Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000334909p
Ethics application status
Submitted, not yet approved
Date submitted
24/02/2020
Date registered
10/03/2020
Date last updated
8/11/2021
Date data sharing statement initially provided
10/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessing safety and feasibility of targeted exercise to suppress bone disease in multiple myeloma patients.
Scientific title
Mechanical suppression of osteolytic bone disease in patients with multiple myeloma using precision exercise medicine: a Phase 1 randomised controlled trial.
Secondary ID [1] 300630 0
None
Universal Trial Number (UTN)
U1111-1248-7158
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma 316401 0
Myeloma Bone Disease 316402 0
Condition category
Condition code
Cancer 314666 314666 0 0
Myeloma
Musculoskeletal 314667 314667 0 0
Other muscular and skeletal disorders
Physical Medicine / Rehabilitation 314756 314756 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A two-armed, single-blinded (investigators blinded to allocation) randomised and controlled (supervised exercise versus usual medical care) trial is proposed to examine the safety and feasibility of a supervised, targeted and dose-escalated exercise medicine program for multiple myeloma patients with myeloma bone disease.

Exercise sessions will be conducted in a small group setting (of up to 6 persons per group) in an exercise clinic suitable for persons with chronic disease including cancer. Resistance exercises will occur through using pin-loaded weight machines, cable resistance machines, smith machines and free weights (dumbbells or barbells). Isometric exercises require body-weight only with no specific or special equipment necessary. Aerobic exercises occur through standard ergometers (such as a treadmill, stationary cycle, arm cycle, or rower).

Intervention adherence and fidelity will be assessed through exercise record logbooks of prescribed versus actual completed (exercises and volume-load), as well as attendance rate to planned exercise sessions.

The exercise arm (intervention) will receive an individually tailored exercise program involving isometric, resistance and aerobic exercise of moderate-to-vigorous intensity in addition to usual medical care.

Participants assigned to the exercise arm will be required to participate in a modular, multi-modal exercise program for 12 weeks, including resistance exercise, aerobic exercise and isometric exercise. The program requires participants to attend three clinic-based exercise sessions per week for 60 minutes in duration, supervised by accredited exercise physiologists with experience delivering exercise to patients with advanced cancers. As multiple myeloma patients with myeloma bone disease may have stable and unstable skeletal structures dependent upon magnitude of disease infiltration, the exercise program will be individually tailored for each patient according to their clinical presentation.

For stable disease-affected bones, a dose-escalation approach will be employed to graduate load from isometric to dynamic mechanical stimuli over the program through targeted muscle contraction and mild to moderate external resistance activities as tolerated. Exercise doses will be escalated if the target lesion sites are asymptomatic and exercises well-tolerated, determined in routine consultation with the participant. Unstable disease-affected bone sites will be avoided in accordance with our teams established modular exercise program used in prior studies with bone metastases. Exercise of regions unaffected by myeloma bone disease will be prescribed as normal, without modifications.

Resistance exercise will incorporate repetition maximums (RM), with six different resistance exercises using major muscle groups, subject to the location and extent of skeletal lesions, at 8–12 RM for three sets per exercise to achieve a moderate intensity and volume. Aerobic exercise will be set at a heart rate (HR) with moderate-to-high intensity exercise shown to reduce circulating tumour cells in colorectal cancer patients. Accordingly, participants will engage in aerobic exercise using treadmill, cycling and rowing ergometers, performed at 60–85% HRmax for 20–30 minutes (moderate-intensity continuous training) or 4 bouts of 4 minutes per bout at 85-95% HRmax (high-intensity interval training) tracked with heart rate monitors. Isometric exercise will require particular positions to be adopted that ensure high levels of muscular contraction to hold stable body positions that ensure the joint(s) surrounding the target bone do not move while the muscle around it contracts. Flexibility exercise will involve static stretching of muscles at all joints considered important for function, and for all muscles engaged during the session, except for locations of unstable lesion sites. Stretches will involve 2–4 sets with 30–60 s hold per set.
Intervention code [1] 316957 0
Lifestyle
Intervention code [2] 316958 0
Rehabilitation
Intervention code [3] 316959 0
Treatment: Other
Comparator / control treatment
The control arm (usual care) will receive their usual medical care during their on-study period and will be asked to maintain current lifestyle activities which will be monitored. Following their on-study period, participants randomised to the control arm will be offered the same exercise program using a wait-list approach to minimise study contamination, participant withdrawal or loss to follow-up. The wait-list period will run 12-weeks as per the on-study period, therefore immediately following the post-study testing/assessment visit, concludes the wait-list and allows patients in the control arm to receive an exercise program as described.
Control group
Active

Outcomes
Primary outcome [1] 322992 0
Safety (number and grade of adverse events and skeletal complications).

These may include muscle strains, muscle pain, incremental bone pain, skeletal fracture, patient fatigue. Visual Analogue Scales (VAS) are used prior to every single exercise visit to measure ongoing status and change of muscle pain, bone pain or fatigue (for intervention patients). Otherwise, patient self-report (to study personnel and clinicians), adverse event logbooks, and clinician review will be used across both study arms.
Timepoint [1] 322992 0
Assessed ongoing (Week 0 through to Week 12)
Primary outcome [2] 322993 0
Feasibility (patient recruitment and trial completion, program adherence and compliance).

Recruitment and Trial Completion pertain to number of patients referred to the clinical trial, the number of patients who were screen fails, or screen successes, and thus those who translated to randomisation. Furthermore, following randomisation, the number of patients who complete through to post-study testing/assessments, number of patients lost to follow-up or who withdrawal will assist with assessing this component.

In relation to program adherence and compliance, this will be measured through exercise attendance levels (relative to planned exercise visits), and completed exercise program rate (relative to prescribed exercise program), specific to modification to programs, missed sessions, or missed exercises.
Timepoint [2] 322993 0
Assessed ongoing (Week 0 to Week 12)
Secondary outcome [1] 380446 0
Bone Health (bone mass and cross-sectional area measures using DXA and pQCT).

All bones will be assessed through areal measures of bone densitometry. A whole-body DXA scan will review whole-body bone area, bone mineral content and bone mineral density. Segmental DXA scan will review higher resolution bone area, bone mineral content and bone mineral density for the lumbar spine, and total hip (inclusive of femoral neck).

Tibia, Fibula and Femur will be assessed through volumetric measures of bone densitometry. A tibiofibular scan will measure the bbone density (vBMD), bone structure (cross-sectional area) and bone strength (stress-strain index) of the tibia and fibula. A femoral scan will measure the bone density (vBMD), bone structure (cross-sectional area) and bone strength (stress-strain index) of the femur.
Timepoint [1] 380446 0
Week 0 (baseline) and Week 12 (post-trial)
Secondary outcome [2] 380448 0
Muscle Health (lean mass and cross-sectional area measured by DXA and pQCT).

All lean mass (fat free soft tissue mass) will be measured in total volume through DXA. Similarly, segmental lean mass will be assessed from the same scan through regions of interest drawn on images, specifically the axial and appendicular skeleton, separate from the arm and forearm, thigh and shank musculature. Muscle cross-sectional area and density of the thigh (quadriceps and hamstrings) and shank (calf muscles) will be measured through pQCT.
Timepoint [2] 380448 0
Week 0 (baseline) and Week 12 (post-trial)
Secondary outcome [3] 380449 0
Adiposity (visceral and subcutaneous fat mass and cross-sectional area measured by DXA and pQCT)
Timepoint [3] 380449 0
Week 0 (baseline) and Week 12 (post-trial)
Secondary outcome [4] 380455 0
Bone Metabolic Activity (through serological and urianalytical biomarkers: bone-specific alkaline phosphatase (bALP) and amino-terminal propeptide of type 1 procollagen (P1NP); bone resorption markers, amino-terminal collagen type-I telopeptide (NTx) and carboxy-terminal collagen crosslink (CTx)).
Timepoint [4] 380455 0
Week 0 (baseline) and Week 12 (post-trial).
Secondary outcome [5] 380456 0
Systemic Inflammation (C-Reactive Protein, CRP).
Timepoint [5] 380456 0
Week 0 (baseline) and Week 12 (post-trial).
Secondary outcome [6] 380457 0
Fasting Glucose and Lipids
Timepoint [6] 380457 0
Week 0 (baseline) and Week 12 (post-trial).
Secondary outcome [7] 380458 0
Muscle Strength (one-repetition maximum; chest press, seated row, leg press, leg extension, hand-grip)
Timepoint [7] 380458 0
Week 0 (baseline) and Week 12 (post-trial).
Secondary outcome [8] 380459 0
Aerobic Capacity (6 minute walk test performance)
Timepoint [8] 380459 0
Week 0 (baseline) and Week 12 (post-trial).
Secondary outcome [9] 380460 0
Physical Function (Timed Up and Go Test)
Timepoint [9] 380460 0
Week 0 (baseline) and Week 12 (post-trial).
Secondary outcome [10] 380461 0
Balance (NeuroCom Sensory Organisation Test)
Timepoint [10] 380461 0
Week 0 (baseline) and Week 12 (post-trial).
Secondary outcome [11] 380462 0
Health-related Quality of Life (Short Form 36, SF-36 IQOLA)
Timepoint [11] 380462 0
Week 0 (baseline) and Week 12 (post-trial).
Secondary outcome [12] 380463 0
Cancer-Specific Quality of Life (General, EORTC-QLQ30).
Timepoint [12] 380463 0
Week 0 (baseline) and Week 12 (post-trial).
Secondary outcome [13] 380464 0
Cancer-Specific Quality of Life (Myeloma; EORTC-MY20)
Timepoint [13] 380464 0
Week 0 (baseline) and Week 12 (post-trial).
Secondary outcome [14] 380465 0
Self-Report Physical Activity Levels - (Godin, Leisure-Time Physical Activity Index).
Timepoint [14] 380465 0
Week 0 (baseline) and Week 12 (post-trial).

Eligibility
Key inclusion criteria
[1] Multiple myeloma patients with myeloma bone disease (confirmed with clinical imaging). [2] Required to have not engaged in regular structured exercise in the past three months.
[3] have no current non-healing skeletal fracture sites,
[4] receive medical clearance to engage in supervised exercise by their haematologist (cancer-specific contraindications), and general practitioner (for other contraindications).
[5] Is prepared to be randomised to either arm of the study
[6] is not currently receiving an experimental therapy (beyond those in standard of care).

Patients with stable and unstable skeletal sites will be included with exercise prescriptions customised based on the location of disease-affected skeletal sites and the stability status of the disease-affected skeletal sites. Skeletal stability will be assessed by study clinicians using previously established clinical tools, including Mirel’s scoring system (long bones) and Taneichi’s scoring system (vertebral column). Owing to potential clinical events surrounding spinal osteolytic activity, the spinal instability neoplastic score (SINS) will also be used as a confirmatory tool to support the Taneichi score. In the event of discordance between the two vertebral scoring tools, the higher score will be chosen to remain risk averse. Within a broader multi-modal exercise program, stable lesion sites will receive a targeted and dose-escalated exercise stimulus through mechanical loading, whereas unstable lesion sites will be avoided as per our previous work with bone metastases as a similar clinical paradigm for comparison.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
[1] Have a cancer diagnosis other than multiple myeloma.
[2] Does not have Myeloma Bone Disease (clinically confirmed through imaging).
[3] Currently engaging in a regular, structured exercise program pre-enrolment.
[4] Is not willing to be randomised.
[5] Does not receive medical clearance to participate
[6] Is currently enrolled in an experimental drug trial.

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)
Patients will be randomly allocated in a ratio of 1:1 to the two study arms: exercise (intervention) or usual care (control), stratified by age (less than 65 years, greater than or equal to 65 years) and gender (male or female) to account for variations in musculoskeletal health.

Study investigators, research assistants, and exercise physiologists conducting study testing procedures will be blinded to patient group allocations (single-blinded). Exercise physiologists outside of the research team will deliver the exercise intervention to maintain the integrity of the blinding process.

Allocation concealment will occur, following sequence generation, by placing randomisation sequencing outcomes in opaque envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A research officer with no patient contact will be responsible for randomisation of patients into each group using a computer-generated coding sequence through a random-assignment program.
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 Corp.; Chicago, IL, USA). Normality of distribution of continuous variables will be determined by the Shapiro-Wilks test and visual inspection of the data. Analyses will include standard descriptive characteristics, independent t-tests, linear mixed models with repeated measures (or analysis of covariance as appropriate) to examine differences between groups over time. Data not normally distributed will be log-transformed or the equivalent non-parametric tests will be used. The Pearson Chi-square test will be used to analyse categorical variables. An alpha level of p = 0.05 will be applied to establish statistical significance. Effect sizes will also be calculated and defined as: d = 0.2 small; d = 0.6 moderate; d = 1.2 large; d = 2.0 very large. Incomplete data and missing values will be primarily managed using an intention-to-treat approach with multiple imputation, using the maximum likelihood imputation of missing values approach. To ensure robustness of our findings, a secondary sensitivity analysis will be conducted using a complete-cases approach.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Other reasons/comments
Other reasons
COVID-19 disruption to funding and delivery of trial during a pandemic.
Date of first participant enrolment
Anticipated
16/03/2020
Actual
Date of last participant enrolment
Anticipated
1/09/2021
Actual
Date of last data collection
Anticipated
17/12/2021
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 15959 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 15960 0
Hollywood Private Hospital - Nedlands
Recruitment hospital [3] 15961 0
Joondalup Health Campus - Joondalup
Recruitment postcode(s) [1] 29452 0
6009 - Nedlands
Recruitment postcode(s) [2] 29453 0
6027 - Joondalup

Funding & Sponsors
Funding source category [1] 305053 0
University
Name [1] 305053 0
Edith Cowan University
Country [1] 305053 0
Australia
Primary sponsor type
University
Name
Edith Cowan University
Address
270 Joondalup Drive, JOONDALUP, Perth, WA, Australia, 6027
Country
Australia
Secondary sponsor category [1] 305418 0
None
Name [1] 305418 0
Address [1] 305418 0
Country [1] 305418 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 305441 0
Edith Cowan University Human Research Ethics Committee
Ethics committee address [1] 305441 0
Ethics committee country [1] 305441 0
Australia
Date submitted for ethics approval [1] 305441 0
27/01/2020
Approval date [1] 305441 0
Ethics approval number [1] 305441 0
REMS-2019-00915-HART

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

Contacts
Principal investigator
Name 100398 0
Dr Nicolas Hart
Address 100398 0
Exercise Medicine Research Institute
Building 21, Room 222
Edith Cowan University
270 Joondalup Drive, JOONDALUP
Perth, WA, Australia, 6027
Country 100398 0
Australia
Phone 100398 0
+61863043436
Fax 100398 0
+61863042499
Email 100398 0
n.hart@ecu.edu.au
Contact person for public queries
Name 100399 0
Nicolas Hart
Address 100399 0
Exercise Medicine Research Institute
Building 21, Room 222
Edith Cowan University
270 Joondalup Drive, JOONDALUP
Perth, WA, Australia, 6027
Country 100399 0
Australia
Phone 100399 0
+61863043436
Fax 100399 0
+61863042499
Email 100399 0
n.hart@ecu.edu.au
Contact person for scientific queries
Name 100400 0
Nicolas Hart
Address 100400 0
Exercise Medicine Research Institute
Building 21, Room 222
Edith Cowan University
270 Joondalup Drive, JOONDALUP
Perth, WA, Australia, 6027
Country 100400 0
Australia
Phone 100400 0
+61863043436
Fax 100400 0
+61863042499
Email 100400 0
n.hart@ecu.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
On a case-by-case basis, written requests will be considered. The data available will be de-identified clinical, safety, feasibility and efficacy information as reported in this clinical trials registration. However, this will be permissible only after publications are produced from the data following analysis.
When will data be available (start and end dates)?
Immediately following publication, for a period of 12 months.
Available to whom?
Researchers or others who provide a suitable, appropriate application in writing to the Exercise Medicine Research Institute ( and the lead researcher ).
Available for what types of analyses?
Only to achieve the purposes of the approved proposal (if any, above); and/or to benefit others preparing systematic reviews and/or meta-analyses.
How or where can data be obtained?
Principal Investigator only, via email, to n.hart@ecu.edu.au [ Dr Nicolas Hart ]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7061Study protocol  n.hart@ecu.edu.au The study protocol is in the process of being publ... [More Details]
7062Statistical analysis plan  n.hart@ecu.edu.au This has been outlined in the ANZCTR Registration;... [More Details]
7063Informed consent form  n.hart@ecu.edu.au This is currently under review of the ECU HREC (Ed... [More Details]
7064Ethical approval  n.hart@ecu.edu.au This is currently under review of the ECU HREC (Ed... [More Details]



Results publications and other study-related documents

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