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Trial registered on ANZCTR


Registration number
ACTRN12616001368426
Ethics application status
Approved
Date submitted
28/09/2016
Date registered
4/10/2016
Date last updated
23/07/2019
Date data sharing statement initially provided
23/07/2019
Date results information initially provided
23/07/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Evaluating the ability of exercise to suppress tumour growth in advanced breast cancer patients with osteolytic bone metastases.
Scientific title
Mechanical modulation of tumour biology in advanced breast cancer patients with osteolytic bone metastases: a randomised, controlled study protocol evaluating safety, feasibility and efficacy of exercise.
Secondary ID [1] 290228 0
None
Universal Trial Number (UTN)
U1111-1188-0631
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 300414 0
Bone Metastases 300415 0
Condition category
Condition code
Cancer 300273 300273 0 0
Breast
Cancer 300274 300274 0 0
Bone

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 women with advanced breast cancer and osteolytic 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 M3EP component of the program will span 45 minutes, whereas the SIT component of the program will span 15 minutes (to make a 60 minute session during supervised sessions, and a 15 minute session during home-based, self-managed sessions). During the supervised exercise clinic sessions, patients will be provided with one-on-one supervision.

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] 296003 0
Lifestyle
Intervention code [2] 296005 0
Treatment: Other
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. This will occur immediately following the trial, therefore the 'delay' to exercise will be 12 weeks from enrolment (if assigned to control for the 'on trial' period).
Control group
Active

Outcomes
Primary outcome [1] 299751 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 osteolytic 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 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] 299751 0
Week 0 (baseline) to Week 12 (post-intervention)
Primary outcome [2] 299752 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] 299752 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [1] 328007 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); bone disorder marker, alkaline phosphate (ALP). All biomarkers will be collected and assessed by the same accredited laboratory (PathWest Diagnostics, Perth, Western Australia).
Timepoint [1] 328007 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [2] 328008 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] 328008 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [3] 328009 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 [3] 328009 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [4] 328010 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 [4] 328010 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [5] 328011 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 [5] 328011 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [6] 328012 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 [6] 328012 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [7] 328013 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 [7] 328013 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [8] 328014 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 [8] 328014 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [9] 328015 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 [9] 328015 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [10] 328016 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 [10] 328016 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [11] 328017 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 [11] 328017 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [12] 328018 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 [12] 328018 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [13] 328019 0
Aerobic Fitness

The 400m walk test will be used as measures for aerobic fitness.
Timepoint [13] 328019 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [14] 328020 0
Physical Function

Time Up and Go test will be used as a measure of physical function.
Timepoint [14] 328020 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [15] 328021 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-BR-23 (breast cancer) survey will also be provided to measure cancer specific indices of quality of life.
Timepoint [15] 328021 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [16] 328022 0
Distress

The Brief Symptom Inventory (BSI-18) will be used to assess psychological distress.
Timepoint [16] 328022 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [17] 328023 0
Sleep Disturbance

Insomnia Severity Index (ISI) will be used to measure sleep quality disturbance,
Timepoint [17] 328023 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [18] 328024 0
Physical Activity Levels

Godin Leisure-Time Exercise questionnaire will examine self-reported physical activity levels.
Timepoint [18] 328024 0
Week 0 (baseline) to Week 12 (post-intervention)
Secondary outcome [19] 328025 0
Functional Balance

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).
Timepoint [19] 328025 0
Week 0 (baseline) to Week 12 (post-intervention)

Eligibility
Key inclusion criteria
* Female, aged greater than or equal to 18 years.
* Histologically documented breast cancer.
* Stable solitary or multiple metastatic osteolytic 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
Gender
Females
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
Not Applicable
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Data will be analysed using SPSS (IBM Corporation; Chicago, IL, USA). Normality of distribution for continuous variables will be determined using the Kolmogorov-Smirnov test and visual inspection of the data. Analyses will include standard descriptive characteristics, t-tests, and two-way (group x time) repeated measures ANOVA (or analysis of covariance as appropriate) to examine differences between groups over time. Any data that is not normally distributed will be log-transformed or non-parametric tests will be used. For categorical variables, the Pearson Chi-square test will be used. An alpha level of p = 0.05 will be applied to establish statistical significance. Effect sizes will also calculated in accordance with Hopkins62: d = 0.2 is small; d = 0.6 is moderate; d = 1.2 is large; d = 2.0 is very large. A per-protocol analysis will be performed, with an intention-to-treat analysis performed as a secondary notion.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 294590 0
Charities/Societies/Foundations
Name [1] 294590 0
National Breast Cancer Foundation
Address [1] 294590 0
National Breast Cancer Foundation
ABN 37 144 841 707
Level 9, 10 Barrack Street,
Sydney
NSW 2000
Country [1] 294590 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] 293458 0
None
Name [1] 293458 0
Address [1] 293458 0
Country [1] 293458 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296031 0
Edith Cowan University Human Research Ethics Committee
Ethics committee address [1] 296031 0
Edith Cowan University
270 Joondalup Drive
Joondalup, WA 6027
Ethics committee country [1] 296031 0
Australia
Date submitted for ethics approval [1] 296031 0
29/12/2015
Approval date [1] 296031 0
24/02/2016
Ethics approval number [1] 296031 0
14266 NEWTON

Summary
Brief summary
Aim?
To examine whether a targeted and supervised exercise program can suppress tumour formation, growth and activity in advanced breast 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 female aged 18 years or more and have histologically confirmed breast cancer 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
http://www.exercisemedicine.org.au/research-activity/projects-open-for-enrolment/mechanical-modulation-of-bone-metastases-in-advanced-breast-cancer-patients-can-targeted-exercise-suppress-osteolytic-tumour-progression
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69306 0
Dr Nicolas Hart
Address 69306 0
Exercise Medicine Research Institute
Edith Cowan University
270 Joondalup Drive
JOONDALUP, Perth, W.A. 6027
Country 69306 0
Australia
Phone 69306 0
+61 8 6304 3436
Fax 69306 0
+61 8 6304 2499
Email 69306 0
n.hart@ecu.edu.au
Contact person for public queries
Name 69307 0
Dr Nicolas Hart
Address 69307 0
Exercise Medicine Research Institute
Edith Cowan University
270 Joondalup Drive
JOONDALUP, Perth, W.A. 6027
Country 69307 0
Australia
Phone 69307 0
+61 8 6304 3436
Fax 69307 0
+61 8 6304 2499
Email 69307 0
n.hart@ecu.edu.au
Contact person for scientific queries
Name 69308 0
Dr Nicolas Hart
Address 69308 0
Exercise Medicine Research Institute
Edith Cowan University
270 Joondalup Drive
JOONDALUP, Perth, W.A. 6027
Country 69308 0
Australia
Phone 69308 0
+61 8 6304 3436
Fax 69308 0
+61 8 6304 2499
Email 69308 0
n.hart@ecu.edu.au

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 previously approved HREC at Edith Cowan University, St John of God Hospital, and Sir Charles Gairdner Hospital - no individual participant data will be available, and will be stored in secure locations within the Exercise Medicine Research Institute.
What supporting documents are/will be available?
Study protocol
How or where can supporting documents be obtained?
Type [1] 1442 0
Study protocol
Citation [1] 1442 0
Link [1] 1442 0
Email [1] 1442 0
Other [1] 1442 0
https://www.ncbi.nlm.nih.gov/pubmed/30572928
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302473/
https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-018-3091-8
Attachment [1] 1442 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary
Data is still being analysed. However, the primary outcome ( to establish the safety and feasibility of exercise for advanced breast cancer patients with osteolytic bone metastases ) was positive. That is, our targeted exercise program was safe, and feasibly delivered, with no skeletal adverse events associated with bone metastatic lesions. All results will be published as analyses of the full data-set are completed through-out 2019.