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

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

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

Centre hospitalier de l'Université de Montréal (CHUM), Queen Elizabeth II Health Sciences Centre, Alberta Health services, Vancouver General Hospital, Université de Montréal, Dalhousie University, University of Alberta, University of British Columbia, University of Toronto

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].

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.

Adolescents and Young Adults, Exercise Therapy, Behavioral and Peer Support, Cardiac Rehabilitation, Cancer Survivor

Participants in the primary RCT (CORE vs CON1 group) will be randomized with open label. Participants in the secondary RCT (PAI vs ExGL vs CON2) will not be informed that they will be randomized into a passive behavioural support strategy or that there are multiple arms in the RCT. This is to limit bias associated with participants' awareness of their group allocation. Such lack of disclosure will minimally impact participants since participants are at most receiving passive behavioural interventions.

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.

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.

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).

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

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.

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).

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).

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).

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.

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.

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.

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.

Assessed via Devereux formula and quantified as LV mass/body surface area: >95 g/m2 for women or >115 g/m2 for men

Assessed via Devereux formula and quantified as LV mass/body surface area: >95 g/m2 for women or >115 g/m2 for men

Measured with an average of 2 readings taken via ECG during the resting period during the cardiac screening procedures.

Measured with an average of 2 readings taken via ECG during the resting period during the cardiac screening procedures.

Calculated as average of 3 readings measured via automated sphygmomanometer per the Hypertension Canada guidelines.

Calculated as average of 3 readings measured via automated sphygmomanometer per the Hypertension Canada guidelines.

Objectively assessed via wrist-worn physical activity/heart rate monitor and reported as Personal Activity Intelligence (PAI) Score

Objectively assessed via wrist-worn physical activity/heart rate monitor and reported as Personal Activity Intelligence (PAI) Score

Subjectively assessed via Godin Leisure Time Physical Activity Questionnaire and reported as moderate-to-vigorous intensity physical activity (MVPA)

Subjectively assessed via Godin Leisure Time Physical Activity Questionnaire and reported as moderate-to-vigorous intensity physical activity (MVPA)

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.

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.

Measured using the Multidimensional Self-Efficacy for Exercise Scale (MSES) to measure three behavioural subdomains: task, scheduling, and coping

Measured using the Multidimensional Self-Efficacy for Exercise Scale (MSES) to measure three behavioural subdomains: task, scheduling, and coping

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.

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.

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.

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.

Defined as the percent of tests that achieve 'peak' termination criteria relative to the total number of tests completed across all time points

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)

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.

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)

Defined as the percent of behavioural support resources accessed, based on the number recommended (one per month)

Defined as the average number of participants achieving their weekly PA goals of meeting and maintaining either a PAI-Score of ≥100 [PAI] or weekly cancer exercise guidelines [ExGL].

Study initiation to end of 66-month study period (Primary and Secondary RCTs - CORE, PAI and ExGL participants)

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)

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)

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)

Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT)

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)

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)

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)

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)

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)

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)

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.