Clinical trial NCT05023785: The HIMALAYAS Trial and Lifestyle Changes in Pediatric, Adolescent and Young Adult Cancer Survivors Study: A Multicentre Randomized Controlled Trial
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Heart Failure
Cardiotoxicity
Cancer
Keywords: Adolescents and Young Adults
Exercise Therapy
Behavioral and Peer Support
Cardiac Rehabilitation
Cancer Survivor
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Centre hospitalier de l'Université de Montréal (CHUM)
name: Queen Elizabeth II Health Sciences Centre
name: Alberta Health services
name: Vancouver General Hospital
name: Université de Montréal
name: Dalhousie University
name: University of Alberta
name: University of British Columbia
name: University of Toronto
First posted: 2021-08-27
Enrollment: 336
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.

Eligibility criteria: 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

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.

Primary outcomes:
measure: Cardiorespiratory fitness
timeFrame: Baseline to 6-month follow-up (Primary RCT)
Secondary outcomes:
measure: Cardiorespiratory fitness
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Ventilatory threshold
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Ventilatory threshold
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Anaerobic threshold
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Anaerobic threshold
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Post-exercise heart rate recovery
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Post-exercise heart rate recovery
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Left ventricular ejection fraction (LVEF)
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Left ventricular ejection fraction (LVEF)
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Global longitudinal strain (GLS)
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Global longitudinal strain (GLS)
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Early (E) and late (A) diastolic mitral inflow velocities and deceleration time
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Early (E) and late (A) diastolic mitral inflow velocities and deceleration time
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Early diastolic mitral septal and lateral annular velocities (e')
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Early diastolic mitral septal and lateral annular velocities (e')
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: TR velocity
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: TR velocity
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Left atrial volume
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Left atrial volume
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Diastolic function - E/e' ratio
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Diastolic function - E/e' ratio
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Left ventricular hypertrophy
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Left ventricular hypertrophy
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Concentric cardiac remodeling
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Concentric cardiac remodeling
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Resting heart rate
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Resting heart rate
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Resting systolic and diastolic blood pressure
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Resting systolic and diastolic blood pressure
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Apolipoprotein B
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Apolipoprotein B
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Total cholesterol
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Total cholesterol
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Low density lipoprotein
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Low density lipoprotein
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: High density lipoprotein
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: High density lipoprotein
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Whole body insulin sensitivity
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Whole body insulin sensitivity
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Hepatic insulin sensitivity
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Hepatic insulin sensitivity
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Pancreatic beta-cell function
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Pancreatic beta-cell function
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Body mass index
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Body mass index
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Objective physical activity
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Subjective physical activity
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Subjective physical activity
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Social support
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Social support
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Exercise self-efficacy
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Exercise self-efficacy
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Anxiety
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Anxiety
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Depression
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Depression
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Health-related quality of life
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Health-related quality of life
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
measure: Health service utilization
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Health service utilization
timeFrame: Baseline to 24-month follow-up (Primary and Secondary RCTs)
Other outcomes:
measure: Therapeutic alliance
timeFrame: Baseline to 6-month follow-up (Primary RCT)
measure: Testing Performance
timeFrame: Study initiation to end of 66-month study period (Primary and Secondary RCTs)
measure: Serious and non-serious adverse events
timeFrame: Study initiation to end of 66-month study period (Primary and Secondary RCTs)
measure: Exercise Adherence
timeFrame: Study initiation to end of 48-month phase I intervention period (Primary RCT - CORE participants)
measure: Medication Compliance
timeFrame: Study initiation to end of 48-month phase I intervention period (Primary RCT - CORE participants)
measure: Behavioural Compliance
timeFrame: Study initiation to end of 66-month study period (Primary RCTs - CORE participants)
measure: Oxygen utilization during HIIT
timeFrame: Study initiation to end of 48-month phase I intervention period (CORE substudy participants; Primary RCT)
measure: Power output during HIIT
timeFrame: Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT)
measure: Heart rate response during HIIT
timeFrame: Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT)
measure: Energy expenditure during HIIT
timeFrame: Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT)
measure: Perceived exertion during HIIT
timeFrame: Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT)
measure: Felt arousal during HIIT
timeFrame: Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT)
measure: Feeling affect during HIIT
timeFrame: Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT)
measure: Resilience
timeFrame: Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT)
measure: Stress
timeFrame: Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT)
measure: Feeling states
timeFrame: Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT)
Locations:
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
Study officials:
References: