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

Cancer Clinical Trial

— HIMALAYAS  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05023785
• Other study ID #: 23-5626
• Status: Recruiting
• Phase: N/A
• Start date: January 1, 2024
• Est. completion date: March 2027

Study information

• Verified date: January 2024
• Source: University Health Network, Toronto
• Contact: Paaladinesh Thavendiranathan, MD
• Phone: 416-340-5326
• Email: dinesh.thavendiranathan[@]uhn.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 336
• Est. completion date: March 2027
• Est. primary completion date: September 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cancer
• Cardiotoxicity
• Heart Failure

Intervention

Behavioral:
• Cardio-oncology Rehabilitation (CORE)
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

Locations

Country	Name	City	State
Canada	University Health Network	Toronto	Ontario

Sponsors (10)

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

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Therapeutic alliance	Measured using the Working Alliance Inventory Short-Revised (WAI-SR) form.	Baseline to 6-month follow-up (Primary RCT)
Other	Testing Performance	Defined as the percent of tests that achieve 'peak' termination criteria relative to the total number of tests completed across all time points	Study initiation to end of 66-month study period (Primary and Secondary RCTs)
Other	Serious and non-serious adverse events	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)	Study initiation to end of 66-month study period (Primary and Secondary RCTs)
Other	Exercise Adherence	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.	Study initiation to end of 48-month phase I intervention period (Primary RCT - CORE participants)
Other	Medication Compliance	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)	Study initiation to end of 48-month phase I intervention period (Primary RCT - CORE participants)
Other	Behavioural Compliance	Defined as the percent of behavioural support resources accessed, based on the number recommended (one per month)	Study initiation to end of 66-month study period (Primary RCTs - CORE participants)
Other	Oxygen utilization during HIIT	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)
Other	Power output during HIIT	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)
Other	Heart rate response during HIIT	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)
Other	Energy expenditure during HIIT	Quantified as total metabolic equivalent of task following HIIT sessions	Study initiation to end of 48-month phase I intervention period (CORE sub-study participants; Primary RCT)
Other	Perceived exertion during HIIT	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)
Other	Felt arousal during HIIT	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)
Other	Feeling affect during HIIT	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)
Other	Resilience	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)
Other	Stress	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)
Other	Feeling states	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)
Primary	Cardiorespiratory fitness	Assessed via cardiopulmonary exercise test and quantified as VO2peak	Baseline to 6-month follow-up (Primary RCT)
Secondary	Cardiorespiratory fitness	Assessed via cardiopulmonary exercise test and quantified as VO2peak	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Left ventricular ejection fraction (LVEF)	Assessed via 2D and 3D echocardiography	Baseline to 6-month follow-up (Primary RCT)
Secondary	Left ventricular ejection fraction (LVEF)	Assessed via 2D and 3D echocardiography	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	Global longitudinal strain (GLS)	Assessed via 2D echocardiography	Baseline to 6-month follow-up (Primary RCT)
Secondary	Global longitudinal strain (GLS)	Assessed via 2D echocardiography	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	Early (E) and late (A) diastolic mitral inflow velocities and deceleration time	Assessed via echocardiography	Baseline to 6-month follow-up (Primary RCT)
Secondary	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)
Secondary	Early diastolic mitral septal and lateral annular velocities (e')	Assessed via tissue Doppler imaging (TDI)	Baseline to 6-month follow-up (Primary RCT)
Secondary	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)
Secondary	TR velocity	Assess via spectral Doppler	Baseline to 6-month follow-up (Primary RCT)
Secondary	TR velocity	Assess via spectral Doppler	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	Left atrial volume	Assess via 2D echocardiography	Baseline to 6-month follow-up (Primary RCT)
Secondary	Left atrial volume	Assess via 2D echocardiography	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Concentric cardiac remodeling	Assessed as >0.42 relative wall thickness	Baseline to 6-month follow-up (Primary RCT)
Secondary	Concentric cardiac remodeling	Assessed as >0.42 relative wall thickness	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Apolipoprotein B	Assessed via blood serum sample	Baseline to 6-month follow-up (Primary RCT)
Secondary	Apolipoprotein B	Assessed via blood serum sample	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	Total cholesterol	Assessed via blood serum sample	Baseline to 6-month follow-up (Primary RCT)
Secondary	Total cholesterol	Assessed via blood serum sample	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	Low density lipoprotein	Assessed via blood serum sample	Baseline to 6-month follow-up (Primary RCT)
Secondary	Low density lipoprotein	Assessed via blood serum sample	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	High density lipoprotein	Assessed via blood serum sample	Baseline to 6-month follow-up (Primary RCT)
Secondary	High density lipoprotein	Assessed via blood serum sample	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	Whole body insulin sensitivity	Assessed via Matsuda index	Baseline to 6-month follow-up (Primary RCT)
Secondary	Whole body insulin sensitivity	Assessed via Matsuda index	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	Hepatic insulin sensitivity	Assessed via homeostasis model assessment insulin resistance (HOMA-IR)	Baseline to 6-month follow-up (Primary RCT)
Secondary	Hepatic insulin sensitivity	Assessed via homeostasis model assessment insulin resistance (HOMA-IR)	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	Pancreatic beta-cell function	Assessed via the insulin secretion-sensitivity index-2 (ISSI-2)	Baseline to 6-month follow-up (Primary RCT)
Secondary	Pancreatic beta-cell function	Assessed via the insulin secretion-sensitivity index-2 (ISSI-2)	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	Body mass index	Calculated as body weight (kg) divided by height (m) squared	Baseline to 6-month follow-up (Primary RCT)
Secondary	Body mass index	Calculated as body weight (kg) divided by height (m) squared	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	Objective physical activity	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	Baseline to 24-month follow-up (Primary and Secondary RCTs)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Health-related quality of life	Measured using the Medical Outcomes Survey Short-Form (SF-12).	Baseline to 6-month follow-up (Primary RCT)
Secondary	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)
Secondary	Health service utilization	Measured using the Health Service Utilization Inventory.	Baseline to 6-month follow-up (Primary RCT)
Secondary	Health service utilization	Measured using the Health Service Utilization Inventory.	Baseline to 24-month follow-up (Primary and Secondary RCTs)