REALIsM-HF Pilot Study

Study Overview
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Brief Summary
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The study aims to explore two marketed devices providing a multimarker monitoring including physical activity under real-life conditions in patients with heart failure with preserved ejection fraction (HFpEF) and with heart failure and reduced ejection fraction (HFrEF). It aims to identify potential novel endpoints for future heart failure trials by exploring clinically relevant changes over time and correlations/associations with conventional endpoints such as the six minute walking distance (6MWD), biomarkers and clinical events. Furthermore, it aims to address the challenges and feasibility of implementing device based measurements under real-life conditions.

Detailed Description
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Device 1 AVIVO Mobile Patient Management System (Medtronic USA), substituted by VitalPatch biosensor (VitalConnect USA) during the course of the study Device 2 DynaPort Move Monitor (McRoberts, NL)

Official Title
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Real Life Multimarker Monitoring in Patients With Heart Failure

Conditions
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Heart Failure

Intervention / Treatment
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* Device: AVIVO Mobile Patient Management (MPM) System
* Device: VitalPatch biosensor
* Device: DynaPort Move Monitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent signed before any study-specific procedure Men or women aged 45 years and older Established diagnosis of chronic heart failure NYHA class II-IV Worsening heart failure requiring hospitalization for the initiation of intensification of heart failure therapy with at least one of the following: a) BNP ≥ 100 pg/mL or NT-proBNP ≥ 400 pg/mL (sinus rhythm) OR BNP ≥ 300 pg/mL or NT-proBNP ≥ 1200 pg/mL (atrial fibrillation); OR b) Radiographic evidence of pulmonary congestion (interstitial edema, pulmonary venous hypertension, vascular congestion, pleural effusion); OR c) Catheterization documented elevated filling pressures at rest (left ventricular end-diastolic pressure ≥15 mmHg or pulmonary capillary wedge pressure ≥ 20 mmHg) or with exercise (pulmonary capillary wedge pressure ≥ 25 mmHg) OR Ambulatory patients with a history of heart failure on individually optimized treatment with HF medications unless contraindicated or not tolerated, for at least 12 weeks and at least one of the following: a) Hospitalization for heart failure within the past 12 months; OR b) BNP ≥ 100 pg/mL or NT-proBNP ≥ 400 pg/mL (sinus rhythm) or BNP ≥ 300 pg/mL or NT-proBNP ≥ 1200 pg/mL (atrial fibrillation) For HFrEF only: EF ≤35% assessed by any imaging modality (e.g. echocardiography, cardiac magnetic resonance, cine levocardiography) within 12 months prior to study inclusion For HFpEF only: EF ≥45% assessed by any imaging modality (e.g. echocardiography, cardiac magnetic resonance, cine levocardiography) within 12 months prior to study inclusion Willingness to wear the DynaPort Move Monitor accelerometer belt and VitalPatch Biosensor during the trial Body size allows wearing of the accelerometer belt as confirmed by ability to comfortably fasten the test belt provided for the screening process Exclusion Criteria Inability to comply with planned study procedures or to comply with study protocol requirements; this includes completing required data collection, and attending required follow up study visits Hemoglobin < 8.0 g/dl Acute coronary syndrome or percutaneous coronary intervention within 3 months prior to informed consent Listing for heart transplantation and / or anticipated implantation of a ventricular assist device Inability to exercise: wheelchair / scooter / walker dependent; dependent on supplemental oxygen Known clinically significant persistent coronary ischemia (based on medical history, a preexisting or a recent clinical stress test) HF is not the primary factor limiting activity within the last three months as indicated by the patient affirming #1, #2 or #3 of the following questionnaire: My ability to be active is most limited by: #1 - Joint, foot, leg, hip or back pain; #2 - Unsteadiness or dizziness impairing daily mobility; #3 - Lifestyle, weather, or I just don't like to be active Occurrence of any of the following within 3 months prior to informed consent: Myocardial infarction, Hospitalization for unstable angina, Stroke or transient ischemic attack, Coronary artery bypass graft (CABG), Percutaneous coronary intervention (PCI), Implantation of a cardiac resynchronization therapy device (CRTD), Major surgery (that could interfere with patients' ability to exercise) PCI, CABG or implantation of a CRTD planned between randomization and Visit 4 Subject who cannot tolerate placement of external patch monitor on chest in the proposed location (ECG lead II orientation) Subject with known allergies or hypersensitivities to adhesives or hydrogels Severe uncorrected valvular heart disease Known clinically relevant ventricular arrhythmias (sustained ventricular tachycardia, ventricular flutter or fibrillation) Severe pulmonary disease with any of the following: Requirement of continuous (home) oxygen or History of chronic obstructive pulmonary disease ≥ GOLD III Previous (within 30 days or 5 half-lives of the investigational drug, whichever is longer) or concomitant participation in another clinical study with investigational medicinal product(s) or device(s) Any condition or therapy, which would make the patient unsuitable for the study, or life expectancy less than 12 months (e.g. active malignancy) Heavy alcohol consumption or the use of illicit drugs that, in the opinion of the investigator, may interfere with the patient's safety and / or compliance Patients who regularly (> 1x per week) swim, do water aerobics or go to the sauna, unwilling to omit this activity while needing to wear the study specific medical devices Active myocarditis Primary hypertrophic cardiomyopathy Constrictive pericarditis or pericardial tamponade Close affiliation with the investigational site, e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site) Previous participate in the study

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HFrEF<br>Participants with established diagnosis of heart failure with reduced ejection fraction (HFrEF; EF ≤ 35%) wore the AVIVO MPM System or VitalPatch biosensor for 5 monitoring periods with patches applied on Day 0, 9, 16, 77 and 84; and the DynaPort Move Monitor belt for 2 monitoring periods with belts applied on Day 9 and Day 77. | Device: AVIVO Mobile Patient Management (MPM) System<br>* Wearable, wireless physiological monitoring and arrhythmia detection system, used by participants for 5 monitoring periods of 5 days each in the study<br>Device: VitalPatch biosensor<br>* Wearable, wireless physiological monitoring and arrhythmia detection system, used by participants for 5 monitoring periods of 5 days each in the study<br>Device: DynaPort Move Monitor<br>* Wearable device for ambulatory monitoring of physical activity, used by participants for 2 monitoring periods of 7 days each in the study<br>|
| Experimental: HFpEF<br>Participants with established diagnosis of heart failure with preserved ejection fraction (HFpEF; EF ≥ 45%) wore the AVIVO MPM System or VitalPatch biosensor for 5 monitoring periods with patches applied on Day 0, 9, 16, 77 and 84; and the DynaPort Move Monitor belt for 2 monitoring periods with belts applied on Day 9 and Day 77. | Device: AVIVO Mobile Patient Management (MPM) System<br>* Wearable, wireless physiological monitoring and arrhythmia detection system, used by participants for 5 monitoring periods of 5 days each in the study<br>Device: VitalPatch biosensor<br>* Wearable, wireless physiological monitoring and arrhythmia detection system, used by participants for 5 monitoring periods of 5 days each in the study<br>Device: DynaPort Move Monitor<br>* Wearable device for ambulatory monitoring of physical activity, used by participants for 2 monitoring periods of 7 days each in the study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily Steps Count | Daily steps count was measured with DynaPort Move Monitor device and evaluated to reflect the amount of daily physical activity. | At Day 9 and Day 77 | 
| Daily Physical Activity Level | Movement intensity of an activity, which was the average body acceleration (g) during this activity, was measured with DynaPort Move Monitor device and evaluated as daily physical activity level (PAL). Higher values indicate higher physical activity level and intensity. | At Day 9 and Day 77 | 
| Total Daily Energy Expenditure | Total daily energy expenditure was measured with DynaPort Move Monitor device and evaluated to reflect the amount of daily physical activity. | At Day 9 and Day 77 | 
| Duration of Daily Physical Activity | Duration of daily physical activity was measured with DynaPort Move Monitor device. | At Day 9 and Day 77 | 
| Time Duration Per Activity Status | Time duration per activity status was measured with DynaPort Move Monitor device and evaluated to reflect the intensity of daily physical activity. Physical Activity intensities use absolute aerobic intensity in terms of Metabolic Equivalent of Task (MET), which is a physiological concept expressing the energy cost of a physical activity as a multiple of Basal Metabolic Rate (BMR). By convention, 1 MET is considered as the resting metabolic rate obtained during quiet sitting. According to the American College of Sports Medicine (ACSM) thresholds for adults: Light-intensity activities are defined as 1.1 MET to 2.9 METs; Moderate-intensity activities are defined as 3.0 to 5.9 METs; Vigorous-intensity activities are defined as 6.0 METs or more. | At Day 9 and Day 77 | 
| Amount of Daily Physical Activity Measured With VitalPatch Biosensor | Amount of daily physical activity was collected and measured with VitalPatch biosensor. | Up to Day 84 | 
| Duration of Daily Physical Activity Measured With VitalPatch Biosensor | Duration of daily physical activity was collected and measured with VitalPatch biosensor. | Up to Day 84 | 
| Intensity of Daily Physical Activity Measured With VitalPatch Biosensor | Intensity of daily physical activity was collected and measured with VitalPatch biosensor. | Up to Day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-minute Walking Distance (6MWD) | 6-minute walking distance (6MWD) is a exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. An increase in the distance walked indicates improvement in basic mobility. | At Day 84 | 
| Sleep Movements | Sleep movements was measured with DynaPort Move Monitor device. | Up to Day 84 | 
| Sleep Patterns | Sleep patterns was measured with DynaPort Move Monitor device. | Up to Day 84 | 
| Sit-to-stand Behaviour | Sit-to-stand behaviour was measured with DynaPort Move Monitor device. | Up to Day 84 | 
| Quality of Life as Measured With the Kansas City Cardiomyopathy Questionnaire Score | The Kansas City Cardiomyopathy Questionnaire (KCCQ) is the leading health-related quality-of-life measure for patients with heart failure (HF). It is a 23-item questionnaire that independently measures the impact of patients' HF, or its treatment, on 7 distinct domains: symptom frequency, symptom burden, physical limitation, quality of life, social limitations, self-efficacy and symptoms stability. Physical Limitation ranges 0-100. Total Symptom Score (range 0-100) combines the Symptom Frequency and the Symptom Burden scores; Clinical Summary Score (range 0-100) combines the Total Symptom and Physical Limitation scores to replicate the NYHA classification; Overall Summary Score (range 0-100) includes the Total Symptom, Physical Limitation, Social Limitations, and Quality of Life scores. Higher scores indicate more favorable states. | At Day 9 and Day 84 | 
| Quality of Life as Measured With the PRO - Activity Scores | REALIsM-HF exploratory daily questionnaire was developed to include patient-reported outcome (PRO) items that can be administered as a daily diary in the study. Overall activity score ranges from 0 to 240 and general physical activity score ranges from 0 to 4. Higher scores indicate more favorable states. | At Day 9 and Day 77 | 
| Quality of Life as Measured With the PRO - Change in Activities and Symptoms | REALIsM-HF exploratory daily questionnaire was developed to include patient-reported outcome (PRO) items that can be administered as a daily diary in the study. Answers to question How have your physical activities changed since you were discharged from the hospital: 1= Very much more physically active; 2= Much more physically active; 3= A little more physically active; 4= No change in physical activities; 5= A little less physically active; 6= Much less physically active; 7= Very much less physically active. Answers to questions How has your feeling of tiredness changed since you were discharged from the hospital, How has your shortness of breath changed since you were discharged from the hospital and How has your swelling in your legs, ankles, or feet changed since you were discharged from the hospital: 1= Very much improved; 2= Much improved; 3= Minimally improved; 4= No change; 5= Minimally worse; 6= Much worse; 7= Very much worse. | At Day 9 and Day 77 | 
| Copeptin | Blood sample for biomarkers including Copeptin were collected from participants in order to validate such biomarkers for clinical use in the context of heart failure. Biomarkers concentration was determined in plasma/serum by a central laboratory using validated assays platforms including appropriate quality controls. | At Day 9 and Day 84 | 
| Galectin-3 | Blood sample for biomarkers including Galectin-3 were collected from participants in order to validate such biomarkers for clinical use in the context of heart failure. Biomarkers concentration was determined in plasma/serum by a central laboratory using validated assays platforms including appropriate quality controls. | At Day 9 and Day 84 | 
| Growth Differentiation Factor 15 (GDF 15) | Blood sample for biomarkers including GDF 15 were collected from participants in order to validate such biomarkers for clinical use in the context of heart failure. Biomarkers concentration was determined in plasma/serum by a central laboratory using validated assays platforms including appropriate quality controls. | At Day 9 and Day 84 | 
| Human Interleukin-1 Receptor 4 / ST2 (sST2) | Blood sample for biomarkers including sST2 were collected from participants in order to validate such biomarkers for clinical use in the context of heart failure. Biomarkers concentration was determined in plasma/serum by a central laboratory using validated assays platforms including appropriate quality controls. Values above upper limit of quantification (ULOQ) were substituted by ULOQ for the calculation of statistics (ULOQ = 80.0) | At Day 9 and Day 84 | 
| Human Insulin-like Growth Factor Binding (IGFBP7) | Blood sample for biomarkers including IGFBP7 were collected from participants in order to validate such biomarkers for clinical use in the context of heart failure. Biomarkers concentration was determined in plasma/serum by a central laboratory using validated assays platforms including appropriate quality controls. | At Day 9 and Day 84 | 
| N-terminal Propeptide of BNP (NT-proBNP) | Blood sample for biomarkers including NT-proBNP were collected from participants in order to validate such biomarkers for clinical use in the context of heart failure. Biomarkers concentration was determined in plasma/serum by a central laboratory using validated assays platforms including appropriate quality controls. | At Day 9 and Day 84 | 
| High Sensitive Troponin T (hsTRT) | Blood sample for biomarkers including hsTRT were collected from participants in order to validate such biomarkers for clinical use in the context of heart failure. Biomarkers concentration was determined in plasma/serum by a central laboratory using validated assays platforms including appropriate quality controls. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation of statistics (LLOQ = 13.0) | At Day 9 and Day 84 | 
| Blood Pressure | Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were collected. | At Day 9, Day 77 and Day 84 | 
| Heart Rate | Heart rate data were collected by electrocardiogram (ECG). | At Day 9, Day 77 and Day 84 | 
| Interventricular Septal Wall Thickness | Interventricular septal wall thickness was measured by echocardiography. | At Day 84 | 
| Diameter of the Left Ventricle in Diastole | Diameter of the left ventricle in diastole was measured by echocardiography. | At Day 84 | 
| Diameter of the Left Ventricle in Systole | Diameter of the left ventricle in systole was measured by echocardiography. | At Day 84 | 
| Left Ventricular End-diastolic Volume | Left ventricular end-diastolic volume was measured by echocardiography. | At Day 84 | 
| Left Ventricular End-systolic Volume | Left ventricular end-systolic volume was measured by echocardiography. | At Day 84 | 
| Left Ventricular Ejection Fraction | Left ventricular ejection fraction was measured by echocardiography. | At Day 84 | 
| Left Atrial End-systolic Volume | Left atrial end-systolic volume was measured by echocardiography. | At Day 84 | 
| Left Atrial End Systolic Volume Index | Left atrial end systolic volume index was measured by echocardiography. | At Day 84 | 
| Mitral Peak Velocity of Early Filling (E) | Mitral peak velocity of early filling (E) was measured by echocardiography. | At Day 84 | 
| Mitral Peak Velocity of Late Filling (A) | Mitral peak velocity of late filling (A) was measured by echocardiography. | At Day 84 | 
| Mitral Lateral Annulus Early Diastolic Peak Velocity | Mitral lateral annulus early diastolic peak velocity was measured by echocardiography. | At Day 84 | 
| Mitral Septal Annulus Early Diastolic Peak Velocity | Mitral septal annulus early diastolic peak velocity was measured by echocardiography. | At Day 84 | 
| Tricuspid Annular Plane Systolic Excursion | Tricuspid annular plane systolic excursion was measured by echocardiography. | At Day 84 | 
| Pressure Gradient of Tricuspid Valve | Pressure gradient of tricuspid valve was measured by echocardiography. | At Day 84 | 
| Right Atrial Mean Pressure | Right atrial mean pressure was measured by echocardiography. | At Day 84 | 
| Heart Rate Variability (HRV) Derived From ECG | Heart rate variability (HRV) derived from ECG were measured with AVIVO MPM and VitalPatch biosensor | Up to Day 84 | 
| Number of Participants Per NYHA Classification by Visit | The New York Heart Association (NYHA) Classification provides a simple way of classifying the extent of heart failure. The Stages of Heart Failure: Class I = No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when walking, climbing stairs etc. Class II = Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity. Class III = Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20 - 100 m). Comfortable only at rest. Class IV = Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. | At Day 9 and Day 84 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure with preserved ejection fraction (HFpEF), Heart failure with reduced ejection fraction (HFrEF)