Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000179437
Ethics application status
Approved
Date submitted
1/02/2016
Date registered
11/02/2016
Date last updated
3/03/2020
Date data sharing statement initially provided
25/02/2019
Date results information initially provided
25/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Can exercise mechanically suppress tumour formation and growth in advanced prostate cancer patients with sclerotic bone metastases? Safety, feasibility and efficacy of a modular, multi-modal exercise program with spinal isometric training (M3EP-SIT).
Scientific title
Can exercise mechanically suppress tumour formation and growth in advanced prostate cancer patients with sclerotic bone metastases? Safety, feasibility and efficacy of the M3EP-SIT program.
Secondary ID [1] 288325 0
None
Universal Trial Number (UTN)
U1111-1178-4487
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prostate Cancer 297291 0
Bone Metastases 297292 0
Condition category
Condition code
Cancer 297489 297489 0 0
Prostate
Physical Medicine / Rehabilitation 297685 297685 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single-blinded (investigators blinded to group allocation), two-armed, randomised and controlled (exercise versus usual care) explorative phase 1 clinical trial which will examine the safety, feasibility and efficacy of combining spinal isometric training with a modulatory, multi-modal exercise program (M3EP-SIT) in men with advanced prostate cancer and sclerotic spinal bone metastases. The exercise group (intervention arm) will receive an individually tailored and supervised three month (12 weeks) exercise program involving resistance, aerobic and flexibility exercises in addition to usual medical care.

Participants assigned to the exercise arm will be required to participate in a modular, multi-modal exercise intervention with spinal isometric training (M3EP-SIT) for 12 weeks (3 months). The combined M3EP-SIT program requires participants to attend three supervised exercise sessions each week spanning 60 minutes in duration (including warm-up and cool-down). Participants will also be asked to perform the SIT program during two additional home-based exercise sessions spanning 15 minutes in duration.

The modular, multi-modal exercise (M3EP) component of the program will be comprised of resistance, aerobic and flexibility exercises undertaken 3 times per week in an exercise clinic setting, supervised by an accredited exercise physiologist (AEP, Exercise & Sport Science Australia). This M3EP component is designed to minimise loads on affected skeletal sites through-out the body. Exercise prescription will be modified based on the location and extent of bone metastases for all activities. Resistance exercise will be set using repetition maximums (RM). Participants will be asked to perform 10-12 RM for 3 sets per exercise to achieve moderate intensity and volume. Aerobic exercise will be set using age-predicted heart rate maximum (HRmax). Participants will engage in cardiovascular exercise using various modes including treadmill, cycling and rowing ergometers, performed at 60-85% HRmax for 20-30 minutes using heart rate monitors (Polar Electro Oy, Finland). Flexibility exercise will involve static stretching of all joints considered important for function, and for all muscles engaged during the session. All stretches will involve 2-4 sets per muscle group with a 30-60 second hold per set.

The spinal isometric training (SIT) component of the program will comprise of exercises that isometrically load deep spinal muscles. These will be performed 5 times per week. Three sessions will be supervised by an accredited exercise physiologist synonymous with the M3EP component at an exercise clinic; with additional two sessions self-managed by the participant. This SIT component is designed to directly target and stimulate spinal lesion site(s) through muscular contraction, thus isometric exercises have been designed to activate the full spinal column due to the commonality of lesions in thoracic and lumbar regions; the feasibility of which has been demonstrated. The SIT program will require the participants to perform five exercises in whole and partial weight-supported prone and supine positions on the floor, whilst maintaining a neutral spine (isometrically) during gentle and dynamic accessory movements. Hip control and stationary spinal isometric exercises will first be used to ensure safe and correct technique during Week 1, prior to progressing to more challenging exercises which include less stability or dynamic accessory movements for Weeks 2 to 12.

Adherence to supervised exercise sessions will be monitored and recorded by the exercise physiologists delivering the intervention. Patients will be provided with an exercise sheet for use during their twice weekly self-managed spinal isometric training sessions. Exercise sheets will be handed to the exercise physiologists at the patients next supervised session. Adherence to self-managed spinal isometric training will be subsequently be monitored and recorded by the exercise physiologist in consultation with the patient. This will be reported as a percentage of actual exercise completed versus prescribed exercise completed; as well as sessions missed as a ratio of sessions prescribed.
Intervention code [1] 293791 0
Treatment: Other
Intervention code [2] 293845 0
Lifestyle
Comparator / control treatment
The control group will receive usual medical care during this time and will be asked not to change their baseline levels of physical activity. Following the trial, the control group will be offered the same exercise program if the intervention is deemed to be feasible and efficacious.
Control group
Active

Outcomes
Primary outcome [1] 297212 0
Tumour Morphology

Tumour morphology will be measured using axial T1-weighted magnetic resonance imaging (MRI) scans (1.5T, Magnetom Essenza, Siemens, Victoria, Australia) in locations where sclerotic lesions have been identified in patients with bone metastases at either thoracic or lumbar spinal regions. Location of metastatic lesions will be previously identified through bone scans provided by the radiation oncologist prior to referral to this study. All scans will be performed on the same MRI machine by the same radiologist who will also report on all images obtained.
Timepoint [1] 297212 0
Baseline (Week 0) and Post-Intervention (Week 12)
Primary outcome [2] 297223 0
Tumour Activity

Metastatic tumour biomarkers, HIF-1.alpha and TGF-beta will be serologically examined to measure hypoxic activity and transformation-growth activity respectively; identified as synergistic drivers of metastatic tumour progression.
Timepoint [2] 297223 0
Baseline (Week 0) and Post-Intervention (Week 12)
Secondary outcome [1] 320366 0
Bone Metabolic Biomarkers

Serological and urianalytical samples will be collected to measure bone metabolic activity. Specifically, bone formation marker, amino-terminal propeptide of type 1 procollagen (P1NP); bone resorption marker, amino-terminal collagen type-I telopeptide (NTx); All biomarkers will be collected and assessed by the same accredited laboratory (PathWest Diagnostics, Perth, Western Australia).
Timepoint [1] 320366 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [2] 320367 0
Inflammation Biomarkers

Serological samples will be collected to measure systemic inflammation, thus C-Reactive Protein (CRP) will be examined. This will be collected and assessed by the same accredited laboratory (PathWest Diagnostics, Perth, Western Australia).
Timepoint [2] 320367 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [3] 320369 0
Prostate-Specific Antigen

Serological samples will be collected to measure prostate specific antigen (PSA) will also be assessed. This will be collected and assessed by the same accredited laboratory (PathWest Diagnostics, Perth, Western Australia).
Timepoint [3] 320369 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [4] 320370 0
Weight

Body mass recorded to the nearest 0.1 kg using an electronic scale (AE Adams CPW Plus-200, Adam Equipment Inc., CT, USA).
Timepoint [4] 320370 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [5] 320371 0
Waist Circumference

Waist circumferences are defined as the mid-point between the 10th rib and iliac crest. Waist circumference will be performed three times for each participant, with the average of each variable retained for analysis.
Timepoint [5] 320371 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [6] 320386 0
Hip Circumference

Hip circumferences are defined as the level of the greater trochanter for both limbs. Hip circumference will be performed three times for each participant, with the average of each variable retained for analysis.
Timepoint [6] 320386 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [7] 320387 0
Muscle Health

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

Appendicular, non-lesion control sites will be scanned to quantify muscle cross-sectional area (Mu.Ar) will also be quantified using peripheral Quantitative Computed Tomography (pQCT; XCT-3000, Stratec, Pzochienheim, Germany).
Timepoint [7] 320387 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [8] 320388 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.

Appendicular, non-lesion control sites 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 [8] 320388 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [9] 320389 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 thigh and shank segments will be measured using pQCT as an indication subcutaneous and intramuscular fat infiltration respectively.
Timepoint [9] 320389 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [10] 320390 0
Bone Pain

The nature, severity and impact of bone pain will be examined using the FACIT Bone Pain questionnaire at baseline and post-intervention.
Timepoint [10] 320390 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [11] 320391 0
Program Safety

Program safety will be assessed by recording the incidence and severity of any adverse events and/or skeletal complications through-out the exercise intervention. Adverse events and skeletal complications will also be recorded for the usual care group. Skeletal complications include heightened pain at bone metastatic sites and/or pathological skeletal fractures.
Timepoint [11] 320391 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [12] 320392 0
Exercise Tolerance

Program tolerance will be quantified by measuring bone pain and fatigue at each exercise session through visual analog scales (VAS, 0-10); and by recording the rating of perceived exertion (RPE; Borg Scale, 0-10) after each exercise session.
Timepoint [12] 320392 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [13] 320393 0
Muscle Strength

Muscle strength will be measured using a one repetition maximum (1RM) test using the leg extension exercise. This exercise was chosen as it can be safely performed by all patients included in this study.
Timepoint [13] 320393 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [14] 320394 0
Aerobic Fitness

The 400m walk test will be used as measures for aerobic fitness.
Timepoint [14] 320394 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [15] 320395 0
Physical Function

Sit-To-Stand test will be used as a measure of physical function.
Timepoint [15] 320395 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [16] 320404 0
Quality of Life

Health-related quality of life outcomes for general health, pain, vitality, social functioning, emotional role and mental health will be measured by the Short Form 36 (SF-36, IQOLA) survey. In addition, EORTC-QLQ-30 (cancer) and EORTC-PR-25 (prostate cancer) survey will also be provided to measure cancer specific indices of quality of life.
Timepoint [16] 320404 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [17] 320405 0
Distress

The Brief Symptom Inventory (BSI-18) will be used to assess psychological distress.
Timepoint [17] 320405 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [18] 320406 0
Sleep Disturbance

Insomnia Severity Index (ISI) will be used to measure sleep quality disturbance,
Timepoint [18] 320406 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [19] 320407 0
Physical Activity Levels

Godin Leisure-Time Exercise questionnaire will examine self-reported physical activity levels.
Timepoint [19] 320407 0
Baseline (Week 0), Post-Intervention (Week 12)
Secondary outcome [20] 320544 0
Functional Balance
Timepoint [20] 320544 0
Patients will complete a comprehensive balance test (NeuroCom Smart Balance Master, Natus Medical Inc., USA), testing balance capability under six different conditions to determine contributions to balance (i.e. somatosensory, vestibular and kinesthetic)

Eligibility
Key inclusion criteria
* Male, aged greater than or equal to 18 years.
* Histologically documented adenocarcinoma of the prostate.
* Stable solitary or multiple metastatic sclerotic lesions in the thoracic or lumbar spine.
* Greater than or equal to 3 months since last change of current primary therapies.
* Greater than or equal to 3 months since commencement of new primary therapies.
* Greater than or equal to 4 weeks since last major surgery and fully recovered
* Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 1
* Medical clearance by treating physician to participate in exercise
Minimum age
18 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
* Brain metastases or small cell neuroendocrine tumours’
* Currently receiving radiotherapy for thoracic or lumbar spinal metastases. Patients are permitted to receive radiotherapy for non-spinal bone metastases only during this intervention.
* Currently receiving any other experimental treatments or non-approved therapies.
* Regular participation in structured aerobic exercise greater than or equal to 2 days per week.
* Regular participation in structured resistance exercise greater than or equal to 2 days per week.
* Cardiovascular or neurological disorders that could inhibit exercise participation.
* Diminished legal or perceived psychological capacity to given informed consent.

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 by computer. Written informed consent will be required prior to any testing or randomisation. Participants who dropout prior to completing baseline testing will not be randomised.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be randomly allocated in a ratio of 1:1 to the two study arms: exercise (M3EP-SIT) or usual care. Stratification between groups will be counterbalanced to approximately match for current treatments (hormone therapy and/or radiotherapy and/or chemotherapy and/or bisphosphonates; yes/no), as well as location and size of sclerotic lesions.

Due to the approximate requirement to match for current treatments, as well as for location and size of sclerotic lesions; a dynamic (adaptive) random allocation method will be used: i.e. randomisation by minimisation.
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
Safety/efficacy
Statistical methods / analysis
Data will be analysed using SPSS (IBM Corporation; Chicago, IL, USA). An intention-to-treat analysis approach will be applied. Analyses will include descriptive characteristics, t-tests, and two-way (group x time) repeated measures ANOVA to examine differences between groups over time. An alpha level of less than or equal to 0.05 will be applied to establish statistical significance. Effect sizes will also calculated.

Due to the novelty of this trial, the sample size was chosen based on: 1) previous animal studies, 2) consideration of recruitment ability for advanced prostate cancer patients with bone metastases during the trial, and 3) our team's experience in previous bone metastases trials.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/03/2016
Actual
24/03/2016
Date of last participant enrolment
Anticipated
1/06/2018
Actual
22/02/2019
Date of last data collection
Anticipated
31/05/2019
Actual
31/05/2019
Sample size
Target
40
Accrual to date
Final
42
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 292802 0
Charities/Societies/Foundations
Name [1] 292802 0
Cancer Council of Western Australia
Country [1] 292802 0
Australia
Funding source category [2] 292803 0
Other
Name [2] 292803 0
Exercise and Sport Science Australia
Country [2] 292803 0
Australia
Primary sponsor type
University
Name
Edith Cowan University
Address
Exercise Medicine Research Institute
Edith Cowan University
270 Joondalup Drive
Joondalup, WA 6027
Country
Australia
Secondary sponsor category [1] 291540 0
Individual
Name [1] 291540 0
Dr Nicolas Hart
Address [1] 291540 0
Exercise Medicine Research Institute, Edith Cowan University, 270 Joondalup Drive - Joondalup, WA, 6027
Country [1] 291540 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294302 0
Edith Cowan University Human Research Ethics Committee
Ethics committee address [1] 294302 0
Edith Cowan University
270 Joondalup Drive
Joondalup, WA 6027
Ethics committee country [1] 294302 0
Australia
Date submitted for ethics approval [1] 294302 0
14/10/2015
Approval date [1] 294302 0
20/01/2016
Ethics approval number [1] 294302 0
13399 HART

Summary
Brief summary
Aim?
To examine whether a targeted and supervised exercise program can suppress tumour formation, growth and activity in advanced prostate cancer patients with bone metastases in Humans and examine the feasibility, safety and efficacy of combining spinal isometric training with a modular multi-modal program M3EP program.

Who is it for?
You may be eligible to join this study if you are a male aged 18 years or more and have histologically confirmed adenocarcinoma of the prostate with one or more metastatic lesions in the thoracic or lumbar spine.

Study details:
Participants in this study will be randomly allocated (by chance) to one of two groups. Participants in one group receive a 12 week exercise intervention. The exercise intervention group will receive a 3-month, supervised and individually tailored modular multi-modal exercise program (M3EP) with spinal isometric training (SIT). M3EP component of the program will be comprised of resistance, aerobic and flexibility exercises undertaken 3 times per week in an exercise clinic setting, supervised by an accredited exercise physiologist. The SIT component of the program will comprise of exercises that isometrically load deep spinal muscles. These will be performed 5 times per week (3 in clinic and 2 at home). Participants in the other group will receive usual care for the duration of the trial. Following the trial, the control group will be offered the same exercise program if the intervention is deemed to be feasible and efficacious. All participants will complete assessments at baseline and after 12 weeks in order to evaluate tumour formation and growth, muscle-bone health, adiposity, physical fitness, functional capacity, and psychosocial health.
Trial website
https://www.exercisemedicine.org.au/research-activity/projects-open-for-enrolment/mechanical-modulation-of-bone-metastases-in-advanced-prostate-cancer-patients-can-targeted-exercise-suppress-sclerotic-tumour-progression-a-pilot-study.
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 62094 0
Dr Nicolas Hart
Address 62094 0
Exercise Medicine Research Institute
Edith Cowan University
Building 21, Room 222
270 Joondalup Drive, JOONDALUP
Perth, Western Australia, 6027
Country 62094 0
Australia
Phone 62094 0
+61 08 6304 3436
Fax 62094 0
+61 08 6304 2499
Email 62094 0
[email protected]
Contact person for public queries
Name 62095 0
Dr Nicolas Hart
Address 62095 0
Exercise Medicine Research Institute
Edith Cowan University
Building 21, Room 222
270 Joondalup Drive, JOONDALUP
Perth, Western Australia, 6027
Country 62095 0
Australia
Phone 62095 0
+61 08 6304 3436
Fax 62095 0
+61 08 6304 2499
Email 62095 0
[email protected]
Contact person for scientific queries
Name 62096 0
Dr Nicolas Hart
Address 62096 0
Exercise Medicine Research Institute
Edith Cowan University
Building 21, Room 222
270 Joondalup Drive, JOONDALUP
Perth, Western Australia, 6027
Country 62096 0
Australia
Phone 62096 0
+61 08 6304 3436
Fax 62096 0
+61 08 6304 2499
Email 62096 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
In accordance with the National Statement, and prior HREC approvals for this project within the Edith Cowan University Human Research Ethics Committee, St John of God Ethics Committee, and Sir Charles Gairdner Hospital Ethics Committee - all individual de-identified data will be stored securely within the Exercise Medicine Research Institute only.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
1443Study protocol    https://bmjopen.bmj.com/content/7/5/e014458 https... [More Details]



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Plain language summaryNo Results are currently awaiting the final few patie... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseCan exercise suppress tumour growth in advanced prostate cancer patients with sclerotic bone metastases? A randomised, controlled study protocol examining feasibility, safety and efficacy.2017https://dx.doi.org/10.1136/bmjopen-2016-014458
N.B. These documents automatically identified may not have been verified by the study sponsor.