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| Name | Class |
|---|---|
| Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), University of Granada, Spain | UNKNOWN |
| University Hospital Virgen de las Nieves | OTHER |
| Hospital Universitario Clínico San Cecilio |
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STEP-IN is a research study that examines the effects of a physical activity program designed to increase the daily steps and cadence of patients with heart failure, compared to standard medical care, on functional capacity and other markers related to heart and brain health.
The primary hypothesis is that participating in the physical activity program for 9 months will improve functional capacity, the primary clinical measure, significantly more than receiving only the standard medical care in people with heart failure. It is also hypothesized that the physical activity program will have positive effects on symptoms and limitations related to heart failure, inflammation, as well as heart and brain health.
Heart failure is associated with disabling symptoms of dyspnea, fatigue, low exercise tolerance, and frequent hospitalizations. Managing heart failure is challenging, as it often coexists with several comorbidities related to cardiovascular- and brain-health (e.g., hypertension, dyslipidemia, cognitive impairment). Physical activity programs represent a promising adjuvant to pharmacological treatments to improve patients' functional capacity, reduce their symptoms, and facilitate long-term physical activity maintenance as patients' exercise tolerance improves. However, few patients with heart failure attend and adhere to traditional structured exercise programs such as cardiac rehabilitation. In response, the overall objective of STEP-IN is to design and test the effectiveness, feasibility and safety of a real-world, individualized step-based physical activity intervention to improve functional capacity, heart failure symptoms and limitations, systemic inflammation and additional heart-brain outcomes in patients with heart failure.
STEP-IN is a two-arm, single-blind multicenter randomized controlled trial. A total of 200 adults with heart failure with reduced (≤40%) or mildly reduced ejection fraction (41-49%) and a II or III NYHA functional class will be enrolled. Participants will be randomized 1:1 to a 9-month step-based physical activity intervention or enhanced usual care. The intervention will leverage wearable devices and a personalized online platform alongside behavior change methods to progressively increase participants' daily step count (volume) and step cadence (intensity), with increments individually planned every 2 weeks. To test the effectiveness of the program all participants will undergo several evaluations at baseline, and 3, 9 and 12 months after randomization, with the main timepoint of interest being from baseline to 9-month follow-up.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Physical Activity | Experimental | 9-month remotely-monitored, goal-oriented, individualized, step-based physical activity program. |
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| Enhanced usual care to manage heart failure | No Intervention | Participants will receive enhanced usual care, consisting of the usual care to manage heart failure (guideline-directed medical therapy) plus an education pamphlet and in-depth evaluations and reports to measure the project outcomes. Specifically, usual care for heart failure generally encompasses optimized treatment titration, patient education and self-management strategies, nurse-led clinical assessments and medication adjustments, monitoring of patient outcomes, and coordinated collaboration with primary care and other specialties. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Physical Activity | Behavioral | Participants will be encouraged to progressively increase the number of daily steps (volume) and the number of minutes per day spent at a higher cadence (intensity). To achieve these goals, the investigators will support participants in the intervention group through behavior change techniques. For example, wearable devices and an online platform will be used to monitor the behavior and track progress using simple graphs; participants will be provided with small, individualized goals which will be updated every two weeks based on the activity levels achieved the prior two weeks; standardized WhatsApp messages will be sent to prompt the behavior and face-to-face coaching sessions will be delivered throughout the intervention. Participants in this group will also receive enhanced usual care, consisting of the usual care to manage heart failure plus an education pamphlet and in-depth evaluations and reports to measure the project outcomes. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in functional capacity | The primary outcome is the change in functional capacity measured with a 6-minute walk test (6MWT). | Baseline, 3 months, 9 months and 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in patient-perceived heart failure-related symptoms and limitations | Measured with the Kansas City Cardiomyopathy Questionnaire - Clinical Summary Scale (KCCQ-CSS). This is scored on a 0-100 scale, with higher scores indicating better heart failure-related health status (i.e., fewer symptoms and less physical limitation); 0 reflects the worst and 100 the best status. | Baseline, 3 months, 9 months and 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in additional heart failure-related patient perceptions | Heart failure-related patient perceptions measured with subscales and individual domains of the Kansas City Cardiomyopathy Questionnaire (KCCQ):
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), University of Granada | Granada | 18016 | Spain |
The protocol and statistical analyses plan will be shared open access.
Data files including individual participant data (IPD) and their corresponding data dictionaries will be shared under restricted access and upon reasonable request (contact Prof. FB Ortega) due to privacy issues and GDPR regulations.
IPD will be available for sharing under the "as open as possible, as closed as necessary" principle. The shared data files will be pseudonymized and include only participants who provided informed consent.
The IPD data will be available 12 months after the primary outcome paper is published, upon reasonable request.
The specific process of data access will be determined at a later stage. Data will be available upon reasonable request to the PI (FB Ortega). The data requests must contain the aim of the research, hypothesis, the specific data being requested, and a data analysis plan. Based on the "as open as possible, as closed as necessary" principle, we will decide whether the data can be shared. A data access committee will be created to discuss and approve any data requests.
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| ID | Term |
|---|---|
| D006333 | Heart Failure |
| D009043 | Motor Activity |
| D002318 | Cardiovascular Diseases |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D001519 | Behavior |
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| ID | Term |
|---|---|
| D015444 | Exercise |
| ID | Term |
|---|---|
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
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| UNKNOWN |
| Hospital Santa Ana de Motril | UNKNOWN |
| Mind, Brain and Behaviour Research Centre (CIMCYC) | UNKNOWN |
| Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición | OTHER |
| Department of Medical BioSciences, Exercise Physiology ResearchGroup, Radboud University Medical Center, Nijmegen, The Netherlands | UNKNOWN |
| Instituto de Investigación Biosanitaria IBS Granada | UNKNOWN |
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Given the nature of the intervention, participants cannot be blinded to their assigned group. Staff conducting the evaluations will be blinded to the participants' allocation group. Staff conducting statistical analyses for the main outcomes will also be blinded.
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| Change in systemic inflammation | Measured with blood-based high-sensitivity C-reactive protein (hs-CRP). Unit: mg/L. | Baseline and 9 months |
| Change in additional pro- and anti-inflammatory markers | Additional pro- and anti-inflammatory markers will be measured from a blood sample, e.g., Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 beta (IL-1β), Interleukin-10 (IL-10), and Interleukin-1 Receptor Antagonist (IL-RA), including novel inflammatory biomarkers that may become available up to the time of analysis. Unit: pg/mL. | Baseline and 9 months |
| Change in counts of steps | Measured with a StepWatch accelerometer as the total counts of steps/day. | Baseline, 3 months, 9 months (within the last 2 weeks of the intervention) and 12 months |
| Change in time spent at light, moderate and vigorous-intensity step cadence | Measured with a StepWatch accelerometer as minutes/day spent at light, moderate (main interest) and vigorous-intensity step cadence. | Baseline, 3 months, 9 months (within the last 2 weeks of the intervention) and 12 months |
| Change in peak cadence | Measured with a StepWatch accelerometer as the minute with the higher number of steps. | Baseline, 3 months, 9 months (within the last 2 weeks of the intervention) and 12 months |
| Change in 24-hour movement behaviors | Physical activity (primary behavior of interest), sedentary, and sleep metrics measured with a Matrix Activity Monitor . | Baseline, 3 months, 9 months (within the last 2 weeks of the intervention) and 12 months |
| Baseline, 3 months, 9 months and 12 months |
| Change in general cognition | Measured with the Montreal Cognitive Assessment (MoCA) total score (1-30). | Baseline and 9 months |
| Change in processing speed | Measured by (i) the Trail Making Test Part A (TMT-A), where shorter completion times indicate better performance; and (ii) the Digit Symbol Substitution Test (DSST), with the outcome defined as the total number of correct responses within the time limit (120 sec). | Baseline and 9 months |
| Change in executive function and attentional/Inhibitory control | Measured by (i) Trail Making Test Part B (TMT-B), where shorter completion times indicate better performance; (ii) Dimensional Change Card Sort (DCCS), and (iii) the Flanker test, both with computed scores representing accuracy and reaction time. | Baseline and 9 months |
| Change in episodic memory | Measured by (i) the free recall item of the Montreal Cognitive Assessment (MoCA), and (ii) the Picture Sequence Memory Test (PSMT), with raw scores indicating memory performance. | Baseline and 9 months |
| Change in brain volume | Measured with magnetic resonance imaging using a T1-weighted Magnetization-Prepared Rapid Acquisition Gradient Echo (MPRAGE) structural sequence. This outcome will be assessed only in participants without MRI incompatibilities | Baseline and 9 months |
| Change in brain area | Measured with magnetic resonance imaging using a T1-weighted Magnetization-Prepared Rapid Acquisition Gradient Echo (MPRAGE) structural sequence. This outcome will be assessed only in participants without MRI incompatibilities. | Baseline and 9 months |
| Change in cortical thickness | Measured with magnetic resonance imaging using a T1-weighted Magnetization-Prepared Rapid Acquisition Gradient Echo (MPRAGE) structural sequence. This outcome will be assessed only in participants without MRI incompatibilities. | Baseline and 9 months |
| Change in brain shapes | Measured with magnetic resonance imaging using a T1-weighted Magnetization-Prepared Rapid Acquisition Gradient Echo (MPRAGE) structural sequence. This outcome will be assessed only in participants without MRI incompatibilities. | Baseline and 9 months |
| Change in white matter microstructure | White matter microstructure will be assessed using diffusion-weighted magnetic resonance imaging, with metrics including mean diffusivity, fractional anisotropy, and tractography-derived measures. This outcome will be assessed only in participants without MRI incompatibilities | Baseline and 9 months |
| Change in white matter hyperintensities | White matter lesions identified as white matter hyperintensities using 3D T2-weighted Turbo Spin Echo (TSE) Fluid-Attenuated Inversion Recovery (FLAIR) magnetic resonance imaging. This outcome will be assessed only in participants without MRI incompatibilities | Baseline and 9 months |
| Change in cerebral blood flow | Cerebral blood flow measured with magnetic resonance imaging using the technique of TGSE-pCASL (turbo gradient spin echo-pseudo continuous arterial spin labeling). This outcome will be assessed only in participants without MRI incompatibilities | Baseline and 9 months |
| Change in blood-brain barrier permeability | Blood Brain Barrier permeability measured by calculating the water exchange rate across the blood-brain barrier using 3D diffusion-prepared arterial spin labelled perfusion magnetic resonance imaging. This outcome will be assessed only in participants without MRI incompatibilities | Baseline and 9 months |
| Change in frailty score | Frailty score calculated using the Fried Frailty Scale. This scale characterizes frailty as the presence of at least three of the following five components: unintentional weight loss, self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. Each component in which the participant meets the frailty criterion is scored as 1. Otherwise, it is scored as 0. The scores from the five criteria are summed up to obtain a final score, which is then used to classify the participant according to the following thresholds: Frail: ≥3 criteria present. Prefrail: 1-2 criteria. Robust: 0 criteria | Baseline and 9 months |
| Change in anxiety symptoms | Reported by participants with the Hospital Anxiety and Depression Scale. The anxiety subscale has 7 items. Each item is rated on a 4-point scale (0-3 points). The total anxiety scores range from 0-21 points. Higher scores mean worse anxiety symptoms. | Baseline and 9 months |
| Change in depression symptoms | Reported by participants with the Hospital Anxiety and Depression Scale. The depression subscale has 7 items. Each item is rated on a 4-point scale (0-3 points). The total depression scores range from 0-21 points. Higher scores mean worse depression symptoms. | Baseline and 9 months |
| Change in cardiovascular health score | Cardiovascular health score calculated using the total score of Life's Essential 8, and the sub-scores related to health factors and behaviors. The health factors include body mass index, blood lipids, blood glucose and blood pressure. Health behaviors consider physical activity, diet, nicotine exposure and sleep health. It yields a cardiovascular health score based on the unweighted average of all components, ranging from 0 to 100 points. A higher score means better cardiovascular health. | Baseline and 9 months |
| Change in subjective memory decline | Reported by participants with the Subjective Memory Decline Scale. It consists of four items assessing self-experienced increasing difficulties in everyday memory, yielding a total score ranging from 0 to 8. Higher scores indicate greater perceived memory decline. | Baseline and 9 months |
| Change in stress | Reported by participants with the Perceived Stress Scale (PSS). It consists of 14 items with a five-point response format. A higher score corresponds to a higher level of perceived stress. | Baseline and 9 months |
| Change in loneliness | Reported by participants with the UCLA Loneliness Scale. Items are rated using a 4-point Likert-type scale. Total scores range from 10 to 40, with higher scores indicating greater loneliness. | Baseline and 9 months |
| Change in social support | Reported by participants with the Multidimensional Scale of Perceived Social Support. The MSPSS is a 12-item self-administered questionnaire that evaluates perceived support from three distinct sources: family, friends, and significant other. Each item is rated on a 7-point Likert scale, with higher scores indicating greater perceived support. | Baseline and 9 months |
| Change in self-esteem | Reported by participants with the Rosenberg Self-Esteem Scale. It is a 10-item self-report questionnaire that assesses global self-esteem by capturing individuals' overall sense of self-worth and self-acceptance. Items are rated on a 4-point Likert scale. Total scores range from 10 to 40, with higher scores indicating greater self-esteem. | Baseline and 9 months |
| Change in independence in basic activities of daily living | Assessed by a trained health professional, through an interview with the participant, using the Barthel Index. The scale has 10 items covering basic activities of daily living (feeding, bathing, groomig, dressing, continence, toilet use, transfers, mobility and stairs). The total score ranges from 0 to 100 points. Higher scores indicate greater independence in basic activities of daily living. | Baseline and 9 months |
| Change in independence in instrumental activities of daily living | Assessed by a trained health professional, through an interview with the participant, using the Lawton and Brody Scale. The scale has 8 items covering instrumental activities of daily living (ability to use the telephone, shopping, food preparation, housekeeping, laundry, mode of transportation, responsibility for own medication, ability to handle finances). Each item is scored dichotomously (independent = 1, dependent = 0). The total score ranges from 0 to 8 points. Higher scores indicate greater independence in instrumental ADL. | Baseline and 9 months |
| Change in clinical-related measures | NYHA category defined by a clinician (I-IV, higher categories denote worse symptoms and limitations), medication prescription | Baseline and 9 months |
| Participants' physical activity enjoyment during the intervention | At the end of every month of the intervention, participants will be asked to rate their physical activity enjoyment using a short version of the Physical Activity Enjoyment Scale (PACES). Higher scores indicate greater enjoyment. This will be assessed only in participants in the intervention group. | During the 9-month intervention |
| Participants' rating of perceived exertion during the intervention | Every two weeks during the intervention, participants will be asked to rate their perceived exertion, thinking about when they were performing step-based physical activities, using the 6-20 Borg scale. Higher scores indicate greater exertion. This will be assessed only in participants in the intervention group. | During the 9-month intervention |
| Adherence to and compliance with the intervention | Measured based on participants' attendance to the coaching sessions, use of Fitbit and achievement of the goals. These will be assessed only in participants in the intervention group | During the 9-month intervention |
| Rate of clinical events during the study | Based on the incidence of clinical events during the study, i.e., during the 9-month intervention and during the 3-month follow-up (12 months after randomization), including worsening heart failure, hospitalization (cardiovascular and non-cardiovascular related), major adverse cardiovascular events and mortality. | During the study period until the 12-month follow-up |
| Rate of long-term clinical outcomes | Incidence of clinical events 5 and 10 years after the completion of the study, including hospitalization (cardiovascular and non-cardiovascular related), major adverse cardiovascular events and mortality. This will be measured using structural funds from the research team. | After study completion, an average of 5 and 10 years |
| Cost-effectiveness | Measured based on analyses of cost-effectiveness. This will be measured using structural funds from the research team. | After study completion, an average of 1 year |
| Social Return on Investment | Measured based on analyses of Social Return on Investment (SROI). This will be measured using structural funds from the research team. | After study completion, an average of 1 year |
| Change in natriuretic peptides | Measured with peripheral blood-based biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP). Unit: pg/dL. | Baseline and 9 months |
| Change in neurotrophic & growth factors | Measured with peripheral blood-based biomarkers such as Brain-Derived Neurotrophic Factor (BDNF). Unit: pg/dL. | Baseline and 9 months |
| Change in cholesterol profile | Measured with peripheral blood-based biomarkers such as total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides. Unit: mg/dL. | Baseline and 9 months |
| Change in glucose profile | Measured with peripheral blood-based biomarkers such as Fasting Plasma Glucose. Unit: mg/dL. | Baseline and 9 months |
| Change in glycated hemoglobin | Measured with peripheral blood-based glycated hemoglobin (HbA1c). Unit: %. | Baseline and 9 months |
| Change in estimated GFR | Estimated as the Glomerular Filtration Rate (eGFR). Unit: mL/min/1.73 m² | Baseline and 9 months |
| Change in markers of renal function | Measured with peripheral blood-based creatinine and urea nitrogen (BUN). Unit: mg/dL. | Baseline and 9 months |
| Change in uric acid | Measured with peripheral blood-based Uric acid. Unit: mg/dL. | Baseline and 9 months |
| Change in markers of liver function | Measured with peripheral blood-based Aspartate aminotransferase, Alanine aminotransferase, Gamma-glutamyl transferase, Alkaline phosphatase, Lactate dehydrogenase, Creatine kinase. Unit: U/L. | Baseline and 9 months |
| Change in total bilirubin | Measured with peripheral blood-based Total bilirubin. Unit: mg/dL. | Baseline and 9 months |
| Change in thyrotropin | Measured with peripheral blood-based Thyrotropin (TSH). Unit: mIU/L. | Baseline and 9 months |
| Change in parathyroid hormone | Measured with peripheral blood-based Parathyroid hormone (PTH, intact). Unit: pg/mL. | Baseline and 9 months |
| Change in markers of coagulation | Measured with peripheral blood-based prothrombin time, and activated partial thromboplastin time. Unit: seconds | Baseline and 9 months |
| Change in fibrinogen | Measured with peripheral blood-based fibrinogen. Unit: mg/dL | Baseline and 9 months |
| Change in electrolytes | Measured with peripheral blood-based sodium, potassium, chloride. Unit: mmol/L. | Baseline and 9 months |
| Change in minerals | Measured with peripheral blood-based calcium, phosphorus, magnesium. Unit: mg/dL | Baseline and 9 months |
| Change in protein status | Measured with peripheral blood-based albumin and total protein. Unit: g/dL | Baseline and 9 months |
| Change in CA 125 | Measured with peripheral blood-based Cancer Antigen 125 (CA 125). Unit: U/mL | Baseline and 9 months |
| Change in iron | Measured with peripheral blood-based iron. Unit: µg/dL | Baseline and 9 months |
| Change in transferrin | Measured with peripheral blood-based transferrin. Unit: mg/dL | Baseline and 9 months |
| Change in transferrin saturation | Measured with transferrin saturation index. Unit: %. | Baseline and 9 months |
| Change in Ferritin | Measured with peripheral blood-based Ferritin. Unit: ng/mL. | Baseline and 9 months |
| Change in Vitamin D | Measured with peripheral blood-based Vitamin D (25 OH). Unit: ng/mL | Baseline and 9 months |
| Change in plasma phosphorylated tau 217 (p-tau217) | Measured with blood-based p-tau217. Unit: pg/mL | Baseline and 9 months |
| Change in plasma phosphorylated tau 181 (p-tau181) | Measured with blood-based p-tau181. Unit: pg/mL | Baseline and 9 months |
| Change in plasma Aβ42/40 ratio | Measured with blood-based amyloid-β 42 to 40 ratio. | Baseline and 9 months |
| Change in plasma neurofilament light (NfL) | Measured with blood-based neurofilament light. Unit: pg/mL | Baseline and 9 months |
| Change in additional novel blood-based biomarkers related to heart and brain health | The investigators will remain open to assessing novel blood-based biomarkers related to heart and brain health that may become available in the literature up to the time of analysis | Baseline and 9 months |
| Change in handgrip strength | Maximal handgrip strength measured at rest using a handheld dynamometer. Higher values indicate better strength. Unit: kg. | Baseline and 9 months |
| Change in 30-second chair stand repetitions | Number of full stands completed in 30 seconds from a standard chair without using arms. Higher values indicate better lower-body function. Unit: repetitions (count). | Baseline and 9 months |
| Change in usual gait speed | Usual-pace gait speed measured over a 4.57-meter course from a standing start. Unit: second (m/s). | Baseline and 9 months |
| Change in resting systolic blood pressure | Measured with an automated blood pressure monitor (OMRON). Unit: mmHg. | Baseline and 9 months |
| Change in resting diastolic blood pressure | Measured with an automated blood pressure monitor (OMRON). Unit: mmHg. | Baseline and 9 months |
| Change in resting heart rate | Measured with an automated blood pressure monitor (OMRON). Unit: beats per minute. | Baseline and 9 months |
| Change in body mass index | Body mass will be measured using a SECA scale, height will be measured using a SECA height measuring system, body mass index will then be calculated (kg/m2). | Baseline and 9 months |
| Change in waist circumference | Measured following standardized procedures with a Lufkin tape measure. Unit: cm. | Baseline and 9 months |
| Changes in biventricular function | Measured using resting ultrasound echocardiography with markers such as 2D and 3D ejection fraction, deformation measures, and additional right-ventricular indices. Due to logistic constraints, this outcome will only be assessed in participants recruited from the hospitals in Granada city. | Baseline and 9 months |
| Change in cardiac diastolic function | Measured using resting ultrasound echocardiography with markers such as E/e' ratio and left atrial strain. Due to logistic constraints, this outcome will only be assessed in participants recruited from the hospitals in Granada city. | Baseline and 9 months |
| Change in cardiac dimensions | Measured using resting ultrasound echocardiography with markers such as left atrial volume index, and other ventricular and atrial diameters and volumes. Unit: mL/m². Due to logistic constraints, this outcome will only be assessed in participants recruited from the hospitals in Granada city. | Baseline and 9 months |
| Change in transcriptomic profile | Gene expression analyses will be conducted using RNA blood samples. | Baseline and 9 months |
| Change in epigenomic profile | DNA methylation analyses will be conducted using blood samples. | Baseline and 9 months |
| Qualitative usability of the intervention with a custom questionnaire | Measured based on patient perceptions collected using a custom usability questionnaire adapted to the intervention and population, derived from the System Usability Scale. These will be assessed only in participants in the intervention group. | End of intervention (9 months) |
| Qualitative usability of the intervention with interviews | Measured based on patient perceptions using semi-structured interviews, such as reported barriers and facilitators. These will be assessed only in participants in the intervention group. | End of intervention (9 months) |
| Qualitative feasibility of the intervention with interviews | Measured based on patient perceptions using semi-structured interviews, such as ability to engage in the program as intended in daily life. These will be assessed only in participants in the intervention group. | End of intervention (9 months) |
| Hospital Universitario Clínico San Cecilio | Granada | Spain |
| Hospital Universitario Virgen de las Nieves | Granada | Spain |
| Hospital Comarcal Santa Ana de Motril | Motril | Spain |