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CORE consists of exercise therapy, CVD risk factor management, and behavioural support for 3 months.

Exercise therapy: Staff will prescribe and deliver a standardized, yet individually tailored (based on CPET results), aerobic exercise programs consisting of two days of supervised, facility- and home-based high-intensity interval training (HIIT) and one day of supervised home-based moderate-intensity continuous training (MICT) per week. Exercise HRs and durations will be monitored using an accurate commercially available wrist-worn HR monitor and PA tracker.

CVD risk factor management: CVD risk factors will be assessed and treated according to Canadian guidelines.

Behavioural support: All participants will receive a planned sequence of educational and instructional material via email and ongoing PAYA-CS tailored education and peer support during the follow-up period using a peer support online system.

The Support group will receive the behavioural support only. The timing and nature of all education, information provided to Support participants will be identical to what is provided to CORE participants. All Support participants will receive the same wrist-worn HR monitor and PA tracker as the CORE participants and will be given the challenge of meeting and maintaining the updated PA guidelines for cancer survivors (i.e., 90 to 150 minutes of moderate to vigorous intensity PA per week).

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

Cardio-oncology Rehabilitation (CORE)

Behavioural support via professionals and peer support and recommended physical activity guidelines for cancer survivors, to encourage physical activity.

Support

Cardiovascular disease (CVD) is a major contributor to morbidity and mortality in pediatric, adolescent and young adult (AYA) cancer survivors (hereafter referred to as PAYA-CS). Exercise is a cornerstone of CVD prevention and treatment; yet, exercise has not been adopted as a standard of care in PAYA-CS at high CVD risk. The HIMALAYAS trial is designed to evaluate the feasibility and preliminary impact of an exercise-based CR on cardiovascular (CV) and psychosocial health, as well as CVD risk, in PAYA-CS with mild heart dysfunction (stage B heart failure (SBHF)). The primary objective of the HIMALAYAS pilot study is to assess the feasibility of a two-phase randomized controlled trial designed to evaluate impact of a 'CR-like' cardio-oncology rehabilitation (CORE) intervention on CV, psychosocial, and behavioural outcomes at 6 and 24 months, compared to behavioural support only (Support) in PAYA-CS. Screened PAYA-CS without SBHF and those with SBHF who do not participate in the RCT will be enrolled in a passive behavioural support (Support) group. The primary outcome is study feasibility, defined according to three primary criteria (i.e., participant recruitment, safety, and adherence). Secondary outcomes include additional feasibility metrics (e.g., intervention safety and tolerability) and exploratory efficacy outcomes including peak cardiorespiratory fitness (VO2peak), cardiac function (e.g., global longitudinal strain (GLS)), CVD risk factor control (e.g. insulin resistance), and patient-reported outcomes (e.g. anxiety). Our central hypothesis is that the conduct of a larger RCT comparing the impact of CORE versus non-intervention control will be feasible indicated by the achievement of our primary feasibility criteria. Our exploratory hypothesis is that we will generate preliminary evidence that CORE can improve VO2peak, cardiac function, CVD risk factor, and patient-reported outcomes over 6- and 24-month timepoints, relative to control.

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 (PAYA-CS) who are expected to live 50-60 years beyond diagnosis. However, PAYA-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 PAYA-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 PAYA-CS. To this end, exercise and best-practices for CVD risk factor modification are integral to a cardiac rehabilitation (CR) 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, PAYA-CS do not meet traditional criteria for initiating CR and are less likely to receive treatments to reduce CVD risk.

PAYA-CS with stage B heart failure (SB¬HF): (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 PAYA-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 PAYA-CS with SBHF a supervised and home-based exercise therapy, CVD risk factor modification, and behavioural support to reduce the risk of CVD. Nevertheless, due to the ambitious nature of the study, it is vital that we conduct a pilot version of the study to determine the feasibility and needed changes to achieve the best possible results.

The primary objective of the HIMALAYAS pilot study is to assess the feasibility, safety, and tolerability of a (1) two-arm RCT-based comparison of the CORE and Support interventions in PAYA-CS with SBHF, and (2) parallel passive behavioural support (PBS) cohort of PAYA-CS at high-risk of cancer-related CVD. The exploratory objectives of the study include (1) to compare the changes in primary exploratory outcome (VO2peak) and secondary exploratory outcomes (markers of cardiac function, CVD risk factor management, and patient-reported outcomes) between a CORE and Support intervention for PAYA-CS from baseline (T0) to 6-month (T1) follow-up and (2) to compare the changes in the primary and secondary exploratory outcomes between (1) CORE and Support from T0 to 12-month (T2) and 24-month (T3) follow-up, and (2) CORE, Support, and PBS from T0 to T3.

Cardio-oncology Rehabilitation (CORE) Group: CORE consists of 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.

Support Group: The Support group will receive the behavioural support only. The timing and nature of all education, information, and peer support provided to Support participants will be identical to what is provided to CORE participants. The key difference in the long-term behavioural support strategy between CORE and Support participants is how weekly exercise goals are defined. Unlike the CORE participants who will be encouraged to use the personal activity intelligence (PAI) Score, Support participants will be given the challenge of meeting and maintaining the updated physical activity (PA) guidelines for cancer survivors (i.e., 90 to 150 minutes of moderate to vigorous-intensity PA per week).

Passive Behavioural Support (PBS) Groups: All PBS cohort participants will receive the same wrist-worn heart rate monitor and PA tracker as the CORE and Support participants. However, PBS participants will be blindly randomized to one of two passive behavioural support interventions (PBS1 and PBS2). PBS1 participants will be asked to download the same PAI Health application as CORE participants and will similarly be given the challenge of meeting and maintaining a weekly PAI Score ≥100 throughout the 18-month follow-up period. PBS2 participants 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 PA guidelines for cancer survivors (i.e., 90 to 150 minutes of moderate to vigorous intensity PA per week).

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

Measured with an average of 3 readings (after discarding an initial test reading) by an automated measurement device as per the Hypertension Canada guidelines.

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

Measured through fasting cholesterol profile and Apo B levels

Measured through whole-body insulin sensitivity (Matsuda index)

Measured through hepatic insulin sensitivity (HOMA-IR)

Measured through pancreatic beta-cell function (ISSI-2).

Measured through Godin Leisure Time PA Questionnaire (GLTPAQ). Score of \>24 = active, score of 14-23 = moderately active, score of \<14 = insufficiently active

Measured through wrist-worn heart rate with physical activity monitor

Measured using the Social Support Survey-Clinical (SSS-C) form, a 5-item survey designed to measure five dimensions of social support (listening, task challenge, emotional reality confirmation, and tangible assistance); higher score = more social support

Measured using the Multidimensional Self-Efficacy for Exercise Scale (MSES) to measure three behavioural subdomains: task, scheduling, and coping; Scale 0-90, higher score indicates higher self-efficacy for exercise.

Measured using the National Health and Nutrition Examination Survey (NHANES) Food Frequency Questionnaire (FFQ), a 139-item, semi-quantitative inventory to assess the potential influence of dietary changes on primary and secondary outcomes.

Measured using self-reported measures to determine the potential influence of changes in smoking habits on primary and secondary outcomes.

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 Medical Outcomes Survey Short-Form, (SF-12).

Measured using the Working Alliance Inventory Short-Revised (WAI-SR) form. Increased score indicates therapeutic alliance.

Defined as the percent of consenting patients based on the total number of otherwise eligible participants (OEP; patients meeting all eligibility criteria) approached

Defined as the number and frequency of testing- and intervention-related serious adverse events (SAEs) according to the Common Terminology Criteria for Adverse Events

Defined as relative dose intensity as the percent of total dose of exercise performed relative to the total planned dose prescribed and quantified according to metabolic equivalents

Defined as the average number of OEP identified each month

Defined as the percent of consenting patients who successfully complete baseline assessments based on the total number of consenting patients

Defined as the number and frequency of testing- and intervention-related non-serious adverse events

Defined as the percent completion of all cardiopulmonary exercise tests (CPETs) tests at baseline (T0) and primary follow-up (T1)

Defined as the percent of all tests which are adapted for functional or safety reasons

Defined as the percent of all exercise sessions which are adapted for functional or safety reasons

Defined as the percent of patients who discontinue intervention participation prior to the planned end of the intervention period

Defined as the percent of patients who miss =\>3 consecutive sessions within the intervention period

Defined as the percent of exercise sessions requiring a dose reduction during training (i.e., intensity or duration) relative to the total number of sessions completed. Total number of exercise sessions with a reduction in intensity or a reduction in duration will be combined into the numerator when calculating the percentage of affected sessions.

Defined as the percent of exercise sessions requiring unplanned early termination

Defined as the percent of sessions which required pre-exercise modification of the target exercise intensity due to a pre-exercise screening indication (e.g., fatigue, pain)

Defined as the percent of exercise sessions completed based on the total number of sessions prescribed.

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 of doses prescribed

defined as the average number of participants achieving their weekly PA goals of meeting and maintaining either a PAI-Score of ≥100 or weekly cancer exercise guidelines (i.e., 90 to 150 minutes of moderate to vigorous intensity PA per week).

Defined as the percent loss to follow-up (not completing follow-up assessments)

University Health Network, Toronto

Participants in the CORE group will have

1. A personalized, supervised exercise program ((in-person at intuition and virtual/ homebased exercises)
2. CV risk factor management,
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.

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.

Paaladinesh Thavendiranathan, MD

Krishna Mohan Chirra CRC

Krishna Mohan CRC

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.

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 Study: A Multicentre Randomized Controlled Trial

Measured using the Working Alliance Inventory Short-Revised (WAI-SR) form.

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)

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

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

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

Quantified as total metabolic equivalent of task following HIIT sessions

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

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

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

Measured using the Brief Relilience Scale (BRS), a 6-item inventory that assesses recovery, resistance, adaptation, and thriving.

Measured using two items based on the Canadian Community Health Survey assessing the average daily stress experienced that day and over the past week.

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

Assessed via cardiopulmonary exercise test and quantified as VO2peak

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.

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 tissue Doppler imaging (TDI)

Calculated using the average of the TDI septal and lateral annular velocities (e')

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

Assessed as \>0.42 relative wall thickness

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

Assessed via homeostasis model assessment insulin resistance (HOMA-IR)

Assessed via the insulin secretion-sensitivity index-2 (ISSI-2)

Calculated as body weight (kg) divided by height (m) squared

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

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 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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Harmonized Interventions to Maintain Health Via Appropriate Risk Factor Modification and Lifestyle Changes in Pediatric, Adolescent and Young Adult Cancer Survivors Pilot Study	NCT04598646	Heart Failure Cardiotoxicity Cancer	Cardio-oncology... Support	18 Years - 45 Years	University Health Network, Toronto
The HIMALAYAS Trial and Lifestyle Changes in Pediatric, Adolescent and Young Adult Cancer Survivors Study: A Multicentre Randomized Controlled Trial	NCT05023785	Heart Failure Cardiotoxicity Cancer	Cardio-oncology...	18 Years - 45 Years	University Health Network, Toronto
The HIMALAYAS Trial and Lifestyle Changes in Pediatric, Adolescent and Young Adult Cancer Survivors Study: A Multicentre Randomized Controlled Trial	NCT05023785	Heart Failure Cardiotoxicity Cancer	Cardio-oncology...	18 Years - 45 Years	University Health Network, Toronto

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