Other
Comparator / control treatment
This study uses two control/comparison groups; 1) prostate cancer patients randomised to Usual Care, and 2) Age-matched men with no cancer diagnosis.

Men with prostate cancer in the Usual Care group will continue to receive usual medical care while on-trial; (that is, continue to receive androgen deprivation therapy or combination therapy for their prostate cancer while enrolled); and will be offered the exercise program after their control period/completion of involvement in the study to thank them for their participation, and as an effective tool to minimise control arm contamination, and minimise patient withdrawal or loss to follow-up.

Age-matched male volunteers (with no cancer diagnosis) will be recruited to form a healthy age-matched comparison to complete all assessments, and will be asked to continue their usual lifestyle habits (i.e. not to change their current behaviour) for their time on-trial (3 months / 12 weeks). All participants (including control patients) will complete a modified Godin leisure-time activity questionnaire, which will be used to assess contamination (if any) of the control group (i.e. if they increase their physical activity or exercise levels during the control period, unsupervised).
Control group
Active

Outcomes
Primary outcome [1] 304653 0
Microbiome Behaviour/DNA/Composition

Gut Health and Function will be assessed through the provision of a 24-hour collection of stool sample(s); subsequently examined/analysed for microbiome behaviour/DNA/composition. The 24-hour collection of fecal samples will also be collected for comprehensive metabolomics analysis.
Timepoint [1] 304653 0
Week 0 (baseline) and Week 13 (post-intervention).
Primary outcome [2] 304865 0
Fecal Calprotectin

An analysis of fecal calprotectin analysis will be provided analysis also provided as an indicator of Gut Health and Function.
Timepoint [2] 304865 0
Week 0 (baseline) and Week 13 (post-intervention)
Secondary outcome [1] 342677 0
Dietary Assessment

Habitual dietary intake will be assessed using the Dietary Questionnaire for Epidemiological Studies (DQES, Version 2.0; Cancer Council of Victoria, Melbourne, Australia); a modified food frequency questionnaire (FFQ) relevant to cancer populations. DQES data will be collated and batch analysed at the conclusion of the study by the Nutritional Assessment Office (Cancer Council of Victoria, Melbourne, Australia).
Timepoint [1] 342677 0
Week 0 (baseline) and Week 13 (post-intervention)
Secondary outcome [2] 342683 0
Blood Biomarkers

Fasting blood samples will be collected and analysed commercially by accredited Australian National Association of Testing Authorities laboratories (Australian Clinical Laboratories, Perth, Western Australia) for glucose, high sensitivity C-reactive protein, triglycerides, total cholesterol, high density lipoprotein and low density lipoprotein cholesterol. Fasting blood samples will also be collected for comprehensive metabolomics analysis using standardised protocols at Edith Cowan Univerity's Centre for Integrative Metabolomics and Computational Biology.
Timepoint [2] 342683 0
Week 0 (baseline) and Week 13 (post-intervention)
Secondary outcome [3] 342684 0
Adiposity

Whole-body, segmental and central subcutaneous adipose tissue (fat mass); central visceral adipose tissue (VAT; area, mass and volume); and android to gynoid ratio will be measured using DXA. Fat area (Fa.Ar) and muscle density (Mu.Den) of the shank segment will be measured using pQCT as an indication subcutaneous and intramuscular fat infiltration respectively.
Timepoint [3] 342684 0
Week 0 (baseline) and Week 13 (post-intervention)
Secondary outcome [4] 342685 0
Muscle Health

Whole-body (axial and appendicular) scans will be performed to examine lean mass using Dual-energy X-ray Absorptiometry (DXA; Discovery A, 1500 Hologic, Waltham, MA).

The lower-leg will be scanned to quantify muscle cross-sectional area (Mu.Ar) and muscle density (Mu.Den) as an indicator of muscle size and muscle quality, which will also be quantified using peripheral Quantitative Computed Tomography (pQCT; XCT-3000, Stratec, Pzochienheim, Germany).
Timepoint [4] 342685 0
Week 0 (baseline) and Week 13 (post-intervention).
Secondary outcome [5] 342686 0
Bone Health

Whole-body, segmental (axial, appendicular) and regional (spinal, hip, femoral) scans will be performed to examine bone area (BA), bone mineral content (aBMC), bone mineral density (aBMD) using Dual-energy X-ray Absorptiometry (DXA; Discovery A, 1500 Hologic, Waltham, MA). Regional analyses (lumbar spine, total hip, femoral neck, femoral trochanter, Wards triangle) will be performed in accordance with Hologic’s manufacturer specifications.

The lower-leg will be scanned to quantify bone material, structure and strength using peripheral Quantitative Computed Tomography (pQCT; XCT-3000, Stratec, Pzochienheim, Germany). Specifically trabecular, cortical, marrow and total volumetric density (Tb.vBMD, Ct.vBMD, Ma.vBMD, Tt.vBMD); trabecular, cortical, marrow and total cross-sectional area (Tb.Ar, Ct.Ar, Ma.Ar, Tt.Ar); cortical thickness (Ct.Th); stress-strain index (SSIPOL); absolute fracture load (FL.Ab) and relative fracture load (FL.Rel) of the left Femur (4% and 38% slices) and left Tibia (4%, 14%, 38% and 66% slices) will be measured.
Timepoint [5] 342686 0
Week 0 (baseline) and Week 13 (post-intervention)
Secondary outcome [6] 342687 0
Program Safety

Program safety will be assessed by recording the incidence and severity of any adverse events through-out the exercise intervention. Adverse events will also be recorded for the usual care group.
Timepoint [6] 342687 0
Week 0 (baseline) and Week 13 (post-intervention).
Secondary outcome [7] 342689 0
Muscle Strength

Muscle strength will be measured using a one repetition maximum (1RM) test using the chest press, seated row and leg press exercises.
Timepoint [7] 342689 0
Week 0 (baseline) and Week 13 (post-intervention)
Secondary outcome [8] 342690 0
Aerobic Fitness

The 400m walk test will be used as a measure of aerobic fitness.
Timepoint [8] 342690 0
Week 0 (baseline) and Week 13 (post-intervention)
Secondary outcome [9] 342692 0
Physical Activity

Godin Leisure-Time Exercise questionnaire will examine self-reported physical activity levels.
Timepoint [9] 342692 0
Week 0 (baseline) and Week 13 (post-intervention)
Secondary outcome [10] 342693 0
Anthropometry

Hip circumference, waist circumference, height and weight will be measured in triplicate.
Timepoint [10] 342693 0
Week 0 (baseline) and Week 13 (post-intervention).
Secondary outcome [11] 343308 0
Physical Function

The "Timed Up and Go" test, seated chair rise test, and 6 metre walk (normal pace, fast pace, and backwards) will all be used as a measure of physical function. The activities balance confidence (ABC) questionnaire will also be used to measure perceived physical function and falls self-efficacy.
Timepoint [11] 343308 0
Week 0 (baseline) and Week 13 (post-intervention)
Secondary outcome [12] 343402 0
Muscle soreness

Muscle soreness at each exercise session will be assessed through a visual analog scales (VAS, 0-10).
Timepoint [12] 343402 0
Each exercise session (3 days per week); intervention arm only.
Secondary outcome [13] 343403 0
Fatigue

Fatigue at each exercise session will be assessed through a visual analog scale (VAS, 0-10).
Timepoint [13] 343403 0
Each exercise session (3 days per week); intervention arm only.
Secondary outcome [14] 343404 0
Exercise Tolerance

Rating of perceived exertion (RPE; Borg Scale, 0-10) after each exercise session will be recorded.
Timepoint [14] 343404 0
Each exercise session (3 days per week); intervention arm only.
Secondary outcome [15] 343405 0
Bone Pain

Program tolerance will be quantified by measuring bone pain through a visual analog scale (VAS, 0-10).
Timepoint [15] 343405 0
Each exercise session (3 days per week); intervention arm only.
Secondary outcome [16] 343406 0
Health-related Quality of Life

Health-related quality of life outcomes will be measured by the Short Form 36 (SF-36, IQOLA) survey.
Timepoint [16] 343406 0
Week 0 (baseline) and Week 13 (post-intervention)
Secondary outcome [17] 343408 0
Cancer-Specific Quality of Life

Cancer-specific indices for quality of life will be assessed using the EORTC-QLQ-30 (cancer) and EORTC-PR-25 (prostate cancer) survey.
Timepoint [17] 343408 0
Week 0 (baseline) and Week 13 (post-intervention).
Secondary outcome [18] 343410 0
Cancer-related Fatigue

The FACIT-Fatigue scale will be used to measure the impact of fatigue.
Timepoint [18] 343410 0
Week 0 (baseline) and Week 13 (post-intervention)
Secondary outcome [19] 343411 0
Psychological Distress

Psychological distress will be assessed using the Brief Symptom Inventory (BSI-18).
Timepoint [19] 343411 0
Week 0 (baseline) and Week 13 (post-intervention)
Secondary outcome [20] 343413 0
Sleep Quality

Sleep quality and disturbance will be assessed using the Insomnia Severity Index.
Timepoint [20] 343413 0
Week 0 (baseline) and Week 13 (post-intervention)

Eligibility
Key inclusion criteria
Men with localised or locally advanced prostate cancer, currently receiving androgen deprivation therapy (ADT) will be eligible to enrol into this study. Men must remain on ADT for the duration of their involvement in the study, and receive medical clearance to participate prior to enrolment.

Age-matched, healthy male volunteers, with no previous or current cancer diagnosis, will be eligible to participate in this study, and will be recruited following the attainment of the two prostate cancer cohorts to ensure approximate balance for age. For inclusion, age-matched, healthy male volunteers will need to receive medical confirmation of their previous and current health status, with no evidence of current major musculoskeletal, cardiometabolic or neurological chronic disease or complications.
Minimum age
18 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
Patients with visceral or bone metastases (i.e. advanced, or castrate-resistant prostate cancer); who have previously received chemotherapy; currently receiving radiation therapy; or who are currently on any experimental therapies will be excluded from this study. Further, men with any physical, mental or other contraindications that could interfere with exercise participation will be excluded. Lastly, men who cannot (or have difficulty) understanding English will also be excluded.

Patients will also be excluded if: their treatment is for secondary cancer; medical records mention cognitive or learning problems; they have had any previous gastrointestinal surgery; and/or if they have taken antibiotics, prebiotics, probiotics, nutritional or ergogenic compliments during the 3 months prior to the study.

Age-matched, healthy male volunteers will be excluded if they cannot provide medical confirmation of their previous / current health status; if they have any current major musculoskeletal, cardiometabolic or neurological chronic disease or complications; medical records mention cognitive or learning problems; they have had any previous gastrointestinal surgery; and/or if they have taken antibiotics, prebiotics, probiotics, nutritional or ergogenic compliments during the 3 months prior to the study.

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)
A research officer with no patient contact will be responsible for randomisation of patient’s into either group. Study investigators and exercise physiologists conducting testing procedures will be blinded to group allocation. Only exercise physiologists who are not in the research team will be permitted to deliver the exercise intervention to participants in order to maintain integrity of the blinding process.

Central randomisation is completed by a computer-generated software program. Written informed consent will be required prior to any testing or randomisation. Participants who drop-out prior to completing baseline testing will not be randomised.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Prostate cancer patients will be randomly allocated in a ratio of 1:1 to the two study arms: exercise or usual care, stratified by age (=<60 years, >60 years), time on ADT (=<6 months, >6 months), and recent surgery or radiation therapy, within 6-months of enrolment (Yes/No) for approximate balance between groups in order to mitigate confounding factors pertaining to variations due to ageing (i.e. differences in physical function, sarcopenia, osteopenia and osteoporosis) and to account for variations in the treatment. This study will thus use a computer-generated system; i.e. simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Primary and secondary end-points will be measured at baseline and following the intervention. Statistical analyses will include descriptive characteristics, t-tests, effect sizes and two-way (group x time) repeated measures ANOVA (or analysis of co-variance). Data will be primarily examined using an intention-to-treat approach with multiple imputations followed by a secondary sensitivity analysis to ensure data robustness using a complete cases approach. Multivariate statistical methods (including Principal Components Analysis, Canonical Correlations Analysis, and Projection to Latent Structures) will be used to understand the covariance between microbial diversity and the gut/host metabolome before and after the intervention. All analysis will be performed using standard cross-validation optimisation, and be assessed for robustness using standard post-hoc testing.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
2/04/2018
Actual
6/02/2019
Date of last participant enrolment
Anticipated
30/06/2021
Actual
Date of last data collection
Anticipated
1/11/2021
Actual
Sample size
Target
60
Accrual to date
8
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 9932 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 9933 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [3] 9934 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [4] 9935 0
St John of God Hospital, Murdoch - Murdoch
Recruitment postcode(s) [1] 18743 0
6009 - Nedlands
Recruitment postcode(s) [2] 18744 0
6150 - Murdoch
Recruitment postcode(s) [3] 18745 0
6008 - Subiaco
Recruitment postcode(s) [4] 18746 0
6000 - Perth
Recruitment postcode(s) [5] 18747 0
6027 - Joondalup

Funding & Sponsors
Funding source category [1] 298565 0
Charities/Societies/Foundations
Name [1] 298565 0
Prostate Cancer Foundation Australia
Country [1] 298565 0
Australia
Primary sponsor type
University
Name
Edith Cowan University
Address
Building 21, Level 2
270 Joondalup Drive
Joondalup WA 6027
Country
Australia
Secondary sponsor category [1] 297714 0
Charities/Societies/Foundations
Name [1] 297714 0
Prostate Cancer Foundation Australia
Address [1] 297714 0
Level 3
39-41 Chandos St
St Leonards NSW 2065
Country [1] 297714 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299532 0
Edith Cowan University, Human Research Ethics Committee
Ethics committee address [1] 299532 0
Ethics committee country [1] 299532 0
Australia
Date submitted for ethics approval [1] 299532 0
19/02/2018
Approval date [1] 299532 0
21/03/2018
Ethics approval number [1] 299532 0
19827 NEWTON

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

Contacts
Principal investigator
Name 80750 0
Prof Robert Newton
Address 80750 0
Deans' Office
Building 21, Level 5.
School of Medical and Health Sciences
Edith Cowan University
270 Joondalup Drive.
JOONDALUP, Perth, WA 6027.
Country 80750 0
Australia
Phone 80750 0
+61 8 6304 3444
Fax 80750 0
+61 8 6304 2499
Email 80750 0
[email protected]
Contact person for public queries
Name 80751 0
Robert Newton
Address 80751 0
Deans' Office
Building 21, Level 5.
School of Medical and Health Sciences
Edith Cowan University
270 Joondalup Drive.
JOONDALUP, Perth, WA 6027.
Country 80751 0
Australia
Phone 80751 0
+61 8 6304 3444
Fax 80751 0
+61 8 6304 2499
Email 80751 0
[email protected]
Contact person for scientific queries
Name 80752 0
Robert Newton
Address 80752 0
Deans' Office
Building 21, Level 5.
School of Medical and Health Sciences
Edith Cowan University
270 Joondalup Drive.
JOONDALUP, Perth, WA 6027.
Country 80752 0
Australia
Phone 80752 0
+61 8 6304 3444
Fax 80752 0
+61 8 6304 2499
Email 80752 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
Individual participant data will not be available for data dictionaries or other formats. The de-identified data will be stored within the Exercise Medicine Research Institute, in accordance with the National Statement, and earlier approval provided by the Human Research Ethics Committee of Edith Cowan University.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
1441Study protocol    The study protocol paper has been submitted to BMJ... [More Details]



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