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

Not Applicable

Recruiting

• Conditions: Heart Failure; Cardiotoxicity; Cancer
• Interventions: Behavioral: Cardio-oncology Rehabilitation (CORE)

• Registration Number: NCT05023785
• Lead Sponsor: University Health Network, Toronto

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2021-04-29
• Study First Submitted QC: 2021-08-19
• Study First Posted: 2021-08-27
• Study Start: 2024-01-01
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-21
• Last Update Posted: 2024-06-24
• Primary Completion: 2026-09
• Study Completion: 2027-03

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 336

Inclusion Criteria

1. Be a PAYA-CS, defined as ≤39 years of age at the time of cancer diagnosis;

2. Be 18-45 years of age at the time of enrolment;

3. Received cancer treatment(s) with known cardiovascular risks (e.g., anthracyclines, trastuzumab, radiotherapy, platinum-based agents, vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors);

4. Be cancer-free at the time of enrollment;

5. Stage B Heart Failure (SBHF)

   • In patients with availability of pre-treatment imaging:

     • ≥10% decrease in LVEF at post-treatment compared to pre-treatment
     • ≥15% decrease in GLS at post-treatment compared to pre-treatment

   • No pre-treatment imaging:

     • LVEF ≤53% in women/51% in men
     • GLS >-18%
     • Left ventricular hypertrophy (LV mass/body surface area: >95 g/m2 for women or >115 g/m2 for men)
     • Concentric remodelling (>0.42 relative wall thickness)
     • Diastolic dysfunction (≥ grade 1)
     • BNP ≥35pg/ml or NT-proBNP ≥125pg/ml

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Exclusion Criteria

1. Have an absolute or unresolved relative contraindication to exercise according to the American College of Sports Medicine guidelines;
2. Have an untreated physical or mental health concern that precludes safe and effective exercise participation;
3. Have established CVD (excluding mildly reduced LVEF as described above);
4. Be pregnant at time of recruitment;
5. Be currently engaging in frequent high-intensity exercise (>1 high-intensity exercise session per week);
6. 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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cardio-Oncology Rehabilitation (CORE)	Cardio-oncology Rehabilitation (CORE)	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.

Primary Outcome Measures

Name	Time	Method
Cardiorespiratory fitness	Baseline to 6-month follow-up (Primary RCT)	Assessed via cardiopulmonary exercise test and quantified as VO2peak

Secondary Outcome Measures

Name	Time	Method
Health service utilization	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Measured using the Health Service Utilization Inventory.
Post-exercise heart rate recovery	Baseline to 24-month follow-up (Primary and Secondary RCTs)	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.
Apolipoprotein B	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed via blood serum sample
Pancreatic beta-cell function	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed via the insulin secretion-sensitivity index-2 (ISSI-2)
High density lipoprotein	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed via blood serum sample
Early diastolic mitral septal and lateral annular velocities (e')	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed via tissue Doppler imaging (TDI)
Resting systolic and diastolic blood pressure	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Calculated as average of 3 readings measured via automated sphygmomanometer per the Hypertension Canada guidelines.
Subjective physical activity	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Subjectively assessed via Godin Leisure Time Physical Activity Questionnaire and reported as moderate-to-vigorous intensity physical activity (MVPA)
Cardiorespiratory fitness	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed via cardiopulmonary exercise test and quantified as VO2peak
Ventilatory threshold	Baseline to 24-month follow-up (Primary and Secondary RCTs)	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).
Left ventricular hypertrophy	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed via Devereux formula and quantified as LV mass/body surface area: \>95 g/m2 for women or \>115 g/m2 for men
Exercise self-efficacy	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Measured using the Multidimensional Self-Efficacy for Exercise Scale (MSES) to measure three behavioural subdomains: task, scheduling, and coping
Total cholesterol	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed via blood serum sample
Whole body insulin sensitivity	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed via Matsuda index
Early (E) and late (A) diastolic mitral inflow velocities and deceleration time	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed via echocardiography
TR velocity	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assess via spectral Doppler
Left atrial volume	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assess via 2D echocardiography
Concentric cardiac remodeling	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed as \>0.42 relative wall thickness
Depression	Baseline to 24-month follow-up (Primary and Secondary RCTs)	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.
Anaerobic threshold	Baseline to 24-month follow-up (Primary and Secondary RCTs)	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.
Left ventricular ejection fraction (LVEF)	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed via 2D and 3D echocardiography
Global longitudinal strain (GLS)	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed via 2D echocardiography
Diastolic function - E/e' ratio	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Calculated using the average of the TDI septal and lateral annular velocities (e')
Resting heart rate	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Measured with an average of 2 readings taken via ECG during the resting period during the cardiac screening procedures.
Low density lipoprotein	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed via blood serum sample
Hepatic insulin sensitivity	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Assessed via homeostasis model assessment insulin resistance (HOMA-IR)
Body mass index	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Calculated as body weight (kg) divided by height (m) squared
Objective physical activity	Baseline to 24-month follow-up (Primary and Secondary RCTs)	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
Health-related quality of life	Baseline to 24-month follow-up (Primary and Secondary RCTs)	Measured using the Medical Outcomes Survey Short-Form (SF-12).
Social support	Baseline to 24-month follow-up (Primary and Secondary RCTs)	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.
Anxiety	Baseline to 24-month follow-up (Primary and Secondary RCTs)	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.

Trial Locations

Locations (1)

University Health Network; 🇨🇦 Toronto, Ontario, Canada