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| Name | Class |
|---|---|
| Centre hospitalier de l'Université de Montréal (CHUM) | OTHER |
| Queen Elizabeth II Health Sciences Centre | OTHER |
| Alberta Health services | OTHER |
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Pediatric, adolescent and young adult cancer survivors (PAYA-CS) are at higher risk of cardiovascular (CV) morbidity and mortality. This is a consequence of prior cancer-related therapies that have the potential of producing cardiac dysfunction, reducing cardiorespiratory fitness (reduced VO2peak) and psychosocial morbidities (i.e., anxiety and depression). A reduction of physical activity levels can evoke functional limitations resulting in a vicious cycle of reduced exercise tolerance and physical deterioration. To date, there is limited evidence on the use of non-pharmacological strategies such as Cardio-Oncology Rehabilitation (CORE) including structured exercise, behavioural support and risk factor management to improve the outcomes of this underserved population. The HIMALAYAS study is a randomized controlled trial designed to evaluate the impact of a CORE intervention (consisting of six-months home and onsite-based structured moderate to high-intensity aerobic exercise training and CVD risk factor management) on CV and psychosocial health, and the cardiovascular disease risk in PAYA-CS with mild heart dysfunction (stage B heart failure) compared to standard of care (i.e. providing guidance on the current exercise recommendations for cancer survivors). The primary objective of the HIMALAYAS study is to determine whether a six-month supervised CORE intervention, consisting of individualized moderate to high-intensity aerobic exercise training, CVD risk factor modification and enhanced online behavioral support, improves cardiorespiratory fitness (VO2peak; primary outcome), cardiac function, CVD risk factors and biomarkers, and patient-reported outcomes (PROs) at six- months follow-up compared to standard of care (CON) in PAYA-CS with stage B heart failure. The secondary objective is to assess the same outcomes at 12- and 24-months follow-up. We will recruit 336 patients across 5 sites in Canada and upto 134 patients at UHN in 3 years and conclude in 6 years.
Over 90,000 North Americans are diagnosed with cancer before the age of 40. Improved cancer therapies have led to an exponential growth in the number of pediatric, adolescent, and young adult cancer survivors (AYA-CS) who are expected to live 50-60 years beyond diagnosis. However, AYA-CS are at increased risk of developing multiple cancer- and treatment-related morbidities including poor fitness (e.g., low VO2peak), hypertension (HTN), diabetes, and poor mental health, which all contribute to premature cardiovascular disease (CVD). The prevalence of CVD events (e.g. heart failure, heart attack, stroke) is up to 23.8% in adult survivors of pediatric cancers with long term follow-up after treatment. The incidence of subclinical CVD, which is a precursor to CVD events, is even higher in AYA-CS; up to 40%, 11%, and 5% experience subclinical cardiomyopathy measured by abnormal global longitudinal strain (GLS), diastolic dysfunction (DD) or mild reduction in left ventricular ejection fraction (LVEF), respectively, and 18% experience reduced aerobic fitness. The treatment of modifiable CVD risk factors must be considered a fundamental target for improving CVD health-related outcomes in AYA-CS. To this end, exercise and best-practices for CVD risk factor modification are integral to a cardiac rehabilitation model. Traditional cardiac rehabilitation models for patients with CVD (consisting of exercise, CVD risk factor treatment, and patient education) are safe and effective in improving HRQoL, morbidity, and mortality risk. However, by virtue of their age and low short-term CVD risk, AYA-CS do not meet traditional criteria for initiating cardiac rehabilitation (CR) and are less likely to receive treatments to reduce CVD risk. AYA-CS with stage B heart failure (SBHF): (1) are at high risk for subsequent HF/CVD death; (2) have lower cardiopulmonary fitness; and (3) are more likely to benefit from CVD risk factor management. Considering that AYA-CS have an estimated 33% prevalence of SBHF, this vulnerable cohort of cancer survivors represent an opportunity for intervention that is highly feasible and potentially impactful. Exercise is a preferred method for optimizing health and survival in PAYA-CS. However, we need models that safely and effectively deliver exercise interventions that meet the unique needs of this population. The cardio-oncology rehabilitation (CORE) model is an intervention that would provide AYA-CS with SBHF a supervised and home-based high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) exercise therapy, CVD risk factor modification, and behavioural support to reduce the risk of CVD. The primary objective of the HIMALAYAS study is to determine whether supervised CORE (Group 1A) improves cardiorespiratory fitness (VO2peak; primary outcome), cardiac function, CVD risk factors and biomarkers, and PROs at 6 months (primary timepoint) as well as 12 and 24 months compared to standard of care group control group (CON) in AYA-CS with SBHF.
The secondary objective of the study is to assess the ongoing behavioural support strategy based on the exercise guidelines for cancer survivors (i.e. 90 to 150 minutes of moderate to vigorous PA per week) on VO2peak, cardiac function, CVD risk factors and biomarkers, and PROs at 24 months compared to standard of care [CON] in AYA-CS with SBHF. Due to the COVID-19 pandemic, CORE intervention will involve a facility-based HIIT session and home-based HIIT session (described as "HIIT at Home") per week.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cardio-Oncology Rehabilitation (CORE) | Experimental | Participants in the CORE group will have
CORE participants will be provided a wrist-worn heart and physical activity monitor to use throughout the 24-month observation period. |
|
| Standard of Care (CON) | No Intervention | Participants in the CON group will receive standard medical care and physical activity will be monitored by a wrist-worn activity tracker for 2 years. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cardio-oncology Rehabilitation (CORE) | Behavioral | Exercise therapy, CVD risk factor management for the first 6 months (as per current standards in CR models) and behavioural support for the entire 2-year intervention period |
| Measure | Description | Time Frame |
|---|---|---|
| Cardiorespiratory fitness | Assessed via cardiopulmonary exercise test and quantified as VO2peak | Baseline to 6-month follow-up (Primary RCT) |
| Measure | Description | Time Frame |
|---|---|---|
| Cardiorespiratory fitness | Assessed via cardiopulmonary exercise test and quantified as VO2peak | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Ventilatory threshold | Estimated using the V-slope method and according to the following criteria: i) an exaggerated response in the volume of carbon-dioxide (i.e., VCO2) relative to the volume of oxygen (i.e., VO2), and ii) the first identifiable break-point in in the minute ventilation (i.e., VE/VO2 vs work rate relationship). |
| Measure | Description | Time Frame |
|---|---|---|
| Therapeutic alliance | Measured using the Working Alliance Inventory Short-Revised (WAI-SR) form. | Baseline to 6-month follow-up (Primary RCT) |
| Testing Performance | Defined as the percent of tests that achieve 'peak' termination criteria relative to the total number of tests completed across all time points |
Inclusion Criteria:
Be a PAYA-CS, defined as ≤39 years of age at the time of cancer diagnosis;
Be 18-45 years of age at the time of enrolment;
Received cancer treatment(s) with known cardiovascular risks (e.g., anthracyclines, trastuzumab, radiotherapy, platinum-based agents, vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors);
Be cancer-free at the time of enrollment;
Stage B Heart Failure (SBHF)
In patients with availability of pre-treatment imaging:
No pre-treatment imaging:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Paaladinesh Thavendiranathan, MD | Contact | 416-340-5326 | dinesh.thavendiranathan@uhn.ca | |
| Nilina Mohabir, MSc | Contact | 437-677-7491 | nilina.mohabir@uhn.ca |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Health Network | Recruiting | Toronto | Ontario | M5G2C4 | Canada |
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| Vancouver General Hospital |
| OTHER |
| Université de Montréal | OTHER |
| Dalhousie University | OTHER |
| University of Alberta | OTHER |
| University of British Columbia | OTHER |
| University of Toronto | OTHER |
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| Baseline to 6-month follow-up (Primary RCT) |
| Ventilatory threshold | Estimated using the V-slope method and according to the following criteria: i) an exaggerated response in the volume of carbon-dioxide (i.e., VCO2) relative to the volume of oxygen (i.e., VO2), and ii) the first identifiable break-point in in the minute ventilation (i.e., VE/VO2 vs work rate relationship). | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Anaerobic threshold | Estimated according to the three-criterion discrimination technique: i) an excess VCO2 response relative to the VO2 response identified per the modified V-slope criteria; ii) the VE/VO2 to VO2 relationship having been flat or decreasing begins to increase without returning to baseline; and iii) there is no reciprocal decrease in PETCO2 at the point where PETO2 starts to rise systematically. | Baseline to 6-month follow-up (Primary RCT) |
| Anaerobic threshold | Estimated according to the three-criterion discrimination technique: i) an excess VCO2 response relative to the VO2 response identified per the modified V-slope criteria; ii) the VE/VO2 to VO2 relationship having been flat or decreasing begins to increase without returning to baseline; and iii) there is no reciprocal decrease in PETCO2 at the point where PETO2 starts to rise systematically. | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Post-exercise heart rate recovery | One-minute HR recovery (HRR; an index of post-exercise parasympathetic reactivation) will be calculated as the HR-difference between peak exercise and following one minute of quiet standing on the treadmill immediately post-test. | Baseline to 6-month follow-up (Primary RCT) |
| Post-exercise heart rate recovery | One-minute HR recovery (HRR; an index of post-exercise parasympathetic reactivation) will be calculated as the HR-difference between peak exercise and following one minute of quiet standing on the treadmill immediately post-test. | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Left ventricular ejection fraction (LVEF) | Assessed via 2D and 3D echocardiography | Baseline to 6-month follow-up (Primary RCT) |
| Left ventricular ejection fraction (LVEF) | Assessed via 2D and 3D echocardiography | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Global longitudinal strain (GLS) | Assessed via 2D echocardiography | Baseline to 6-month follow-up (Primary RCT) |
| Global longitudinal strain (GLS) | Assessed via 2D echocardiography | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Early (E) and late (A) diastolic mitral inflow velocities and deceleration time | Assessed via echocardiography | Baseline to 6-month follow-up (Primary RCT) |
| Early (E) and late (A) diastolic mitral inflow velocities and deceleration time | Assessed via echocardiography | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Early diastolic mitral septal and lateral annular velocities (e') | Assessed via tissue Doppler imaging (TDI) | Baseline to 6-month follow-up (Primary RCT) |
| Early diastolic mitral septal and lateral annular velocities (e') | Assessed via tissue Doppler imaging (TDI) | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| TR velocity | Assess via spectral Doppler | Baseline to 6-month follow-up (Primary RCT) |
| TR velocity | Assess via spectral Doppler | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Left atrial volume | Assess via 2D echocardiography | Baseline to 6-month follow-up (Primary RCT) |
| Left atrial volume | Assess via 2D echocardiography | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Diastolic function - E/e' ratio | Calculated using the average of the TDI septal and lateral annular velocities (e') | Baseline to 6-month follow-up (Primary RCT) |
| Diastolic function - E/e' ratio | Calculated using the average of the TDI septal and lateral annular velocities (e') | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Left ventricular hypertrophy | Assessed via Devereux formula and quantified as LV mass/body surface area: >95 g/m2 for women or >115 g/m2 for men | Baseline to 6-month follow-up (Primary RCT) |
| Left ventricular hypertrophy | Assessed via Devereux formula and quantified as LV mass/body surface area: >95 g/m2 for women or >115 g/m2 for men | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Concentric cardiac remodeling | Assessed as >0.42 relative wall thickness | Baseline to 6-month follow-up (Primary RCT) |
| Concentric cardiac remodeling | Assessed as >0.42 relative wall thickness | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Resting heart rate | Measured with an average of 2 readings taken via ECG during the resting period during the cardiac screening procedures. | Baseline to 6-month follow-up (Primary RCT) |
| Resting heart rate | Measured with an average of 2 readings taken via ECG during the resting period during the cardiac screening procedures. | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Resting systolic and diastolic blood pressure | Calculated as average of 3 readings measured via automated sphygmomanometer per the Hypertension Canada guidelines. | Baseline to 6-month follow-up (Primary RCT) |
| Resting systolic and diastolic blood pressure | Calculated as average of 3 readings measured via automated sphygmomanometer per the Hypertension Canada guidelines. | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Apolipoprotein B | Assessed via blood serum sample | Baseline to 6-month follow-up (Primary RCT) |
| Apolipoprotein B | Assessed via blood serum sample | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Total cholesterol | Assessed via blood serum sample | Baseline to 6-month follow-up (Primary RCT) |
| Total cholesterol | Assessed via blood serum sample | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Low density lipoprotein | Assessed via blood serum sample | Baseline to 6-month follow-up (Primary RCT) |
| Low density lipoprotein | Assessed via blood serum sample | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| High density lipoprotein | Assessed via blood serum sample | Baseline to 6-month follow-up (Primary RCT) |
| High density lipoprotein | Assessed via blood serum sample | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Whole body insulin sensitivity | Assessed via Matsuda index | Baseline to 6-month follow-up (Primary RCT) |
| Whole body insulin sensitivity | Assessed via Matsuda index | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Hepatic insulin sensitivity | Assessed via homeostasis model assessment insulin resistance (HOMA-IR) | Baseline to 6-month follow-up (Primary RCT) |
| Hepatic insulin sensitivity | Assessed via homeostasis model assessment insulin resistance (HOMA-IR) | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Pancreatic beta-cell function | Assessed via the insulin secretion-sensitivity index-2 (ISSI-2) | Baseline to 6-month follow-up (Primary RCT) |
| Pancreatic beta-cell function | Assessed via the insulin secretion-sensitivity index-2 (ISSI-2) | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Body mass index | Calculated as body weight (kg) divided by height (m) squared | Baseline to 6-month follow-up (Primary RCT) |
| Body mass index | Calculated as body weight (kg) divided by height (m) squared | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Objective physical activity | Objectively assessed via wrist-worn physical activity/heart rate monitor to measure the intensity and duration of all planned and unplanned exercise during the study period | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Subjective physical activity | Subjectively assessed via Godin Leisure Time Physical Activity Questionnaire and reported as moderate-to-vigorous intensity physical activity (MVPA) | Baseline to 6-month follow-up (Primary RCT) |
| Subjective physical activity | Subjectively assessed via Godin Leisure Time Physical Activity Questionnaire and reported as moderate-to-vigorous intensity physical activity (MVPA) | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Social support | Measured using the Social Support Survey-Clinical (SSS-C) form, a 5-item survey designed to measure five dimensions of social support + a single item to assess cancer-specific social support. | Baseline to 6-month follow-up (Primary RCT) |
| Social support | Measured using the Social Support Survey-Clinical (SSS-C) form, a 5-item survey designed to measure five dimensions of social support + a single item to assess cancer-specific social support. | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Exercise self-efficacy | Measured using the Multidimensional Self-Efficacy for Exercise Scale (MSES) to measure three behavioural subdomains: task, scheduling, and coping | Baseline to 6-month follow-up (Primary RCT) |
| Exercise self-efficacy | Measured using the Multidimensional Self-Efficacy for Exercise Scale (MSES) to measure three behavioural subdomains: task, scheduling, and coping | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Anxiety | Measured using the Generalized Anxiety Disorder (GAD-7), a 7-item inventory that assesses 2-week anxiety symptom frequency on a 0-3 scale, with higher scores reflecting higher symptom frequency. A cut-off of ≥10 indicates some degree of clinical anxiety. | Baseline to 6-month follow-up (Primary RCT) |
| Anxiety | Measured using the Generalized Anxiety Disorder (GAD-7), a 7-item inventory that assesses 2-week anxiety symptom frequency on a 0-3 scale, with higher scores reflecting higher symptom frequency. A cut-off of ≥10 indicates some degree of clinical anxiety. | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Depression | Measured using the Patient Health Questionnaire (PHQ-9), a 9-item inventory that assesses 2-week depressive symptom frequency on a 0-3 scale, with higher scores reflecting higher symptom frequency. The PHQ-9 has been validated in cancer survivors using a cut-off of ≥8 to indicate some degree of clinical depression. | Baseline to 6-month follow-up (Primary RCT) |
| Depression | Measured using the Patient Health Questionnaire (PHQ-9), a 9-item inventory that assesses 2-week depressive symptom frequency on a 0-3 scale, with higher scores reflecting higher symptom frequency. The PHQ-9 has been validated in cancer survivors using a cut-off of ≥8 to indicate some degree of clinical depression. | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Health-related quality of life | Measured using the Medical Outcomes Survey Short-Form (SF-12). | Baseline to 6-month follow-up (Primary RCT) |
| Health-related quality of life | Measured using the Medical Outcomes Survey Short-Form (SF-12). | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Health service utilization | Measured using the Health Service Utilization Inventory. | Baseline to 6-month follow-up (Primary RCT) |
| Health service utilization | Measured using the Health Service Utilization Inventory. | Baseline to 24-month follow-up (Primary and Secondary RCTs) |
| Study initiation to end of 66-month study period (Primary and Secondary RCTs) |
| Serious and non-serious adverse events | Defined as the number and frequency of testing-, intervention-, and non-intervention-related serious (i.e. Grade 3 to 5; NCI-CTCAE criteria) and non-serious (i.e. Grade 1 to 2; NCI-CTCAE criteria) | Study initiation to end of 66-month study period (Primary and Secondary RCTs) |
| Exercise Adherence | This variable applies only to CORE participants. Exercise adherence is defined as the relative dose intensity (i.e. the percent of total dose of exercise performed, relative to the total dose prescribed) and quantified according to metabolic equivalents. | Study initiation to end of 48-month phase I intervention period (Primary RCT - CORE participants) |
| Medication Compliance | Defined as the percent of pharmaceutical doses taken based on the total number of doses prescribed (applicable only to those that are provided pharmaceutical therapy for CVD risk factor modification) | Study initiation to end of 48-month phase I intervention period (Primary RCT - CORE participants) |
| Behavioural Compliance | Defined as the percent of behavioural support resources accessed, based on the number recommended (one per month) | Study initiation to end of 66-month study period (Primary RCTs - CORE participants) |
| Oxygen utilization during HIIT | Quantified as timepoint measures of oxygen utilization assessed via portable metabolic measurement system within the final 30 seconds of the warm-up, work and recovery periods, and the cool down during pre-specified high-intensity interval training sessions | Study initiation to end of 48-month phase I intervention period (CORE substudy participants; Primary RCT) |
| Power output during HIIT | Quantified as power output (watts) assessed cycle ergometer within the final 30 seconds of the warm-up, work and recovery periods, and the cool down during pre-specified high-intensity interval training sessions | Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT) |
| Heart rate response during HIIT | Quantified via heart rate monitor or single-lead ECG within the final 30 seconds of the warm-up, work and recovery periods, and the cool down during pre-specified high-intensity interval training sessions | Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT) |
| Energy expenditure during HIIT | Quantified as total metabolic equivalent of task following HIIT sessions | Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT) |
| Perceived exertion during HIIT | Assessed via rating of perceived exertion scale (6-20) within the final 30 seconds of the warm-up, work and recovery periods, and the cool down during pre-specified high-intensity interval training sessions | Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT) |
| Felt arousal during HIIT | Affective arousal is evaluated via the felt arousal scale that assesses energy/arousal level on a scale of 1 (low arousal) to 6 (high arousal) within the final 30 seconds of the warm-up, work and recovery periods, and the cool down during pre-specified HIIT sessions | Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT) |
| Feeling affect during HIIT | The feeling scale is used to assess affective valence (pleasure/displeasure; feeling good/bad) on a scale of -5 (vey bad) to +5 (very good) within the final 30 seconds of the warm-up, work and recovery periods, and the cool down during pre-specified high-intensity interval training sessions | Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT) |
| Resilience | Measured using the Brief Relilience Scale (BRS), a 6-item inventory that assesses recovery, resistance, adaptation, and thriving. | Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT) |
| Stress | Measured using two items based on the Canadian Community Health Survey assessing the average daily stress experienced that day and over the past week. | Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT) |
| Feeling states | Assessed via ecological momentary assessments using brief reports completed 6 times a day on intervention weeks 1, 7, 16, 22, four weeks post intervention, and 26 weeks post intervention | Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT) |
| ID | Term |
|---|---|
| D006333 | Heart Failure |
| D066126 | Cardiotoxicity |
| D009369 | Neoplasms |
| D001519 | Behavior |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D064420 | Drug-Related Side Effects and Adverse Reactions |
| D064419 | Chemically-Induced Disorders |
| D011832 | Radiation Injuries |
| D014947 | Wounds and Injuries |
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