Trial Review

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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
19/11/2021
Date data sharing statement initially provided
20/02/2019
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
Update: The prevalence of functional disability (Defined as a VO2peak <18.0 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
Primary outcome [2] 323063 0
The predictive ability of impaired cardiac reserve (defined as <2-fold increase in cardiac output from rest to high intensity exercise) versus resting left-ventricular ejection fraction measured at the completion of anthracycline chemotherapy to predict the subsequent development of functional disability (defined as VO2 peak <18.0 mL/kg/min) measured at 12 months
Timepoint [2] 323063 0
1) Cardiac reserve and resting left ventricular ejection fraction will be assessed at baseline; 2) Functional disability will be assessed at 12-months.
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] 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 [2] 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 [3] 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 [3] 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 [4] 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 [4] 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 [5] 338866 0
LVEF, cardiac mass and diffuse myocardial fibrosis will be assessed via CMR.
Timepoint [5] 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 [6] 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 [6] 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 [7] 338871 0
Maximal muscle power assessed by a vertical countermovement jump test.
Timepoint [7] 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 [8] 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 [8] 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 [9] 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 [9] 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 [10] 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 [10] 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 [11] 338879 0
Health-related quality of life will be assessed via the FACT-B questionnaire.
Timepoint [11] 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 [12] 338880 0
Fatigue will be assessed by the FACT-F questionnaire.
Timepoint [12] 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 [13] 338881 0
Mood and distress will be assessed by the Hospital Anxiety and Depression Scale
Timepoint [13] 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 [14] 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 [14] 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 [15] 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 [15] 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 [16] 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 [16] 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 [17] 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 [17] 339312 0
(2) 4-months - 3 weeks after the last administration of anthracycline chemotherapy
Secondary outcome [18] 367166 0
Symptoms of peripheral neuropathy will be assessed using the EORTC QLQ-CIPN20 questionnaire
Timepoint [18] 367166 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 [19] 367167 0
Workplace and general productivity will be assessed using the Work Productivity Activity and Impairment - Specific Health Problem Questionnaire.
Timepoint [19] 367167 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

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
Sex
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
Our sample size of 100 subjects will address Primary Aims 1 and 2 with sufficient compensation for expected attrition. The sample size estimations for Aim 1, that significantly fewer patients undergoing exercise therapy will be functionally disabled at 12 months, are based on our pilot study experience in which 29% of patients met this criteria at treatment completion and in which there was a 7-fold greater proportion of functional disability in the usual care arm. In the current proposal, we have used a conservative 24% incidence of functional disability (cf. 29% in the pilot) and 3-fold difference between groups (cf. 7-fold in the pilot). To detect a 36% vs 12% difference in the prevalence of functional disability, 45 subjects in each group is required (ß=80%, a=5%).
The second aim of the study is to compare the predictive ability of standard-of-care measures (LVEF) with peak cardiac output measured by ExCMR in identifying patients who will meet criteria for functional disability at 12 months. A multivariate regression will be used with 5 variables entered (age, LVEF, GLS, study group and peak cardiac output). The sample size estimated for such an analysis can be calculated as 90 subjects (50 + 8 x no. of variables) using the method suggested by Green. 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. We have allowed a 10% attrition rate to account for subject drop-out, consistent with our pilot study in which 2 subjects withdrew (moved interstate and severe treatment related illness).

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. Primary analyses will be analysed on an intention-to-treat basis in line with the CONSORT guidelines. All models will be adjusted for potentially important covariates explaining residual outcome variance (e.g. age, chemotherapy regime, anaemia). 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 analysis (per-protocol) will explore influence of exercise adherence (>66%, 2 of 3 weekly sessions) on the outcomes. The significance level for statistical analysis will be set at P < 0.05.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
16/10/2017
Actual
2/11/2017
Date of last participant enrolment
Anticipated
2/10/2020
Actual
15/03/2021
Date of last data collection
Anticipated
31/12/2021
Actual
Sample size
Target
100
Accrual to date
Final
103
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
Country [1] 297541 0
Australia
Funding source category [2] 305095 0
Charities/Societies/Foundations
Name [2] 305095 0
World Cancer Research Fund International
Country [2] 305095 0
Belgium
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
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
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 2057 2057 0 0
/AnzctrAttachments/373668-305-17 Ethics approval certificate 25-Aug-2017 (1).pdf (Ethics approval)
Attachments [2] 2076 2076 0 0
/AnzctrAttachments/373668-BCstudy_ConsentToContact_V1.0_140717.pdf (Supplementary information)
Attachments [3] 2077 2077 0 0
/AnzctrAttachments/373668-SF02962_BCstudy_PICF_305-17_v1.1_17072017_Final.docx (Participant information/consent)
Attachments [4] 2474 2474 0 0
/AnzctrAttachments/373668-BCstudy_305-17_Fast Facts for Referring Doctors_v1.0_29012018.pdf (Supplementary information)

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
[email protected]
Contact person for public queries
Name 77731 0
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
[email protected]
Contact person for scientific queries
Name 77732 0
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
[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
Our ethics approval does not currently allow for sharing of individual participant data. Individual participant data may be made available upon request pending ethics and research governance approval.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
1302Study protocol    A detailed protocol for the study will be publishe... [More Details]



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseExercise as a diagnostic and therapeutic tool for preventing cardiovascular morbidity in breast cancer patients- The BReast cancer EXercise InTervention (BREXIT) trial protocol.2020https://dx.doi.org/10.1186/s12885-020-07123-6
EmbaseExercise for the Prevention of Anthracycline-Induced Functional Disability and Cardiac Dysfunction: The BREXIT Study.2023https://dx.doi.org/10.1161/CIRCULATIONAHA.122.062814
N.B. These documents automatically identified may not have been verified by the study sponsor.