The HIMALAYAS Trial and Lifestyle Changes in Pediatric, Adolescent and Young Adult Cancer Survivors Study: A Multicentre Randomized Controlled Trial

Study Overview
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Brief Summary
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Cardiovascular disease (CVD) is a major contributor to morbidity and mortality in pediatric, adolescent and young adult (AYA) cancer survivors (hereafter referred to as AYA-CS). Exercise is a cornerstone of CVD prevention and treatment; yet, exercise has not been adopted as a standard of care in AYA-CS at high CVD risk. The HIMALAYAS trial is designed to evaluate the impact of an exercise-based cardiac rehabilitation program on cardiovascular (CV) and psychosocial health, as well as CVD risk, in AYA-CS with mild heart dysfunction (stage B heart failure (SBHF)). The primary objective of the HIMALAYAS study is to determine whether supervised Cardio-oncology Rehabilitation [CORE; Group 1A], consisting of moderate to high-intensity aerobic exercise training, CVD risk factor modification and enhanced online behavioural support, improves cardiorespiratory fitness (VO2peak; primary outcome), cardiac function, CVD risk factors and biomarkers, and patient-reported outcomes (PROs) at 6, 12, and 24 months compared to standard of care [CON1; Group 1B] in AYA-CS with SBHF. Additionally, AYA-CS with and without SBHF will participate in a secondary randomized controlled trial (RCT) to assess the independent effects of two passive behavioural support strategies based on the attainment of the personal activity intelligence (PAI) score [PAI; Group 2A] or the exercise guidelines for cancer survivors [ExGL; Group 2B] on cardiorespiratory fitness, cardiac function, CVD risk factors and biomarkers, and PROs at 24 months compared to standard of care [CON2; Group 2C].

Detailed Description
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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 (CON1; Group 1B) in AYA-CS with SBHF. The secondary objective of the study is to assess the independent effects of two passive behavioural support strategies based on the attainment of a weekly PAI score ≥100 [PAI; Group 2A] or the exercise guidelines for cancer survivors (i.e. 90 to 150 minutes of moderate to vigorous PA per week; [ExGL; Group 2B]) on VO2peak, cardiac function, CVD risk factors and biomarkers, and PROs at 24 months compared to standard of care [CON2; Group 2C] in AYA-CS with and without 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. The study will include a pre-trial pilot and a substudy within the Primary RCT to develop and validate HIIT at Home methods.

Official Title
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The Harmonized Interventions to Maintain Health Via Appropriate Risk Factor Modification and Lifestyle Changes in Pediatric, Adolescent and Young Adult Cancer Survivors (HIMALAYAS) Study

Conditions
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Heart Failure, Cardiotoxicity, Cancer

Intervention / Treatment
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* Behavioral: Cardio-oncology Rehabilitation (CORE)
* Behavioral: PAI Group (PAI)
* Behavioral: Exercise Guidelines for Cancer Survivors (ExGL)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be an AYA-CS, defined as ≤39 years of age at the time of cancer diagnosis; Be ≥18 years of age at the time of enrolment; Received cancer treatment(s) with known cardiovascular risks (e.g. anthracyclines, radiotherapy, trastuzumab, platinum-based agents, vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors) in the previous 5 years; Be cancer-free at the time of enrollment; For Primary RCT: Confirmed diagnosis of SBHF at baseline (LVEF<53/54%, GLS >-18%, left ventricular hypertrophy (LV mass/body surface area: >95 g/m2 for women or >115 g/m2 for men), concentric remodeling (>0.42 relative wall thickness), or diastolic dysfunction (≥ grade 1). Exclusion Criteria: Have an absolute or unresolved relative contraindication to exercise according to the American College of Sports Medicine guidelines; Have an untreated physical or mental health concern that precludes safe and effective exercise participation; Have established CVD (excluding mildly reduced LVEF as described above); Be pregnant at time of recruitment; Be currently engaging in frequent high-intensity exercise (>1 high-intensity exercise session per week); Have substantial barriers to participating, including (1) living too far from study centre or (2) being unable or willing to comply with the study protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cardio-Oncology Rehabilitation (CORE)<br>Participants in the CORE group will have (1) 2 HIIT sessions (1 facility- and 1 home-based) and 1 home-based MICT session, (2) CV risk factor management, and (3) behavioural support for the first 6 months. The behavioural support will continue for CORE participants from months 7-24. Behavioural support includes professionally guided and peer-enhanced exercise behavioural support based on behaviour change stage theories. CORE participants will be provided a wrist-worn heart and physical activity monitor to use throughout the 24-month observation period. After the supervised 6 month exercise period, participants will be asked to maintain a PAI Score of ≥100 for the remainder of the study period via the PAI Health App. | Behavioral: Cardio-oncology Rehabilitation (CORE)<br>* 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<br>|
| No Intervention: Standard of Care 1 (CON1)<br>Participants in the CON1 group will receive standard medical care only. | |
| Active Comparator: PAI Group (PAI)<br>Participants in the PAI group will be asked to download the same PAI Health application as CORE participants and be challenged to meet and maintain a weekly PAI Score ≥100 throughout the 24-month follow-up period. | Behavioral: PAI Group (PAI)<br>* Participants in the PAI group will be asked to download the same PAI Health application as CORE participants and be challenged to meet and maintain a weekly PAI Score ≥100 throughout the 24-month follow-up period.<br>|
| Active Comparator: Exercise Guidelines for Cancer Survivors (ExGL)<br>Participants in the ExGL group will be asked to download and use the Map My Walk (Under Armour, Baltimore) application and will be challenged to meet and maintain the updated weekly physical activity guidelines for cancer survivors (i.e. 90-150 minutes of moderate to vigorous-intensity physical activity). | Behavioral: Exercise Guidelines for Cancer Survivors (ExGL)<br>* Participants in the ExGL group will be asked to download and use the Map My Walk (Under Armour, Baltimore) application and will be challenged to meet and maintain the updated weekly physical activity guidelines for cancer survivors (i.e. 90-150 minutes of moderate to vigorous-intensity physical activity).<br>|
| No Intervention: Standard of Care 2 (CON2)<br>Participants in the CON2 group will receive standard medical care only. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiorespiratory fitness | Assessed via cardiopulmonary exercise test and quantified as VO2peak | Baseline to 6-month follow-up (Primary RCT) | 

Secondary Outcome Measures

| Outcome Measure | 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). | 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 and reported as Personal Activity Intelligence (PAI) Score | Baseline to 6-month follow-up (Primary RCT) | 
| Objective physical activity | Objectively assessed via wrist-worn physical activity/heart rate monitor and reported as Personal Activity Intelligence (PAI) Score | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adolescents and Young Adults, Exercise Therapy, Behavioral and Peer Support, Cardiac Rehabilitation, Cancer Survivor