Exercise to Prevent AnthraCycline-based Cardio-Toxicity Study 2.0 (EXACT2) (EXACT 2)

EXercise to Prevent AnthraCycline-based Cardio-Toxicity 2.0 (EXACT2) in Individuals With Breast Cancer

Although great progress has been made in treating breast cancer, long-term health may be impaired by cancer therapy. For example, some chemotherapy drugs (e.g., anthracyclines) are known to cause declines in heart health. While the impact can vary, some will experience substantial heart damage that may lead to heart failure and death. As these treatments are highly effective, there is a need to find ways to reduce the damaging effects while not interfering with its anticancer potential. As it is well-known that regular exercise can improve heart health, the purpose of this study is to explore the role of exercise as a heart protective therapy for breast cancer patients receiving heart damaging chemotherapy.

Study Overview

• Status: Recruiting
• Conditions: Cardiovascular Diseases; Cardiotoxicity; Cancer, Breast
• Intervention / Treatment: Behavioral: Aerobic exercise

Detailed Description

As a result of advances in cancer treatment, the number of breast cancer (BC) survivors is increasing in Canada. Unfortunately, the drugs used to treat BC can have a negative impact on the long term health and welfare of the BC survivors (BCS). For example, commonly used cancer therapies, such as anthracyclines (AC) are known to cause declines in heart health. While the impact can vary, some individuals treated with these medications will experience substantial heart damage that may lead to heart failure and death. As a result, risk of cardiovascular morbidity/mortality has become a major concern for BCS that received AC treatment. As a result, there is an immediate need to find therapies that can be used to prevent damage to the heart without limiting the anticancer potential of AC.

A growing body of evidence suggests that aerobic exercise training may help protect the heart against the damaging effects of AC therapy. These studies, which were conducted using animal models, have shown that performing aerobic exercise before or while undergoing AC therapy helps to maintain heart function and prevent structural changes in the heart. However, to the author's knowledge similar studies have not been conducted in BCS undergoing treatment, thus it remains unclear whether exercise has the same cardioprotective effect in BCS. As a first step in answering this question, our research group conducted a pilot study that showed a 12-week aerobic exercise program is safe and feasible for BCS undergoing chemotherapy. The next step in our research is to determine whether aerobic exercise decreases or prevents cardiotoxicity in BCS receiving AC treatment. Therefore, the purpose of this study is to determine whether a 12-week home based aerobic exercise program mitigates AC-mediated cardiotoxicity in BCS on active treatment. The specific objectives of the study are to determine whether the aerobic exercise program: 1) prevents structural and functional changes in the heart; 2) maintains peak aerobic capacity throughout the treatment process; and 3) decreases biological markers associated with heart damage.

This is a randomized control trial with repeated measures. BCSs will be randomly assigned to either the wait-list control (CTL) group (standard of care (SOC) or the aerobic exercise (AEX; SOC + 12-week home-based aerobic exercise program). One hundred BCS (18-65 years of age) on AC treatment will be recruited from two sites, Halifax, NS (n=50) and Winnipeg, MB (n=50). Patients in the AEX group will perform two exercise sessions per week that will range from low intensity (~45 min) to vigorous intensity (~20 min). BCS will monitor their exercise intensity with Polar A370 HR monitors, which they will be given for the duration of the study.The primary outcome measure for the study is cardiac function as determined by echocardiography and a cardiac stress test. Secondary outcome measures include serum biomarkers associated with cardiotoxicity (e.g. c-reactive protein, hsTNT, NT-proBNP). Patient-reported outcomes including levels of fatigue and quality of life will also be assessed. The study outcome measures will be assessed prior to the participants starting AC therapy (week-0), post-exercise intervention (week-12) and 6 months after the completion of the AEX. Of note, upon completion of the 6 month follow-up testing participants in the CTL group, if interested, will be given the home-based AEX as well the necessary support to complete the program.

This research will provide the first direct evidence that aerobic exercise protects the heart from AC-mediated damage in BCS undergoing cancer treatment. Both the medical and research communities will benefit from this research as it could lead to the improvement of long term health of cancer survivorship as well as improve the understanding of how the heart health can be maintained during cancer therapy. Given the significant impact of AC therapy on improving BC prognosis, and the potential protective effects of exercise training, this study will be important in improving BC care via the improvement of the quality of life and increased survivorship.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Scott A Grandy, PhD; Phone Number: 902-494-4303; Email: scott.grandy@dal.ca

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
      • Not yet recruiting
      • St. Boniface Hospital
      • Contact: Davinder S Jassal, MD; Phone Number: 204-233-8563; Email: djassal@sbgh.mb.ca
      • Sub-Investigator: Davinder S Jassal, MD
      • Sub-Investigator: Thang Nguyen, MD
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V8
      • Recruiting
      • QEII Health Sciences Centre
      • Contact: Scott A Grandy, PhD; Phone Number: 902-494-4303; Email: scott.grandy@dal.ca
      • Principal Investigator: Scott A Grandy, PhD
      • Sub-Investigator: Melanie R Keats, PhD
      • Sub-Investigator: Tallal Younis, MD
      • Sub-Investigator: Nicholas Giacomantonio, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• 1) must be 18 years or older.
• diagnosed with breast cancer (stages I-III) and not have started therapy.
• must be scheduled to receive AC- based chemotherapy (minimum dose of 240 mg/m2 of DOX or 300 mg/m2 of DAN).
• are able to undertake a 12-week home-based, progressive aerobic exercise program.
• have medical clearance from a cardiologist (e.g. based on stress test results) to participate in the study.

Exclusion Criteria:

• significant cognitive limitations.
• pre-existing medical condition that would otherwise contraindicate aerobic exercise.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; Participants will receive standard of care treatment for their breast cancer.
Experimental: Exercise; Participants will receive standard of care treatment for their breast cancer plus be given a 12-week home based aerobic exercise program.	Behavioral: Aerobic exercise; All participants will receive standard of care for their cancer as well as given a 12-week, home-based progressive aerobic exercise (AE) program. A nonlinear progressive training approach will be used whereby each participant will perform two AE sessions (e.g. walking), on non-consecutive days, per week. AE sessions will vary between low (35-45% heart rate reserve (HRR)), low-moderate (46-55% HRR), high-moderate (56-70% HRR) and high (71-85% HRR) intensity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Left Ventricular (LV) Function	LV function will be assessed using serial transthoracic echocardiography (TTE) as well as tissue velocity imaging (TVI) and strain imaging (SI.) For 2-dimensional (2D) LV cavity dimensions and LVEF will be determined from the acquired 2D images according to established criteria. Tissue Doppler-derived indexes will be recorded at the base of the lateral mitral annuli to determine longitudinal endocardial velocities. The indexes that will be assessed are systolic (S'), early diastolic (e') and late diastolic (a') velocities. Doppler-independent strain will be assessed offline using semi-automated speckle tracking techniques. These will be performed using parasternal and apical views to determine both global longitudinal and radial strain.	LV function will be assessed at baseline (week 0), post-intervention (week-13) and 6 months after the completion of the intervention.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cardiac Electrical Activity	Cardiac electrocardiogram at rest will be assessed using a 12 lead ECG (General Electric Case System). Specifically, the duration (ms) of the PR interval, RR interval, QRS interval and QT interval will be determined.	The cardiac ECG will be assessed at baseline (week 0), post-intervention (week-13) and 6 months after the completion of the intervention.
Change in Aerobic Fitness	Cardiac Stress Tests results will be used to predict peak oxygen consumption (ml/kg/min). In brief, participants will perform a graded exercise test until they reach volitional fatigue or the test is terminated due to adverse physiological changes. Predictive equations will then be used to predict the participant's peak oxygen uptake based on the total duration (seconds) of the treadmill test.	Outcome will be assessed at baseline (week 0), post-intervention (week-13) and 6 months after the completion of the intervention.
Change in Blood biomarkers	Venipuncture will be performed by a nurse/phlebotomist to collect blood samples which will be used to quantify systemic levels of c-reactive protein (CRP), high sensitivity troponin (hs-TNT) and NTproBNP levels. Upon collection, blood samples will be processed, and the serum will be extracted and stored at -20°C until it is required for analysis. CRP, hs-TNT and N-terminal pro b-type natriuretic peptide (NTproBNP) levels will be assessed using commercially available ELISA kits. All biomarkers will be measured in pg/ml.	Outcome will be assessed at baseline (week 0), post-intervention (week-13) and 6 months after the completion of the intervention.
Change in Functional Assessment for Cancer Therapy	The Functional Assessment for Cancer Therapy survey for patients with breast cancer (FACT-B) will be used to assess quality of life. The FACT-B includes sub-scales for assessing physical, social/family, emotional, and functional well-being. FACT-B total score ranges from 0-148.	Outcome will be assessed at baseline (week 0), post-intervention (week-13) and 6 months after the completion of the intervention.
Change in Fatigue	The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) is a 13 item questionnaire (maximum score =160) that will be used to assess cancer-related fatigue. Higher scores are indicative of higher levels of fatigue.	Outcome will be assessed at baseline (week 0), post-intervention (week-13) and 6 months after the completion of the intervention.

Collaborators and Investigators

• Sponsor: Nova Scotia Health Authority
• Collaborators: Canadian Institutes of Health Research (CIHR); Canadian Cancer Society (CCS)

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2019
• Primary Completion (Anticipated): June 30, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: November 13, 2018
• First Submitted That Met QC Criteria: November 19, 2018
• First Posted (Actual): November 21, 2018

Study Record Updates

• Last Update Posted (Estimate): December 6, 2022
• Last Update Submitted That Met QC Criteria: December 2, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Aerobic exercise; Breast cancer; Anthracyclines; Cardiotoxic; Cardiac structure; Cardiac function; CVD risk
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Heart Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Wounds and Injuries; Breast Diseases; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Cardiovascular Diseases; Breast Neoplasms; Cardiotoxicity
• Other Study ID Numbers: 1024489 (Other Identifier: Nova Scotia Health Authority)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No