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Trial registered on ANZCTR


Registration number
ACTRN12617001408370
Ethics application status
Approved
Date submitted
28/09/2017
Date registered
5/10/2017
Date last updated
5/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Exercise for diagnosis and treatment of heart dysfunction among breast cancer patients
Scientific title
Exercise as a diagnostic and therapeutic tool for the prevention of cardiovascular morbidity in breast cancer survivors - a randomised trial
Secondary ID [1] 292912 0
None
Universal Trial Number (UTN)
U1111-1202-3814
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 304768 0
Cardiac Dysfunction 304769 0
Condition category
Condition code
Cancer 304086 304086 0 0
Breast
Cardiovascular 304087 304087 0 0
Other cardiovascular diseases
Physical Medicine / Rehabilitation 304273 304273 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Exercise Training:
The exercise training will consist of three phases: Phase 1 (exercise during chemotherapy: 4 months), Phase 2 (exercise rehabilitation following chemotherapy: 2 months) and Phase 3 (a step-down maintenance program: 6 months).

Phase 1 (Structured Exercise During Anthracycline Chemotherapy, 0-4 months):
Patients will be provided with an individualised training program in which they will be prescribed three 60-minute sessions of structured exercise per week at a local health and fitness centre throughout the Melbourne metropolitan region and supervised by qualified exercise trainers. Exercise training will be prescribed by an Accredited Exercise Physiologist (AI Foulkes) and will include a brief warm-up and cool-down, moderate-continuous (60-80% maximal capacity) progressing to high-intensity interval training (HIIT) of approximately 4 x 4 minutes of cycling at >80% of maximal capacity separated by 2 minutes of active recovery, and 20-25 minutes of progressive resistance training consisting of 5-6 exercises targeting major muscle groups. Participants will perform 1-2 sets at 55-85% of their 1 repetition max (RM; equivalent to 8-15 RM). Exercise volume will be increased by 2-10% (via increases in exercise intensity and/or duration) per week with the exception of each week of chemotherapy administration. A 5-10% reduction in exercise volume will be scheduled for the week following chemotherapy administration individualised to each participant based on their heart rate reserve and rating of perceived exertion responses to exercise. This allows for increased recovery whilst participant symptoms are at their peak.

Phase 2 (Structured Exercise Rehabilitation Following Anthracycline Chemotherapy):
Participants will be continue with structured exercise training for a further 2 months following the completion of anthracycline chemotherapy. This will consist of two supervised sessions consisting of HIIT and the progressive resistance training as outlined above, and two sessions of moderate-intensity continuos training (45-60 minutes at 60-70% VO2peak) being performed by the participants without supervision. Unsupervised sessions will be performed at a local health and fitness centre (YMCA) or as a home-based exercise session. During the supervised sessions, participants will receive feedback and guidance on structuring and performing their independent exercise sessions in order to increase their self-efficacy towards exercise. There will also be an emphasis on motivational interviewing and goal setting to assist participants in incorporating a regular exercise routine into their lifestyle and to assist in the transition to phase 3 of the exercise program.

Phase 3 (Step-down Maintenance Program, 6-12 Months):
Participants will be provided with ongoing support for the final 6 months of the study via the prescription of a structured, individualised program for the subject to complete in an unsupervised environment, along with fortnightly telephone- and weekly text reminders. This program will consist of continued aerobic and resistance exercises focused on maintaining improvements in fitness, strength and physical function obtained in phase 1 and 2. Participants will attend up to five 60-minute supervised sessions in order to discuss their progress and update their training program. The frequency of these sessions will be determined in consultation with each participant based on their personal goals and confidence in performing exercise independently. In addition to their five supervised sessions, participants will also receive remote feedback on their training program via an online exercise prescription platform (Physitrack®). Participants will be provided with written feedback by their trainer each week, however participants have the ability to send direct messages to the trainer regarding any queries or issues related to the exercise program that require more immediate follow-up. Resistance exercises will be prescribed and monitored via the Physitrack® online patient engagement platform. Participants will be provided with wrist-worn heart rate monitors, which will be used to prescribe and monitor adherence to the aerobic exercise prescription remotely.
Intervention code [1] 299140 0
Lifestyle
Intervention code [2] 299141 0
Rehabilitation
Intervention code [3] 299142 0
Treatment: Other
Comparator / control treatment
Participants allocated to usual care will receive ongoing care from their oncology team but will not receive additional access to supervised exercise training. Control group participants will receive usual lifestyle advice as part of their routine clinical care where they will be encouraged to be physically active during treatment..
Control group
Active

Outcomes
Primary outcome [1] 303405 0
The prevalence of functional disability (Defined as a VO2peak <15.4 mL/kg/min). This will be assessed with a maximal cardiopulmonary exercise test (CPET) on an upright cycle ergometer with breath-by-breath expired gas analysis. VO2peak is defined as the highest oxygen uptake measured over the final 30 seconds of exercise using 5-second averages of breath-by-breath data.
Timepoint [1] 303405 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [1] 338849 0
Change in cardiac reserve (difference between resting ejection fraction and resting ejection fraction during high intensity exercise) measured during exercise cardiac magnetic resonance imaging (exCMR). Subjects will perform supine cycle exercise using an electronically braked cycled ergometer whilst laying in the bore of the MRI. Real-time ‘free breathing’ CMR images will be taken at rest, and at 20%, 40% and 60% of the peak watts achieved during the CPET, corresponding to low, moderate and high intensity exercise respectively. Additional measures of cardiac reserve will include change in cardiac output, stroke volume, end-systolic volume and end-diastolic volume from rest to high intensity exercise.
Timepoint [1] 338849 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [2] 338850 0
The predictive ability of impaired cardiac reserve (defined as <2-fold increase in cardiac output from rest to high intensity exercise) versus left-ventricular ejection fraction measured at the completion of anthracycline chemotherapy to predict the subsequent development of functional disability (defined as VO2 peak <15.4 mL/kg/min) measured at 12 months
Timepoint [2] 338850 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [3] 338851 0
Other echocardiographic indices of systolic (Left Ventricular Ejection Fraction. LVEF; Global Longitudinal Strain, GLS) and diastolic ventricular function (filling velocities, relaxation times) will be assessed by a trans-thoracic echocardiogram performed by a trained sonographer.
Timepoint [3] 338851 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [4] 338852 0
Absolute (L/min) and relative (mL/kg/min) VO2peak will be assessed by a maximal CPET with breath-by-breath gas analysis on an upright cycle ergometer. VE/VCO2 slope, the percentage of VO2peak at the ventilatory threshold and the relationship between VO2peak and lower body lean body mass will also be assessed.
Timepoint [4] 338852 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [5] 338862 0
Aortic pulse-wave velocity and change in aortic diameter from systole to diastole will be used as indices of aortic stiffness. These will be obtained from images of the proximal ascending and descending aorta taken during the CMR.
Timepoint [5] 338862 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [6] 338866 0
LVEF, cardiac mass and diffuse myocardial fibrosis will be assessed via CMR.
Timepoint [6] 338866 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [7] 338869 0
Dynamic muscle strength as assessed by the 1 repetition maximum test using leg press and seated row resistance machines. Maximal isometric grip strength assessed by a digital handgrip dynamometer.
Timepoint [7] 338869 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [8] 338871 0
Maximal muscle power assessed by a vertical countermovement jump test.
Timepoint [8] 338871 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [9] 338874 0
Physical performance will be assessed by a timed stair climb up one flight of 12 stairs (17cm per step), a 30-second sit to stand test and usual- and fast 4-metre walk tests.
Timepoint [9] 338874 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [10] 338876 0
Cognitive function will be assessed via a battery of short verbal and paper-based cognitive tests. The Rey Auditory Verbal Learning Test will be used to assess memory and learning. The Digit Span Test will be administered to assess working memory and the Trail Making Test (Parts A and B) will be administered to assess executive function. The National Adult Reading Test will be administered to assess verbal, performance, and full-scale intelligence quotas as an estimate of premorbid intelligence.
Timepoint [10] 338876 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [11] 338877 0
Physical activity and sedentary behaviour will be objectively measured by the Actigraph GT3X+ and activPAL3TM monitors, which are to be worn for 7 days following the testing session.
Timepoint [11] 338877 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [12] 338879 0
Health-related quality of life will be assessed via the FACT-B questionnaire.
Timepoint [12] 338879 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [13] 338880 0
Fatigue will be assessed by the FACT-F questionnaire.
Timepoint [13] 338880 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [14] 338881 0
Mood and distress will be assessed by the Hospital Anxiety and Depression Scale
Timepoint [14] 338881 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [15] 338947 0
Muscle size and muscle fat infiltration of the thigh will be assessed via 2-point Dixon MRI of the mid-thigh on the dominant leg.
Timepoint [15] 338947 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [16] 338948 0
A 20mL non-fasting blood sample will be taken for the assessment of blood-based cardiac biomarkers (Troponin I and B-type Natriuretic Peptide) and a full-blood examination.
Timepoint [16] 338948 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [17] 338949 0
Body composition, body fat distribution and bone-mineral density of the hip and lumbar spine assessed by Dual-Energy X-Ray Absorptiometry (DXA).
Timepoint [17] 338949 0
(1) Baseline - prior to commencing anthracycline chemotherapy
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
(3) 12-months - 12 months since the first administration of anthracycline chemotherapy
Secondary outcome [18] 339312 0
The prevalence of functional disability (Defined as a VO2peak <15.4 mL/kg/min). This will be assessed with a maximal cardiopulmonary exercise test (CPET) on an upright cycle ergometer with breath-by-breath expired gas analysis. VO2peak is defined as the highest oxygen uptake measured over the final 30 seconds of exercise using 5-second averages of breath-by-breath data.
Timepoint [18] 339312 0
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy

Eligibility
Key inclusion criteria
Women aged 40-75 years who have been diagnosed with breast cancer and are scheduled to undergo anthracycline-based chemotherapy will be eligible to participate in the study. All eligible participants must also obtain medical approval from their physician before participating.
Minimum age
40 Years
Maximum age
75 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded if they (1) have known structural heart disease (such as symptomatic ischemic heart disease, significant valvular disease or inherited cardiomyopathies), (2) have contraindications to the CMR procedure (pacemakers, implanted metallic foreign body or device), (3) have the presence of any serious contraindication or uncontrolled medical condition that would limit participation in the exercise program, (4) an inability to complete questionnaires in english language or (5) significant cognitive impairment.

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)
All outcome assessors will be blinded to pre-chemotherapy values for foll0w-up assessment. The sonographer performing the cardiac ultrasound (echocardiography) and the researcher analysing the cardiac MRI scans will also be blinded to group allocation. For the MRI analysis, scans will be coded with a random number to blind the researcher analysing the scans from group allocation and study time point. The code needed for re-identification and to determine study group allocation will be available on a separate computer datasheet not accessible to the researcher analysing the CMR scans.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Following baseline testing, participants will be randomly allocated by an independent researcher to either the exercise or usual care groups using blocked randomisation stratified by age (<60 or >60 years) and anti-HER2 directed therapy with a 1:1 allocation via a computer-generated random number generator.
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
In our pilot study, 22% of patients had a VO2peak =15.4 mL/kg/min, an incidence lower than the 33% observed in a large cohort of BC patients that included women with more advanced disease. The rationale for restricting inclusion to BC patients aged 40-75 years is to ensure adequate power to address the study hypotheses given that 0/4 patients in our pilot study aged under 40 years were functionally disabled after chemotherapy. Assuming a conservative 1 in 6 women (17%) will have a VO2peak =15.4 mL/kg/min, this will provide 85% power (a = 0.05) of detecting a 2-fold reduction in functional disability in the exercise group, assuming a maximum 10% drop-out rate. Furthermore, guided by the peak cardiac output values from the pilot study (13.0 ± 2.1 L/min) this sample size will provide 97% power (a = 0.05) to detect a 10% reduction in peak cardiac output from baseline to post-chemotherapy and 84% power to detect a 10% difference between the exercise and usual care groups. Finally, in our pilot study, 29% of subjects had impaired cardiac reserve (<2-fold increase in cardiac output). Estimating a conservative 20% prevalence of impaired cardiac reserve, our sample size provides 78% power for predicting a 2-fold increase in the risk of functional disability.

Following recent recommendations on data analysis of randomised controlled trials, generalised linear mixed models (GLMMs) with random intercepts will be used to evaluate the differential effects of the intervention on the selected outcomes. All data will be analysed on an intention-to-treat (ITT) basis in line with the CONSORT guidelines. All models will be adjusted for potentially important covariates explaining residual outcome variance (eg. Age, chemotherapy regime, anemia) and baseline values for the outcome of interest. GLMMs are appropriate for correlated data (repeated measures) with various distributional assumptions and can accommodate incomplete datasets. For those with missing data, multiple imputation will be used, with subsequent sensitivity analysis to test a range of scenarios assuming plausible arm-specific differences in the outcomes. Pre-planned subgroup analyses (per-protocol) will explore the influence of exercise adherence (>66%, 2 of 3 weekly sessions) on the outcomes.

Recruitment
Recruitment status
Recruiting
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)
VIC

Funding & Sponsors
Funding source category [1] 297541 0
Charities/Societies/Foundations
Name [1] 297541 0
The Australian National Heart Foundation Future Leader Fellowship
Address [1] 297541 0
Level 12, 500 Collins Street, Melbourne Victoria 3000
Country [1] 297541 0
Australia
Primary sponsor type
Other
Name
Baker Heart and Diabetes Institute
Address
75 Commercial Road, Melbourne, Victoria 3004, Australia
Country
Australia
Secondary sponsor category [1] 296570 0
None
Name [1] 296570 0
Address [1] 296570 0
Country [1] 296570 0
Other collaborator category [1] 279733 0
University
Name [1] 279733 0
Deakin University
Address [1] 279733 0
Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, 221 Burwood Highway, Burwood, Victoria
Country [1] 279733 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298637 0
Alfred Health Human Research Ethics Committee
Ethics committee address [1] 298637 0
The Alfred Hospital, Ground Floor, Linay Pavillion, 55 Commercial Road, Melbourne, Victria, 3004
Ethics committee country [1] 298637 0
Australia
Date submitted for ethics approval [1] 298637 0
27/07/2017
Approval date [1] 298637 0
25/08/2017
Ethics approval number [1] 298637 0
Project 305/17

Summary
Brief summary
The chemotherapy medications used for breast cancer treatment are important for achieving a cure but a potential side effect is that they can affect heart function. Current tools used to assess your heart function during and following breast cancer treatment cannot accurately predict those who will go on to develop heart problems. Aerobic fitness is an important predictor of outcomes in people with certain forms of heart disease, and having a particularly low level of aerobic fitness (termed functional disability) appears very closely linked with the risk of developing heart failure. Importantly, functional disability also reflects an exercise capacity that would limit your ability to perform basic activities of daily living such as walking briskly, climbing stairs or gardening.

We are conducting a study which aims to identify how anthracycline chemotherapy affects your exercise capacity and risk of functional disability. We would also like to assess how the standard test used to measure your heart function at rest compares to state of the art MRI imaging of the heart in being able to predict your risk of becoming functionally disabled. Furthermore, we are testing whether exercise training during and following your chemotherapy is helpful in protecting against functional disability.

Who is it for?
You may be eligible to join this study if you are between the ages 40 and 75 years old, have been diagnosed with breast cancer and are scheduled for Anthracycline-based chemotherapy.

What is involved?
You will be participating in a randomised controlled research project. You will be randomly assigned to one of two groups (just like a coin toss); the control group which receives usual care for your breast cancer, or the exercise group which participates in a 12 month supervised exercise intervention plus usual care. You will have an equal chance of being randomised into either the exercise or usual care group.

You will then undergo a series of assessments at the Baker Heart and Diabetes Institute within two weeks of starting your chemotherapy (Baseline), after finishing chemotherapy (4 months) and again at 12 months after starting chemotherapy. Each round of testing will be split across two days, and last between 1.5-3.5 hours each. This means you will visit the Baker Heart and Diabetes Institute on 6 occasions, totalling approximately 15 hours. The testing sessions will include assessment of your heart function, exercise capacity, body composition, muscle strength/function, cognitive function and quality of life. The exercise program will consist of three to four sessions 60-minute exercise sessions per week of moderate-high intensity endurance (i.e cycling, walking, jogging) and resistance exercise aimed at improving your heart and muscle function. The training program will be prescribed by an Accredited Exercise Physiologist (AEP) who is experienced in prescribing exercise for individuals undergoing cancer treatment.
Trial website
https://www.baker.edu.au/research/laboratories/sports-cardiology/project-exercise-breast-cancer
Trial related presentations / publications
Public notes
Attachments [2] 2076 2076 0 0
Attachments [3] 2077 2077 0 0

Contacts
Principal investigator
Name 77730 0
A/Prof Andre La Gerche
Address 77730 0
Baker Heart and Diabetes Institute, Alfred Centre, Level 4, 99 Commercial Road, Melbourne, VIC, 3004
Country 77730 0
Australia
Phone 77730 0
+61 (0)3 8532 1111
Fax 77730 0
+61 (0)3 8532 1899
Email 77730 0
andre.lagerche@baker.edu.au
Contact person for public queries
Name 77731 0
Mr Stephen Foulkes
Address 77731 0
Baker Heart and Diabetes Institute, Alfred Centre, Level 4, 99 Commercial Road, Melbourne, VIC, 3004
Country 77731 0
Australia
Phone 77731 0
+61 3 8532 1111
Fax 77731 0
Email 77731 0
steve.foulkes@deakin.edu.au
Contact person for scientific queries
Name 77732 0
A/Prof Andre La Gerche
Address 77732 0
Baker Heart and Diabetes Institute, Alfred Centre, Level 4, 99 Commercial Road, Melbourne, VIC, 3004
Country 77732 0
Australia
Phone 77732 0
+61 (0)3 8532 1111
Fax 77732 0
+61 (0)3 8532 1899
Email 77732 0
andre.lagerche@baker.edu.au

No data has been provided for results reporting
Attachments/websites
Type [1] 1302 0
Study protocol
URL/details/comments [1] 1302 0
A detailed protocol for the study will be published in a peer-reviewed journal
Attachment [1] 1302 0
Summary results
Not applicable