Randomized Controlled Multicenter Trial for the Validation of Vitalera Platform
Phase: NA
Conditions: Chronic Patients, Heart Failure
Sponsor: humanITcare

Clinical Research Plan
HumanITcare
Version 
Date 
Author 
NCT number
4.0
23/10/2023
Followhealth S.L.
NCT05825755

Content
1 Generalities
6
2 Synopsis of clinical research
7
3 Product under investigation
7
4 Justification of the clinical research design
8
5 Risks and benefits of the investigational product, clinical procedure and clinical research
10
6 Objectives and hypotheses of clinical research
11
6.1 Main objectives
11
6.2 Secondary objectives
12
6.3 Hypotheses
12
7 Clinical research design
12
7.1 Generalities
12
7.1.1 Type of study
12
7.1.2 Duration of the investigation
12
7.1.3 Variables
13
7.1.4 Sample calculation
14
7.2 Subject selection
14
7.2.1 Inclusion criteria
14
7.2.2 Exclusion criteria
15
7.2.3 Withdrawal criteria
15
7.3 Recruitment
16
7.3.1 Estimated recruitment time
17
7.4 Investigation procedure
17
7.5 Conducting the research
21
7.6 Monitoring plan
21
8 Design and statistical analysis
21
8.1 Methodology and analysis
21
9 Data management
22
9.1 Data Collection Notebook (CRD) and Source Data Management
22
9.2 Record keeping
28
9.3 Confidentiality
28
10 Modifications to the PIC
31
11 Deviations from the clinical research plan
32
12 Civil liability insurance
32
13 Ethical aspects
32
13.1 Ethical conduct of research
32
13.2 Ethics Committee
33
13.3 Regulatory authorities - Authorization/approval/notification
33
13.4 Information and consent of the subject
33
14 Adverse events and product deficiencies
34
14.1 Security parameters and definitions
34
14.1.1 Adverse event (AA)
34
14.1.2 Device deficiency (DD)
34
14.1.3 Adverse Device Effect (EAD)
34
Page 2 of 42

14.1.4 Serious adverse event (SAE)
35
14.1.5 Serious Adverse Device Effects (SAED)
35
14.1.6 Unexpected Adverse Event (AAI)
36
14.1.7 Unexpected Adverse Device Effect (EAID)
36
14.2 Reportable events
36
14.3 Assessment of causality of adverse events
37
14.4 Security plan
39
14.4.1 Registration and collection of adverse events
39
14.4.2 Reporting period for adverse events
40
14.4.3 Notification of AAGs/ EAGDs/ EAIDs
40
14.4.4 Report
41
14.4.5 Notification periods
41
14.4.6 Expedited notification of other relevant safety information
41
14.4.7 Monitoring of adverse events
42
14.4.8 Adverse events associated with the investigational device
42
15 Suspension or early termination of IC
42
15.1 Termination and Discontinuation Criteria
42
15.2 Completion of the investigation
43
15.2.1 Plan for monitoring and care of subjects after the completion of the clinical research
43
16 Publication Policy
43
16.1 Preparation of the final clinical research report
43
16.2 Clinical evaluation plan
43
17 Bibliography
44
Page 3 of 42

Abbreviations
Abbreviation
Full name
AA
Adverse event
AAG
Serious adverse event
CITY
Unexpected adverse event
API
Application programming interface
BPC
Good Clinical Practice
CDD
Direct data capture
CEIm
Drug Research Ethics Committee
CRD
Data Collection Notebook
CV
Cardiovascular/es
DD
Device deficiency
EAD
Adverse effect of the device
EAGD
Serious device adverse events
EAID
Unexpected adverse effect of the device
eCRD
Electronic Data Collection Notebook
EHFScB
European Heart Failure Self-care Behavior Scale
EIC
European Innovaton Council
EU
European Union
fevi
Left ventricular ejection fraction
HFmrEF
Heart failure with mid-range ejection fraction
HFpEF
Heart failure with preserved ejection fraction
HFrEF
Heart failure with reduced ejection fraction
IA
Artificial intelligence
IC
Heart failure
IT
Information technologies
LVAD
left ventricular assist device
MDPQ
Mobile Device Competency Questionnaire
NT-pro BNP
Propéptido natriurético cerebral N-terminal
NYHA
New York Heart Association class
PIC
Clinical Research Plan
PSSUQ
Post-Study System Usability Questionnaire
RRP
Patient-reported outcomes
SDK
Software development kit
THEIR
System Usability Scale
Page 4 of 42

TM
Telemonitoring (Remote Monitoring)
UC
Usual care (Traditional follow-up)
Page 5 of 42

1
Generalities
Promoter
Nombre: Followhealth S.L.
Address: Calle Aristides Maillol, 17 - FLOOR 9 PTA. 4, Barcelona, ​08028, Barcelona
Email: info@humanitcare.com
Telephone: +34628994983
Monitor
Number: Júlia Altarriba Paracolls
Address: Calle Aristides Maillol, 17 - FLOOR 9 PTA. 4, Barcelona, ​08028, Barcelona
Email: julia.altarriba@humanitcare.com
Telephone: +34613004525
Principal investigator
Number: Dr. Marta Farrero Torres
Address: Hospital Clínic of Barcelona. Department of cardiology. Villarroel 170. 08036 Barcelona, ​Spain
Email: mfarrero@clinic.cat
Telephone: +34932275400
Coordinating researcher 1
Name: Dra Ilana Forado Benatar
Address: Hospital Clínic de Barcelona, ​Department of Cardiology. Villarroel 170. 08036 Barcelona, ​Spain
Email: forado@clinic.cat
Telephone: +34618717325
Coordinating researcher 2
Name: Dr Joan Guzman Bofarull
Address: Hospital Clínic de Barcelona, ​Department of Cardiology. Villarroel 170. 08036 Barcelona, ​Spain
Email: jguzman@clinic.cat
Telephone: +34699206128
Centers in which the study is planned to be carried out
Clinical Hospital of Barcelona
Denia Hospital
Hospital of Alcoy
Lozano Blesa Clinical Hospital of Zaragoza
Torrejón Hospital
General University Hospital of Elche
Vinalopó Hospital
Hospital of Terrassa
Sant Joan de Reus University Hospital
2
Synopsis of clinical research
HumanITcare has implemented a cloud platform for telemonitoring of chronic patients through wearable
medical devices and an alarm-based system that issues health alerts when a patient's biomedical
Page 6 of 42

measurement is outside a predefined clinical range. The platform frees doctors and caregivers from
reviewing each patient's data for anomalies, speeding up the decision-making process and reducing
hospital visits. With the present study we aim to validate the effectiveness of the app for patients and
digital platform for medical professionals by evaluating the increase in the quality of life of patients and
measuring the reduction in the incidence of the main critical events of HF. Additionally, the study will
validate the new API interoperability standards and platform architecture and evaluate the usability of
the platform by delivering satisfaction questionnaires to patients and professionals at the end of the
study.
This study is being carried out within the framework of a European project promoted by the European
Innovation Council (EIC).
Evidence to date
In 2020, a single-center study was carried out at the Torrevieja Hospital in which an early version of the
digital platform was validated. (Sanchez et al., 2020). A total of 32 patients participated, 16 as the control
group and 16 as the study group. The study group was monitored remotely using the HumanITcare
digital platform and wearable devices (smart scale, blood pressure monitor, pulse oximeter and smart
watch) for 3 months, while the control group continued normal clinical practice.
The results showed that patients monitored by the HumanITcare platform are less likely to return to the
emergency department. Additionally, the study group showed a reduction in hospital readmissions and
92% of patients would recommend using the platform. Finally, 100% of clinical professionals agreed that
the platform improves health care and services, saves time on visits and satisfies remote medical care,
which is an easy-to-use and easy-to-use system. learn to use. In addition, professionals affirm that the
way of interacting with the system is pleasant and that the platform fulfills all the expected tasks.
3
Product under investigation
HumanITcare is telemedicine software for monitoring patients who require continuous and remote
monitoring of their health status. It is a platform that processes information that comes from
questionnaires and/or different sensors interconnected to the patient's App and that is transmitted to a
medical portal so that the health professional can make decisions for therapeutic or diagnostic purposes
or set alarms when the parameters are above or below thresholds defined by the clinician himself.
HumanITcare has different functionalities related to this data:
●
Tracking and monitoring of health data obtained through interconnected sensors:
●
blood pressure monitor
●
pulse oximeter (pulse and oxygen saturation)
●
smartwatch (heart rate, physical activity and sleep)
Page 7 of 42

●
smart scale (weight)
●
thermometer (temperature)
●
glucometer (blood glucose)
●
monitoring of self-reported responses through questionnaires (validated symptoms, quality of
life, self-care questionnaires, etc.)
●
annotation of data from the patient's medical history (necessary for correct monitoring, since
alerts must be personalized to each condition)
●
configuration of medical alerts (healthcare professionals can define several alerts per patient
when certain parameters are above or below thresholds defined by the same clinician).
The platform intelligently monitors users in a fully automated manner, with real-time communication of
their data, with special emphasis on passive data, thus demanding less attention from them.
The HumanITcare software offers the doctor the possibility of viewing all this monitored information in
each user's profile to be able to interpret it more easily along with their history. This allows you to see:
●
The evolution of chronic diseases
●
Patient adherence to treatment
●
The evolution of a patient after an intervention
●
The need to make possible changes in medication or treatment due to a detected complication
All information about the product is found in the Researcher's Manual.
4
Rationale for clinical research design
Evaluation of preclinical trial results
The preclinical tests in order to verify the effectiveness and safety of the HumanITcare software have
been brought together in the validation and verification documents of the MDSW Test Plan and MDSW
Test Report software, following the indications of the MDR Regulation 745/2017 and the EN 62304:2006
standard. /A1:2015. This standard establishes a series of activities to be carried out during the software
development and maintenance process, necessary to generate quality, highly reliable and secure medical
software. HumanITcare complies with all activities required by the standard to determine the risks
resulting from the operation of the software. These activities are detailed in the Software Development
Plan document.
Clinical data evaluation
Heart failure (HF) is a prevalent and fatal clinical syndrome that affects the quality of life of millions of
people worldwide. Between 17% and 45% of patients with HF die within the first year and the rest die
within 5 years (Tripoliti et al., 2017). Furthermore, these patients have a high risk of rehospitalization,
their associated healthcare costs are enormous, and the longer the life expectancy, the higher the
prevalence of the disease. (McDonagh et al., 2021). Symptoms of IC commonly include shortness of
Page 8 of 42

breath, excessive tiredness, and swelling of the legs that may worsen with decompensation. (Schiff et al.,
2003), so traveling to medical centers represents a disadvantage for these people. Remote monitoring
technologies provide a feasible solution that allows for earlier identification of decompensation and
better adherence to lifestyle changes and medication (Brahmbhatt & Cowie, 2019). Although
telemonitoring using smartphones shows potential to reduce both the frequency and duration of
hospitalizations for HF (Koulaouzidis et al., 2016) cannot be associated with reduced mortality from any
cause (Koehler et al., 2011). Therefore, there is a need to search for more effective and precise
methodologies. In recent years, the use of portable devices (wearables) that allow daily monitoring of
the patient's physiological data combined with Artificial Intelligence (AI) has shown enormous potential
to predict diseases related to the cardiovascular system, their adverse events and the patient's health
status (Lee et al., 2022), including patients with HF (Guidi et al., 2015).
HumanITcare is a platform that allows this remote monitoring through the integration of different
medical devices and self-reported data. The platform allows you to customize a monitoring plan so that
healthcare professionals can adapt this tool to the needs of a specific patient group or at the individual
patient level.
The HumanITcare platform has been used in different therapeutic areas to improve personalized patient
monitoring. Some of the areas in which an improvement in patient monitoring and health status has
been demonstrated would be cardiology (IC - (Sanchez et al., 2020); cardiac rehabilitation - (Calvo-López
et al., 2023), palliative care (Castillo Padrós et al., 2022), respiratory diseases, or oncology, among others.
5
Risks and benefits of the product in investigation, clinical
procedure and clinical research
Benefits
During the usual clinical practice of monitoring newly decompensated HF patients, the patient must
monitor their vital signs daily and, if alarming values ​occur, communicate this by telephone or through a
visit to the emergency room to the medical team in charge of their case. That's why hea digital platform
for medical professionals and the application for patients provides the following benefits:
1.
Greater patient participation. The patient app can provide patients with the tools and resources
needed to self-manage their condition and improve their understanding of treatment plans and
lifestyle changes, leading to greater patient engagement and adherence.
2.
Increased quality of life. With the app, patients can monitor their symptoms, vital signs and
medications from their homes, which it is very beneficial in patients who have mobility
problems such as patients with insufficiencycardiac surgery.
Page 9 of 42

3.
Better outcomes for patients. Telemonitoring can help medical professionals identify early signs
of deterioration in patients with HF and trigger timely interventions to prevent exacerbations,
ultimately leading to improved clinical outcomes.
4.
Digital health tools. Integrating telemonitoring with other remote monitoring technologies and
digital health tools can provide a more complete view of a patient's health status and improve
overall management of their condition in real time.
Adverse reactions
The safety profile will be evaluated by recording, reporting and analyzing initial medical conditions,
adverse events, physical examination findings, including vital signs and laboratory tests.
The notification of adverse events will be carried out as established by the latest guideline on Safety
Notification in clinical investigations with medical devices for compliance with Regulation (EU) 2017/745
(MDCG 2020-10/1-Safety reporting in clinical investigations of medical devices under the Regulation (EU)
2017/745).
Associated risks
The benefit/risk ratio for patients using HumanITcare is very high or high, since there are potentially no
risks from the use of the product or the tests performed.
The manufacturer FollowHealth SL, Through risk management documents, establishes and commits to
maintaining a continuous process during the life cycle of the product and its accessories to identify the
hazards associated with a product, estimating and evaluating the associated risks, controlling these risks
and monitoring the effectiveness of the controls.
This process follows the instructions of the EN ISO 14971:2019 standard and is carried out as follows:
●
The risks are analyzed.
●
The risks are evaluated.
●
Actions are implemented to control risks.
●
Residual risks are evaluated.
●
The benefit versus risk is analyzed if there is an unacceptable residual risk after the
implementation of the corrective actions.
●
All product production and post-production information is collected to carry out a review of the
risk management carried out.
The procedure for carrying out product risk management is explained in detail in the associated
documentation that can be found in the risk management plan and associated procedures: Risk
Management Plan.
Page 10 of 42

The results of the analysis, including the identification of the main risks, their evaluation and the
corrective measures to be applied, are collected in the Risk Management Matrix.
It should be noted that no residual risks associated with the use of HumanITcare have been described.
6
Objectives and hypotheses of clinical research
6.1 Main objectives
●
To evaluate the effectiveness of telemonitoring to improve the quality of life of patients with HF.
●
To study the impact of telemonitoring on patients' psychological well-being, including anxiety,
depression, and sense of control over their condition.
●
To evaluate the feasibility and acceptability of integrating telemonitoring technologies and
digital health tools, and investigate their potential impact on patient outcomes as well as
treatment adherence.
●
Identify any adverse events or unintended consequences associated with telemonitoring of
patients with heart failure, such as privacy issues or technical problems.
6.2 Secondary objectives
●
To evaluate the role of telemonitoring in identifying early signs of deterioration in patients with
heart failure and triggering timely interventions to prevent exacerbations.
●
Improve clinical outcomes for patients with heart failure, as well as reduce hospital
readmissions.
6.3 Hypothesis
The hypothesis of the study is that the implementation of a telemonitoring system in patients with heart
failure will improve the quality of life and psychological well-being in patients, which will result in a
decrease in symptoms of anxiety and depression, as well as a increased feeling of control over your
state. Additionally, the incorporation of digital health and telemonitoring tools is expected to increase
treatment adherence and improve patient clinical outcomes. On the other hand, telemonitoring is
expected to be feasible and acceptable to patients, without generating significant adverse events or
unwanted consequences. Ultimately, it is hypothesized that telemonitoring will allow early identification
of signs of worsening in patients with heart failure, enabling timely implementation of therapeutic
interventions to prevent exacerbations and optimize the clinical management of these patients.
Page 11 of 42

7
Clinical research design
7.1 Generalities
7.1.1
Study type
This is a multicenter, randomized (1:1) controlled trial.
7.1.2
Duration of the investigation
Patients will be monitored for 3 months. The duration of the study has been defined based on the period
of time in which recently decompensated HF patients are more likely to relapse and suffer harmful
clinical events, and therefore to present a deterioration in their perception of quality of life.
7.1.3
Variables
Endpoint principal
●
Composite of quality of life, self-care and adherence to treatment by the patient (Change in the
scale value of each questionnaire at 3 months)
The variables are quantified using validated scales. These measures are:
-
Patient-Reported Self-Care Behavior Scale Measures (EHFScB Scale)
-
Quality of life assessed through the “Minnesota Questionnaire for People with Heart Failure
(MLHF questionnaire)”
-
Patient adherence to treatment and medication intake (SMAQ Simplified Medication Adherence
Questionnaire)
Secondary endpoints
●
Quality of life evaluated through the “Minnesota Questionnaire for People with Heart Failure”
(Change in the value of the questionnaire scale at 3 months)
●
Patient-Reported Self-Care Behavior Scale Measures (EHFScB Scale) (Change in Questionnaire
Scale Value at 3 Months)
●
Patient adherence to treatment and medication intake (SMAQ Simplified Medication Adherence
Questionnaire) (Change in the value of the questionnaire scale at 3 months)
●
Death from cardiovascular (CV) causes (Total number of patients who died in 3 months)
Page 12 of 42

●
Mortality from any cause (Total number of patients who died in 3 months)
●
Acute HF decompensation (first and recurrent) during the follow-up period (Number of total
decompensations in 3 months).
An acute decompensation of HF is defined as a new episode of symptoms and signs that requires
intravenous decongestive treatment or increased oral diuretics either on an outpatient basis (e.g., day or
home hospitalization for HF) or at home. emergency department or requiring an unplanned hospital
admission.
●
Hospital readmission due to HF decompensation (Total number of hospitalizations in 3 months)
●
Hospital readmission for CV causes (Total number of hospitalizations in 3 months)
●
Visits to the emergency room due to HF decompensation (Total number of visits to the
emergency room in 3 months)
●
Visits to the emergency room for CV causes (Total number of visits to the emergency room in 3
months)
●
Medical care costs (Sum of costs for medication consumption, hospitalization, emergency care
and medical transportation in 3 months)
7.1.4
Sample calculation
The sample calculation has been made based on the fact that a change of 5 points on the scale of the
Minnesota Questionnaire for People with Heart Failure (MLHF questionnaire) between the control group
and the experimental group (telemonitored) is clinically significant. (Rector, n.d.). Assuming an alpha risk
= 0.05 and a beta error of 20%, we need to recruit a total of 253 participants divided into a control group
and an experimental group.
7.2 Subject selection
The target population includes patients recently decompensated by Heart Failure (HF).
All recruited subjects will meet the inclusion criteria and none of the exclusion criteria and will provide
written informed consent.
7.2.1
Inclusion criteria
●
Patients with heart failure (HF) with NYHA functional class >= II (according to 2021 EU
guidelines).
●
Patients over 18 years of age.
Page 13 of 42

●
Patients who have suffered acute HF decompensation (first and recurrent) in the 30 days prior
to enrollment in the study.
*An acute decompensation of HF is defined as a new episode of symptoms and signs that requires
intravenous decongestive treatment or increased oral diuretics either on an outpatient basis (e.g., day or
home hospitalization for HF) or at home. emergency department or requiring an unplanned hospital
admission.
●
NT-pro BNP ≥300 pg/ml at study inclusion for patients without ongoing atrial fibrillation/flutter.
If ongoing atrial fibrillation/flutter, NT-pro BNP should be ≥600 pg/mL
●
Patients must have had an echocardiogram during their HF hospitalization or in the previous 12
months.
●
Before starting any procedure, the hospital will ensure that the patient obtains an informed
consent document.
●
All patients will be eligible regardless of LVEF level: HFrEF, HFmrEF and HFpEF.
●
Patients with minimal skills in handling mobile applications.
7.2.2
Exclusion criteria
●
Oncology patients with metastasis or ongoing chemotherapy treatment.
●
Patients participating in other studies or trials.
●
Patients who do not wish to participate.
●
Patients weighing more than 150 kg.
●
Patients who do not speak Catalan, Spanish, English, Portuguese, Italian, Dutch, German,
Swedish, Hungarian, Romanian or French.
●
Patients without a mobile phone.
●
Patients without internet connection.
●
Patients with moderate or severe cognitive impairment without a competent caregiver.
●
Patients with severe psychiatric illness.
●
Patients with planned cardiac surgery.
●
Patients with planned heart transplant or LVAD implant.
7.2.3
Withdrawal criteria
Page 14 of 42

Subjects will be informed that they can withdraw from the research whenever they wish, without this
affecting in any way their subsequent medical care.
Complete withdrawal of consent for research means that the subject no longer wishes to use the
investigational product and is unwilling or unable to continue participation in the research. Any subject
may withdraw full consent to participate in the research at any time during the research. The
investigator will discuss with the subject the most appropriate way to withdraw to ensure their health.
Every effort should be made to complete and report observations as widely as possible up to the date of
withdrawal. All information must be included in the corresponding data collection notebooks.
The withdrawal criteria established for clinical research are as follows:
●
Disease progression
●
Withdrawal of consent or desire to terminate treatment or investigational product or failure to
cooperate with research requirements
●
Toxicity, adverse event, or intercurrent illnesses, in the opinion of the investigator, that justify
discontinuation of treatment or investigational product
●
Decision of the principal investigator, whether withdrawal is necessary to safeguard the
interests of the patient
●
Patient death
●
New exclusion criteria clinically relevant to participants and affecting their safety
●
Failure to comply with or significant deviation from the clinical research plan
If the participant withdraws from the study, their data will be automatically anonymized by the platform
at the end of the study. This anonymization is not carried out if the participant gives explicit consent. The
withdrawn participant will receive standard follow-up care designated by their respective medical
professional.
7.3 Recruitment
After verifying that the selected subjects meet the inclusion and exclusion criteria, they will be offered to
participate. A user ID (automatically generated on the HumanITcare platform) will be assigned to each
subject who has given written informed consent to participate in the research. User IDs will not be
reused for different participants. The investigator must maintain a selection/enrollment record of all
selected subjects. This record must be carried out on a separate medium so that only the medical team
at each center can relate the user ID to a specific subject.
The participant must personally sign and date the latest approved version of the informed consent form
before performing any research-specific procedures.
Written and verbal versions of the patient information sheet and informed consent will be presented to
participants, detailing, at a minimum, the following:
●
The exact nature of the study
Page 15 of 42

●
The implications and limitations of the clinical research plan
●
Known side effects and any risks involved with participation
It will be clearly indicated that the participant is free to withdraw from the research at any time and for
any reason, without prejudice to future care, and without obligation to indicate the reason for
withdrawal.
The participant will be given as much time as they wish to consider the information, and the opportunity
to question the researcher to decide whether or not to participate in the study. Written informed
consent will then be obtained by the participant's signature and the signature of the person who
submitted and obtained informed consent.
7.3.1
Estimated recruitment time
Patients will be included in the study, based on the aforementioned eligibility criteria, for 3 months and
will be monitored for 3 months. Each hospital will decide when to include their patients based on their
particular clinical practice (either in the discharge planning process or during the first follow-up visit, i.e.,
approximately 1 week after discharge or after decompensation).
Medical professionals from each hospital will be in charge of recruiting participants. Patients will be
recruited for 3 months.
Participants will be randomized in a 1:1 ratio to the control group (UC arm) or the intervention group
(TM arm) at the recruitment stage. Randomization will be carried out at each center using the
HumanITcare platform, which will indicate the arm to which each patient belongs. Stratification is
performed with covariate adaptive randomization methods.
7.4 Investigation procedure
January - February 2023
Selection and coordination of partners.
PIC Design Discussion
April 2023
CEIm Presentation
June 2023
CEIms approvals
November 2023
AEMPS approvals
November 2023
Start of the study. Register researchers on the platform. Start patient
recruitment.
November 2023
First patient - first visit
January 2023
Last patient - first visit
Page 16 of 42

January 2023
First patient - last visit
April 2023
Last patient - last visit
April 2023
Analysis of results. Draft version of the article
All patients included in the study will be followed for 3 months. The medical professionals responsible
for the study will be responsible for including patients in the study following the inclusion criteria. They
will explain the characteristics of the study to the patient and ask if they are willing to be included. The
patient will sign the informed consent, which includes acceptance of the use of active and passive data.
Once accepted, medical professionals will register the user on the platform, which will randomly assign
them to the UC or TM arm, complete all required data on their sociodemographics and risk factors, and
train them in the proper use of the application and the devices (in the TM case).
The particular clinical practice for the UC and TM arms is specified below:
UC arm tracking
Follow-up of patients in the UC arm will be carried out according to the usual clinical practice of each
recruiting center. All recruiting centers have active and mature CI programs in progress and therefore
each center will decide how to follow up the patient. However, medical professionals will be required to
register each patient on the platform, enter their baseline data (sociodemographic and risk factors) and
enter all possible clinical events (death, non-fatal HF event, hospitalization or visit to the emergency
room). that the patient could suffer during the entire follow-up period. Doses and medication changes
will also be recorded by medical professionals for each patient in the UC arm. Patients will answer
health-related questionnaires through the app. The frequency and type of questionnaire will be the
same for both study groups and are specified in Table 1. HumanITcare does not giveit will be to himpa
axisPatients in the control group (UC) will not have any device for taking measurements, therefore
patients in the UC group will not have to enter their vitals through the application.
The monitoring schedule per day is specified below.
●
Day 0: First visit and study enrollment before or after hospital discharge for HF, or after acute
decompensation. This first visit will include,
○
Explanation of the study to the patient and clarification of doubts
○
Explanation of the terms and conditions, and signing of the informed consent
○
Patients will be registered within the platform and the study group (UC or TM) will be
automatically assigned from the software. In this case the UC.
○
Registration of information on sociodemographic variables and patient risk factors on
the platform by the medical professional.
○
Patients will answer the European Heart Failure Self-Care Behavior Scale (EHFScB
scale), the Minnesota Questionnaire for People with Heart Failure (MLHF), the
Page 17 of 42

Simplified Medication Adherence Questionnaire (SMAQ), and the Mobile Device
Proficiency questionnaires. through the app.
●
Health questionnaires will be periodically delivered through the app to the patient. Specifically,
the self-care, quality of life, and mobile device competency questionnaires will be administered
once at the beginning and once at the end of the study, and the medication adherence
questionnaire will be answered once each month during the study (see Table 1).
●
Day 0 until end of study: Medical professionals will track health questionnaire responses
through the platform. Doctors will make a follow-up call in case of missing data.
●
Day 0 until the end of the study: Medical professionals must report each hospital readmission,
mortality or emergency visit for each patient, specifying its cause each time it occurs through
the platform. If you cannot register the event now, you can register events later by specifying
the corresponding date(s) and duration.
●
Day 0 until the end of the study: Medical professionals are required to report each medication
change through the platform, whether due to a decision derived from an alarm or derived from
a clinical evaluation.
●
Day 90 (3 months): Last follow-up visit and end of the study: The patient's follow-up will end 3
months after inclusion in the study (first hospital discharge). Patients must answer the
European Heart Failure Self-Care Behavior Scale (EHFScB scale), Minnesota Questionnaire for
People with Heart Failure (MLHF), Simplified Medication Adherence Questionnaire (SMAQ),
Mobile Device Competency Questionnaire and the “System Usability Scale” (SUS). Medical
professionals will change the patient's status to "finished" on the platform.
●
Medical professionals will be asked to answer the PSSUQ questionnaire at the end of the entire
study period.
●
Medical professionals may schedule patients for more in-person visits depending on the specific
clinical practice of each center.
TM Arm Tracking
Patients in the TM arm will be followed with the HumanITcare platform and app according to the
guidelines specified below.
●
Day 0: First visit and study enrollment before or after hospital discharge for HF, or after acute
decompensation. This first visit will include,
○
Explanation of the study to the patient and clarification of doubts
○
Explanation of the terms and conditions, and signing of the informed consent
○
Patients will be registered within the platform and the study group (UC or TM) will be
automatically assigned from the software. In this case the TM.
○
Patients will receive a scale, blood pressure monitor, smartwatch and pulse oximeter.
The devices will sync with the app (or the carrier's app in some cases). The patient
must wear the smartwatch throughout the study period, charging its battery every
time it is about to run out and putting it back on just when it is fully charged.
○
Registration of information on sociodemographic variables and patient risk factors on
the platform by the medical professional.
○
Patients will answer the European Heart Failure Self-Care Behavior Scale (EHFScB
scale), the Minnesota Questionnaire for People with Heart Failure (MLHF), and Mobile
Device Proficiency questionnaires via the app.
Page 18 of 42

●
Day 0 until the end of the study: Recording of measurements and questionnaires: Patients will
be notified through the app each time they need to record a measurement or answer a health
questionnaire. Weight, blood pressure (systolic and diastolic), and oxygen saturation (via pulse
oximeter) will be recorded daily. The times for each record are specified in the Table 1.
Smartwatch device measurements are automatically recorded once synchronized with the
application. The patients They must wear the smartwatch throughout the study period (except
when it is being charged).
●
Health questionnaires will be periodically delivered through the app to the patient. Specifically,
the symptomatology questionnaire will be delivered twice a week (Monday and Thursday),
self-care, quality of life and device competence questionnaires Mobile phones will be delivered
once at the beginning and once at the end of the study, and the medication adherence
questionnaire will be answered once every month during the study(see Table 1).
●
Day 0 until end of study: Medical professionals will track patients' adherence to the study by
verifying their measurements and health questionnaire responses through the platform.
Doctors will make follow-up calls in case there is missing data.
●
Day 0 to end of study: Medical professionals should note each alarm each time they receive it
and verify its relevance. If they cannot evaluate it at the time of appearance, they are allowed
to do so later. However, we recommend writing down alarms, if any, daily. Annotations will
include adding information about the relevance of an alarm and evaluating the patient's health
status.
●
Day 0 until the end of the study: Medical professionals must report each hospital readmission,
mortality or emergency visit for each patient, specifying its cause each time it occurs through
the platform. If you cannot register the event now, you can register events later by specifying
the corresponding date(s) and duration.
●
Day 0 until the end of the study: Medical professionals are required to report each medication
change through the platform, whether due to a decision derived from an alarm or derived from
a clinical evaluation.
●
Day 7 to 10: First follow-up visit: Medical professionals will schedule patients for an in-person
follow-up visit depending on the particular clinical practice of each recruiting center.
●
Day 90 (3 months): Last follow-up visit and end of the study: The patient's follow-up will end 3
months after inclusion in the study (first hospital discharge). Patients must answer the
European Heart Failure Self-Care Behavior Scale (EHFScB scale), the Minnesota Questionnaire
for People with Heart Failure (MLHF), the Mobile Device Competence Questionnaire and the
“System Usability Scale” (SUS) . They will then be asked to return the medical devices and
medical professionals will change the patient's status to "finished" on the platform.
●
Medical professionals will be asked to answer the PSSUQ questionnaire at the end of the entire
study period.
●
Medical professionals may schedule patients for more in-person visits depending on the specific
clinical practice of each center.
7.5 Conducting the research
The sponsor or designated person will carry out the quality assurance and control activities of this
research.. The monitor is responsible for supervising that data collection is done correctly, checking that
the data collected in the CRD matches the source data and that the protocol is followed appropriately.
Page 19 of 42

The sponsor will arrange for audits to be carried out as part of the implementation of quality assurance
to ensure that the research is being carried out in accordance with this clinical research plan, standard
operating procedures, good clinical practice (GCP) and all relevant regulatory requirements. The audits
will be independent and will be carried out apart from the usual monitoring and quality control
activities.
7.6 Monitoring plan
The study will be monitored to ensure that it is conducted and documented in accordance with the good
clinical practice (GCP) protocol, and all applicable regulatory requirements.
Monitoring of the clinical study will be done through the following steps:
1.
Verification of patient selection: The doctors at each center will be responsible for verifying that
patients meet the inclusion and exclusion criteria of the clinical study. As patient randomization
is done automatically through the platform, the risk of errors being made is very low.
2.
Clinical research evaluation: The company monitor will review clinical research records for each
site to ensure that it is conducted in accordance with the PIC, written procedures, and
applicable regulatory requirements.
3.
Data Quality Assessment: The company monitor will review patient records weekly to ensure
that clinical and follow-up data are being collected and recorded correctly. In addition, the
quality of the data provided by medical professionals will also be reviewed.
4.
Notification of findings: Healthcare facilities will notify the company of any findings that may
have implications for patient safety or data integrity.
5.
Documentation and archiving: The sponsor and the health centers will maintain a complete
record of all monitoring activities and will ensure that all records and documents related to the
clinical study are properly archived.
8
Design and statistical analysis
8.1 Methodology and analysis
Specific subgroup analyzes will be performed based on the different baseline data and risk factors
available for the project. We will also test interactions between each pair of subgroups and the main
effect of treatment.
Independent t tests or Mann-Whitney U tests will be used to compare the questionnaire scores based on
the distribution of the data, whether normally distributed or not, respectively.
The incidence of secondary endpoint events in the two study groups will be described using
Kaplan-Meier survival curves, which will be compared using the log-rank test. The hazard ratio will also
be obtained using Cox proportional hazards regression models comparing the TM and UC groups. The
time of each event will be calculated from the day of registration. We will compare the number of
readmissions and days of hospitalization between the two groups using the Wilcoxon rank sum test.
Page 20 of 42

9
Data management
All data is collected in the database that acts as eCRD.
Participants will be informed of the pseudonymization and confidentiality of their data. They will be
informed of the research, its objectives and methods, orally and in writing.
Participants who wish to participate in the research will receive a consent form for the processing of
their data that they must sign in order to continue in it. The researchers will preserve the privacy of the
participant's data by using only those data necessary for the purposes of the research and in compliance
with the principle of data minimization, keeping them pseudonymized for the main purpose of validating
the platform. The data may also be used for scientific purposes in the future.
The sociodemographic and clinical data and the administered scales will be stored in encrypted form,
and only the researchers will have access to them.
Informed consent will be requested and collected by a research assistant prior to subject inclusion in the
study.
9.1 Data Collection Notebook (CRD) and Source Data
Management
Study data must be verifiable against the source data, necessitating access to all original records and
subject records. Therefore, the researcher must agree to allow access to subject records and source data
must be available for all study data. Subjects or their legal representatives must also allow access to the
subjects' medical records and will be informed of this need and will express their agreement when
providing informed consent.
The researcher will at all times have full responsibility for the accuracy and authenticity of the clinical
and laboratory data that are included in the eCRD. The source documents about the patients will be the
doctor's patient records that will be maintained at the center where the study is conducted.
The researcher/center must allow direct access to the source (original) data/documents for activities
related to study monitoring, audit, review by ethics committees and inspection by regulatory authorities.
The source data from the electronic health products used during the research will be considered direct
data capture (CDD), and will be stored directly in the database that acts as eCRD.
Likewise, the patient-reported results (PRR) will be recorded directly in the database that acts as eCRD.
The eCRD will not be completed for subjects who are failures to screen.
A complete description of the data that will be collected is presented below in Table 1, specifying which
data will be collected for each follow-up arm, and the frequency of recording.
Page 21 of 42

Table 1: Data collected through the platform for each follow-up arm (TM or UC), specified in bold in the
first column.
Class and
tracking arm
Input measure
(units)
Units
Registration
frequency
Device
(Brand)
Collection
Physiological
measurements
TM
heart rate
Barks per minute
(bpm)
Continuous.
One record
every minute.
Smart watches
(Garmin,
Fitbit)
API or SDK.
Patients
through the
app
Calories
Kilocalories (kcal)
step counting
Steps
Physical activity
Minutes (min)
Oxygen saturation
Percentage (%)
Heart rate
variability
Milliseconds (ms)
Stress levels
Scale from 0 to 100
Accelerometer
Matrix of x,y,z
values ​in milligrams
(mG)
Dream
Minutes (min)
Systolic blood
pressure
Millimeters of
mercury (mmHg)
Daily. Once 2
hours after
taking the
medication
after breakfast.
Blood
pressure
monitor
(Beurer,
Lifevit)
API or SDK.
Patients
through the
app
Diastolic blood
pressure
Weight
Kilogram (kg)
Daily. Once
always at the
same time and
with the same
clothes.
Scale (Lifevit)
API or SDK or
manual
registration.
Patients
through the
app
Height
Metro (m)
Initial data
At the time of
inclusion.
Medical
professionals
through the
platform
IMC
Kilogram per
square meter
(kg/m²)
Daily,
depending on
weight
measurement.
Automatically
calculated
Oxygen saturation
Percentage (%)
Daily. Once 2
hours after
taking the
medication
after breakfast.
Pulse
oximeter
(Beurer and
Lifevit)
API or SDK.
Patients
through the
app
pulse rate
Barks per minute
(bpm)
Sociodemogra
phics
TM + UC
Sex
Whole
Initial data
At the time of
inclusion.
Medical
professionals
through the
platform
Age
Years
ethnic group
White, black, Asian,
Pacific Islander, or
Latin-South
American
Employment
Salaried/self-emplo
yed, retired, taking
Page 22 of 42

care of home
and/or family,
unemployed, doing
unpaid or voluntary
work, student,
none
Education
Primary, secondary,
higher level
Vigilante
yes or no
number of people
living with the
patient
Whole
Risk factors
TM + UC
Comorbidities
Comma separated
text
Initial data
At the time of
inclusion.
Medical
professionals
through the
platform
Diabetes
Yes or no
Hypertension
Smoker
alcohol
consumption
History of heart
disease
TM + UC
NYHA Class
Scale from 1 to 4
Initial data and
if it is modified
At the time of
inclusion.
Medical
professionals
through the
platform
TM + UC
Ejection fraction
level (LVEF)
Percentage (%)
Initial data and
if it is modified
At the time of
inclusion.
Medical
professionals
through the
platform
Medication
TM + UC
Lipid-lowering
medications
Milligrams per day
(mg/day) or grams
per day (g/day)
Initial data and
if it is modified
Medical
professionals
through the
platform
PCSK9 inhibitors
Beta blockers
Anticoagulant
agents
ACE
inhibitors/angiote
nsin
receptor-neprilysi
n inhibitor
Antiarrhythmic
drugs
Anti-inflammatory
medications
Aldosterone
antagonists
Page 23 of 42

Antidiabetic
agents
vericiguat
Diuretics
SGLT2 inhibitor
(Dapaglifrocin/em
pagliflocin)
Ivabradina
Symptoms
TM
chest pain
Yes or no
2 times a week.
On Monday and
Thursday
Patients via
app
questionnaire
Difficulty
breathing
Edema
Clinical events
TM + UC
Hospital
readmission
Number and dates
In the
occurrence
Medical
professionals
through the
platform
Urgent visit with
intravenous
decongestant
Emergency
Department Visits
Death
Yes/No and date
Questionnaires
TM + UC
European Heart
Failure Self-Care
Behavior Scale
(EHFScB scale)
From 0 to 100
2 times: when
included in the
study and at
the end of the
study at 3
months
Patients via
app
questionnaire
Minnesota
Questionnaire for
People with Heart
Failure (MLHF)
Mobile Device
Proficiency Quiz
From 8 to 40
Simplified
Medication
Adherence
Questionnaire
(SMAQ)
from 0 to 4
3 times: when
included in the
study and once
a month
The questionnaires given to patients are specified below and added in Annex 1:
●
Minnesota Questionnaire for People with Heart Failure (MLHF) (Garin et al., 2008)
●
European Heart Failure Self-Care Behavior Scale (EHFScB scale) (Jaarsma et al., 2009)
Page 24 of 42

●
Symptom Report Questionnaire: six questions to capture worsening heart disease symptoms,
primarily worsening HF, and one question to capture overall deterioration.
●
The “System Usability Scale” (SUS) (Brooke, 1995) and the “Post Study Usability Questionnaire”
(PSSUQ) (Lewis, 1992) They will be delivered at the end of the study.
●
Mobile Device Proficiency Questionnaire (MDPQ) (Roque & Boot, 2018)
●
Simplified Medication Adherence Questionnaire (SMAQ) (Ortega Suárez et al., 2011)
9.2 Record keeping
All records related to the conduct of this research must be retained by the researcher for 10 years as
specified in Regulation (EU) 2017/745.
Prior to the transfer or destruction of these records, the Promoter must be notified in writing and given
the opportunity to continue storing such records. The Investigator will allow representatives of the
Sponsor's supervisory members (and applicable regulatory authorities) to inspect all study records,
eCRDs and applicable portions of the study patient's and/or hospital's medical records at regular
intervals. throughout the study. These inspections are intended to verify compliance with the clinical
research plan, the integrity and accuracy of the data filled in the electronic CRD, and compliance with
applicable regulations.
The sponsor and the investigator agree to keep the medical records of the research patients confidential.
No patient will be identified by name in the clinical investigation report.
9.3 Confidentiality
All material, information (oral or written), unpublished documentation that is provided to researchers,
including this Clinical Research Plan, the Data Collection Notebooks and the Investigator's Manual, must
be considered the exclusive property of the Promoter, having the category confidential, and being
delivered as confidential for review and exclusive use for the purposes of the investigation.
This confidential nature of the information, as well as the obligation to keep it confidential throughout
the duration of the investigation, weighs on both the researcher and his collaborators, with the
researcher guaranteeing that all his collaborators respect this confidential nature.
Said data and/or material may not be disclosed, in part or in full, by the principal investigator and/or his
team to any unauthorized person, without the prior formal written consent of the promoter and must
not be used other than the purposes of the study.
It is the obligation of the Researcher and/or his team to consider as confidential and ensure at all times
the confidentiality of the documents and results generated during the course of the investigation, except
for those that legislation defines as disclosable.
Page 25 of 42

The researcher and/or his team will guarantee that all people involved will respect the confidentiality of
any information about the research subjects.
All parties involved in a clinical investigation will maintain the strictest confidentiality so that the
personal or family privacy of the subjects participating in it is not violated. Likewise, appropriate
measures must be taken to prevent access by unauthorized persons to the research data.
Taking into account the confidential nature, the personal data of the subjects included in the study will
comply with the General Data Protection Regulation in force as of May 25, 2018 (Regulation (EU)
2016/679) (if applicable) and with other national law(s) or regulatory requirements applicable in the
countries where the research is conducted.
The data from this study will be pseudonymized, since the researcher will receive the data without any
identification, although the person who extracts it will keep the information that allows its
re-identification. There is technical and functional separation between the researcher and the person
extracting the data, as required by the Second Additional Provision of Organic Law 3/2018, of December
5, on the Protection of Personal Data and guarantee of digital rights. Regulation (EU) 2016/679 of the
European Parliament and of the Council of 27 April 2016 on the protection of natural persons with
regard to the processing of personal data and the free circulation of such data will apply, and repealing
Directive 95/46/EC (General Data Protection Regulation or GDPR).
"Good Clinical Practices" will be applied, which were adopted in the EU in July 1996 and are imposed by
Directives 2001/20/EC, Directive 2001/83/EC, 2005/28/EC and the art. 47 of Regulation 536/2014,
applying the set of internationally recognized ethical and scientific quality requirements, which must be
met in the planning, implementation, registration and communication of clinical research involving
human beings.
Furthermore, the Researcher and the Promoter undertake to respect the principles of confidentiality of
personal data in relation to the subjects, the Researcher and their collaborators involved in the study.
Specs:
a)
Data protection considerations
FOLLOWHEALTH S.L has cloud servers located in Ireland that comply with the General Data Protection
Regulation of 05/25/2018 and the LOPD. In addition, participant data is encrypted both on the access
platform of the research assistant and the study's technical (IT) administrators and on the server. There is
no international data transfer.
In addition, FITBIT and/or its suppliers comply with the European Data Protection Regulation and the
participant must accept their privacy policy in order to use the device.
a)
Pseudonymization
Page 26 of 42

Participant Data Encryption: Each participant is assigned a randomly generated 8-character ID (e.g.
"d4w192bg"), and all participant data is connected only to that ID.
b)
Data encryption
All data on phones, on the server and in transit uses industry standard encryption techniques. The phone
also uses asymmetric encryption, meaning that even the phone can't read its own data; Data recorded
on the phone can only be read on the server.
The fact that the server and platform are encrypted makes it impossible to identify the user.
Furthermore, FOLLOWHEALTH S.L. It has a technical team that monitors and protects the cloud, the
server and the database.
c)
Possible confidentiality violations
Only one type of data can contain personally identifiable information: GPS data (which records location).
The GPS data in the app provides enough detail to identify individual buildings or street addresses with
some degree of confidence, although a fair amount of analysis will be required to transform a set of GPS
coordinates into a residential address for a participant. The smartphone app is completely customizable
when it comes to data collection, so a particular study could disable GPS data collection from a study, if
desired, if it is not part of the research question.
10 Modifications to the PIC
Any modification in the conditions authorized for clinical research that is considered relevant cannot be
carried out without the prior favorable opinion of the corresponding Clinical Research Ethics Committee
and the authorization of the Spanish Agency for Medicines and Health Products.
Without prejudice to the above, if the modification refers exclusively to specific documents that must be
evaluated only by the Clinical Research Ethics Committee, only the favorable opinion of said Committee
will be required for its application. On the contrary, if the modification refers to the documentation that
must be evaluated only by the Spanish Agency for Medicines and Health Products, only its authorization
will be required.
If circumstances arise that could endanger the safety of the subjects, the sponsor and the researcher will
adopt the appropriate urgent measures to protect the subjects from any immediate risk. The promoter
will inform both the Spanish Agency for Medicines and Health Products and the Clinical Research Ethics
Committees involved in the investigation of said circumstances and the measures adopted as soon as
possible.
Relevant modifications are considered those that are detailed in the Instructions for carrying out clinical
research with health products that will be published by the Ministry of Health and Consumer Affairs.
Page 27 of 42

The request must be submitted in writing, dated and signed by the promoter and researcher, to the
Spanish Agency for Medicines and Health Products and to the corresponding Clinical Research Ethics
Committees. The request will comply with the provisions of the Instructions for carrying out clinical
research with health products that will be published by the Ministry of Health and Consumer Affairs.
If the sponsor proposes to introduce modifications to a clinical investigation that may have a substantial
impact on the safety, health or rights of the subjects, or on the robustness or reliability of the clinical
data generated by the investigation, it shall inform the Member States in which the clinical research is to
be carried out, within a period of one week and through the electronic system mentioned in article 73 of
the MDR, the reasons and nature of these modifications. The promoter will include an updated version
of the corresponding documentation referred to in Chapter II of Annex XV of the MDR as part of the
notification. Modifications to the corresponding documentation must be clearly identifiable.
The Member State shall evaluate any substantial modification of the clinical investigation in accordance
with the procedure established in Article 71 of the MDR.
The promoter may apply the modifications referred to in section 1 at least 38 days after the notification
provided for in said section, unless:
a)
the Member State in which the clinical investigation is to be carried out has notified the sponsor
of its refusal for the reasons indicated in Article 71(4), or taking into account considerations of
public health or health and safety of users, public order , either
b)
an ethics committee of that Member State has issued a negative opinion in relation to the
substantial modification of the clinical research, which, in accordance with national law, is valid
throughout the territory of that Member State.
The Member State or States concerned may extend the period indicated in paragraph 3 for a further
seven days for the purpose of consulting with experts.
The request for authorization of the modification will be accompanied by the clinical research plan in
which the proposed modification has been included.
11 Deviations from the clinical research plan
Any change, divergence or deviation from the study design or procedures defined therein is considered a
deviation from the PIC. Here are some deviations:
●
Final number of patients enrolled in the program in the recruitment phase.
●
Modifications in the training or recruitment process.
●
Estimated time for the pilot phase.
●
Modifications in the generation of alerts from where the information is sent.
Page 28 of 42

The impact of possible deviations on the veracity of the data generated and on the conclusions that can
be drawn from the research on the performance and safety of the HumanITcare product, will be
evaluated by the promoter.
In emergency circumstances, deviations from the PIC to protect the rights, safety and well-being of
subjects may proceed without prior approval from the sponsor and the CEIC. Such deviations must be
documented and notified to the sponsor and the CEIC as soon as possible.
12 Civil liability insurance
FollowHealth S.L. has contracted civil liability insurance, if necessary a copy of the policy can be
provided.
13 Ethical aspects
13.1 Ethical conduct of research
This research will be carried out in accordance with the ethical principles originating from the
Declaration of Helsinki and its most recent amendments, in accordance with the approved clinical
research plan, the ICH-GCP guidelines, the Clinical Trials Regulations. of the EU and other national laws
or regulatory requirements applicable in the countries where the study is carried out.
13.2 Ethics committee
Prior to the initiation of the investigation, the sponsor is responsible for ensuring that the clinical
investigation plan and consent form have been reviewed and approved by a relevant CEIC. The CEIC must
be properly constituted and perform its functions in accordance with the ICH-BPC guidelines and local
requirements, as applicable.
The CEIC will approve all modifications to the clinical investigation plan (except logistical or
administrative changes), updates to written informed consent documents, patient recruitment
procedures (e.g. advertisements), written information to be provided to patients, the investigator's
manual, available safety information, payment information, the investigator's curriculum vitae and/or
other qualification evidence and any other documents requested by the CEIM and the Regulatory
Authority (Competent Authority), as appropriate.
13.3 Regulatory authorities -
Authorization/approval/notification
The clinical research plan and all applicable documentation will be presented or notified to the health
authorities in accordance with the regulations of the countries involved in the research.
Page 29 of 42

13.4 Subject information and consent
The researcher will obtain free written consent from each subject after adequate explanation of the
objectives, methods, anticipated benefits, potential dangers and many other aspects of the research,
which are relevant to the subject's decision to participate. The research subject must have sufficient
time to consider participating in the research before obtaining consent. The informed consent form must
be signed and dated by the subject and the researcher who has provided information about the research
before the subject is exposed to any research-related procedures.
The Patient Information Sheet and the Informed Consent Form will be delivered to the subject, in the
recruitment phase, by the researcher. Any doubt, question or explanation requested by the subject will
be resolved by the researcher before the IC is signed and returned.
The researcher will explain that the subject is completely free to refuse to participate in the research or
withdraw from it at any time, without consequences for their subsequent care and without the need to
justify their decision.
The subject will receive a copy of the informed consent documents.
Research subjects will be informed of new information and new consent will be obtained.
14 Adverse events and product deficiencies
The safety profile will be evaluated by recording, reporting and analyzing initial medical conditions,
adverse events, physical examination findings, including vital signs and laboratory tests.
The provisions of the latest Safety Notification guide in clinical research with medical devices have been
taken into account for compliance with Regulation (EU) 2017/745 (MDCG 2020-10/1-Safety reporting in
clinical investigations of medical devices under the Regulation (EU) 2017/745).
14.1 Security parameters and definitions
14.1.1 Adverse event (AA)
Any adverse medical event in a patient or other clinical research participant participating in a trial of a
medical device, which does not have to have a causal relationship with the product investigated.
Therefore, an AE can be any unfavorable and unintentional sign, symptom or illness temporarily
associated with the use of the product, whether or not considered related to the product.
14.1.2 Device deficiency (DD)
Page 30 of 42

Any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational
product, including errors in use or insufficiency of information provided by the manufacturer or
inadequacy of information provided by the manufacturer.
14.1.3 Adverse Device Effect (ADE)
All adverse and involuntary responses to the medical device.
All cases that the qualified medical professional or sponsor consider to have a reasonably presumed
causal relationship with the product are considered effects of the product.
This also includes any event resulting from inadequacies or inadequacies in the instructions for use or
deployment of the product and includes any event resulting from user error.
14.1.4 Serious adverse event (SAE)
A Serious Adverse Event (SAE) is defined as an AE that meets one of the following conditions:
•
Death during the study period (this means that the AE contributes directly or indirectly to
the patient's death).
•
Threat to life (defined as a subject at immediate risk of death at the time of the event).
•
Requires or prolongs hospitalization.
•
Causes a permanent or significant disability or disability (for example, the event disrupts
the participant's normal daily activities).
•
Any other significant medical event that, based on appropriate medical judgment, may
endanger the subject and may require medical or surgical intervention to prevent one of
the above outcomes.
All adverse events that do not meet any severity criteria should be considered as non-serious adverse
events.
The investigator must report in the data collection notebook (CRD) all adverse events that are
immediately suspected or those that are spontaneously reported by study participants, regardless of
their attribution.
The AAG must be communicated to the promoter immediately by a personal telephone call.
The collection of information about AEs begins with the signing of the consent form. The subject will be
questioned about any new adverse events or the evolution of previous adverse events.
Information about adverse events should be communicated as follows:
Page 31 of 42

•
Description
•
Duration and resolution: start date and resolution date
•
Maximum intensity of symptoms
•
Causal relationship with study treatment
•
Maximum seriousness
•
Measures adopted and resolution of the event
14.1.5 Serious adverse device effects (SAEs)
A serious adverse device effect (SAED) is any adverse medical event observed in a patient that can be
attributed in whole or in part to the product and that gave rise to any of the characteristics or led to a
characteristic of a serious adverse effect.
An EAGD is also any event that could have led to these consequences if appropriate measures had not
been taken or intervened or if the circumstances had been less opportune.
All cases judged by the reporting qualified medical professional or the promoter.
14.1.6 Unexpected adverse event (AAI)
An unexpected adverse event is any experience whose nature and severity of the event does not
correspond to the information about the study condition or intervention in the clinical investigation plan,
consent form, product manual, or investigator manual. Reports that add significant information about
the specificity or severity of a known and already documented serious adverse event constitute
unexpected events. For example, a more specific or more serious problem than that described in the
Investigator's Manual would be considered "unexpected."
14.1.7 Unexpected Adverse Device Effect (EAID)
Any serious adverse health or safety effect of the product, or any life-threatening problem or death
caused by or associated with a product, if such effect, problem or death was not previously identified as
to its nature , severity or degree of impact on the research plan or request (including a supplemental
plan or request), or any other serious unforeseen problem associated with a product that is related to
the rights, safety or well-being of the subject.
14.2 Reportable events
For the purposes of the guidance cited above and based on the definitions described above, the
following events are considered reportable events in accordance with Article 80(2) of the MDR:
a)
Any serious adverse event that has a causal relationship with the investigational product,
the comparator or the investigational procedure or when such a causal relationship is
reasonably possible.
Page 32 of 42

b)
Any product deficiency that could have resulted in a serious adverse event if appropriate
action had not been taken, intervention would not have been required, or circumstances
would have been less fortunate.
c)
Any new findings in relation to any of the events mentioned in letters a) and b).
14.3 Assessment of causality of adverse events
Investigators will request information about AEs/SAEs/DDs each time they come into contact with a
patient. All AEs/SAEs/DDs reported by the patient or study personnel will be recorded in the patient's
medical record and CRD.
The researcher will evaluate the causality of each AA/AAG/DD that is recorded in the corresponding CRD.
To ensure consistency in causality assessments, researchers should apply the following general rules:
Is there a reasonable possibility of a causal relationship between the study device and an adverse
event based on the facts, evidence, scientific data, and appropriate medical judgment?
AND
A temporal relationship between the AA/AAG/DD and the device under study that
indicates a possible causal relationship, when the existence of other devices,
therapeutic interventions or underlying disorders do not sufficiently explain the
observed event.
NO
A temporal relationship between the AA/AAG/DD and the device under study that
indicates an unlikely causal relationship, or the AA/AAG can be satisfactorily
explained by the existence of other devices, therapeutic interventions, or underlying
disorders.
Board 2. Causality of AEs
The sponsor and investigators will use the following definitions to evaluate the relationship of the
serious adverse event to the investigational device, comparator, or investigational procedure.
Causality categories include:
1.
Unrelated: The relationship with the product, comparator or procedure can be excluded when:
-
the event is not temporally related to the use of the investigational device, or the
procedures related to the application of the investigational product;
-
the serious adverse event does not follow a known response pattern to the medical device
(if the response pattern is previously known) and is biologically implausible;
-
The interruption of the application of the medical device or the reduction of the
activation/exposure level - when clinically feasible - and the reintroduction of its use (or the
increase in the activation/exposure level) do not impact the serious adverse event;
Page 33 of 42

-
the event affects a place in the body or an organ that cannot be affected by the product or
procedure
-
the serious adverse event may be attributed to another cause (for example, an underlying
or concurrent disease/clinical condition, an effect of another device, medication, treatment
or other risk factors)
-
the event does not depend on a false result given by the investigational device used for the
diagnosis, if any;
To establish non-relationship, all of the criteria listed above may not be met at the same time, depending
on the type of device/procedure and the serious adverse event:
2.
Possible: The relationship with the use of the investigational device or comparator, or the
relationship with the procedures, is weak but cannot be completely ruled out. Alternative
causes (for example, an underlying or concurrent disease/clinical condition or/and an effect of
another device, medication or treatment) are also possible. Cases where the relationship
cannot be assessed, or no information has been obtained, should also be classified as possible.
3.
Probable: The relationship with the use of the investigational product or comparator, or the
relationship with the procedures, appears relevant and/or the event cannot be reasonably
explained by another cause.
4.
Causal relationship: the serious adverse event is associated with the investigational product, the
comparator or with the procedures beyond a reasonable doubt when:
-
the event is a known side effect of the product category to which the product belongs or
similar devices and procedures;
-
the event has a temporal relationship to the use/application or procedures of the
investigational device;
-
The event affects a place in the body or an organ that:
o
the product or procedures under investigation are applied;
o
on which the investigational product or procedures have an effect
-
the serious adverse event follows a known response pattern to the medical device (if the
response pattern is previously known);
-
Discontinuing the application of the medical device (or reducing the trigger/exposure level)
and reintroducing its use (or increasing the trigger/exposure level) impact the serious
adverse event (when clinically feasible);
Page 34 of 42

-
other possible causes have been adequately ruled out (for example, an underlying or
concurrent disease/clinical condition or/and an effect of another device, medication or
treatment);
-
the damage to the subject is due to an error in use;
-
the event depends on a false result given by the investigational device used for diagnosis
where applicable;
To establish the relationship, not all of the criteria listed above may be met, depending on the type of
device/procedure and the serious adverse event.
The sponsor and investigators will distinguish between serious adverse events related to the
investigational product and those related to procedures (any procedure specific to the clinical
investigation). An adverse event may be related to both the procedures and the device under
investigation.
Complications caused by concomitant non-clinical investigational treatments are
considered unrelated to the clinical investigation plan. Likewise, those routine diagnostic or patient
management procedures, performed independently of the clinical research plan, if they are not
described by the clinical research plan, the complications caused by them are also considered unrelated.
In some particular cases, the event may not be adequately evaluated because the information is
insufficient or contradictory and/or the data cannot be verified or complemented. The promoter and
investigators will make every effort to define and categorize the event and avoid these situations.
Where no investigator assessment is available and/or the sponsor is unsure of the serious adverse event
classification of serious adverse events, the sponsor should not exclude the relationship; the event of the
relationship; the event should be classified as "possible" and notification should not be delayed.
Particular attention will be paid to the assessment of causality of unforeseen serious adverse events.
Their occurrence could suggest that clinical research places participating subjects at a greater risk of
harm than could be expected beforehand.
14.4 Security plan
14.4.1 Registration and collection of adverse events
During scheduled evaluation visits and for the purpose of evaluating participants (study visits, phone
calls, etc.), a uniform methodology will be established for asking the patient about any AEs without
suggesting an answer to the questions. Below are some examples of open questions:
How have you been feeling since your last visit?
Have you experienced any new problems with your health since our last contact?
Page 35 of 42

All adverse events occurring during the clinical investigation observed by the investigator or reported by
the participant, whether or not attributed to the device under investigation, will be recorded in the CRD
as specified in the Clinical Research Plan.
The following information will be recorded: description, start date and end date, severity, assessment of
relationship to the investigational device, other suspected drug or device, and action taken. Tracking
information should be provided as necessary.
14.4.2 Reporting period for adverse events
The relationship of the AEs to the device will be evaluated by a qualified investigator or by the
sponsor/manufacturer and will be followed until resolution or until the event is considered stable.
All EADs that result in a participant's withdrawal from the research or are present at the end of the study
should be followed up until a satisfactory resolution occurs.
14.4.3 Notification of AAGs/ EAGDs/ EAIDs
The investigator must report any AAG/EAGD/EAIDs or laboratory problems to the sponsor immediately
but no later than 3 calendar days after learning of the event; regardless of the relationship to the device.
Communication will be made by email to the address: help@humanitcare.com. The following
information must be specified in the email in order to manage the incident as quickly as possible:
-
Name of participating center
-
Platform Tracking Plan ID
-
User ID (in case the incident is related to a specific user)
-
Detailed description of the incident
-
Support where the incident occurred (web platform + browser / mobile app + operating system)
-
Date on which the described incident occurred
The sponsor must inform the health authorities, the Clinical Research Ethics Committee and the
investigators, in accordance with Article 80(2) of the MDR, the ICH-GPC guidelines, the EU Clinical Trials
Regulation and other national laws or regulatory requirements applicable in the countries in which the
research takes place, of the following:
-
All SAEs that have a causal relationship with the investigational product, the comparator or the
procedure, or whose causal relationship is reasonably possible.
-
Product deficiencies that could have led to an AAG if appropriate measures had not been taken,
intervention had not occurred, or circumstances had been less fortunate.
-
Any new discovery related to both situations (AAG and deficiencies).
The minimum information to be communicated includes the identification of the subject, identification
of the AE, start date, reason why it is considered serious, and name of the person who initially reported
the event.
Page 36 of 42

Any additional information regarding previously reported unexpected AEs should also be entered into
the relevant form as soon as possible.
Additionally, the information must be entered into the CRD.
14.4.4 Report
The sponsor will report all adverse events that are serious and have reasonable potential causality with
the investigated product or procedure, in the opinion of the investigator or the sponsor, to the relevant
parties within the stipulated time frames and in accordance with local regulations.
Se utilizará el formato de la MDCG 2020-10/1 Safety reporting in clinical investigations of medical
devices under the Regulation (EU) 2017/745 del Appendices 12 Clinical Investigation Summary Safety
Reporting Form.
14.4.5 Notification periods
The sponsor shall ensure that all relevant information on suspected serious and unexpected adverse
events of the product, which are fatal or life-threatening, is recorded and communicated as soon as
possible to the competent authorities of all affected Member States and to the Ethics Committee.
In the case of Spain, notifications will be made to the AEMPS through the mailbox psinvclinic@aemps.es.
In any case, the promoter will send the information immediately and no later than 2 calendar days from
the moment the promoter becomes aware of the case. This information must be completed, if possible,
within the following eight days.
14.4.6 Expedited notification of other relevant safety information
The sponsor must expeditiously notify all information that could modify the risk/benefit ratio of the
medical device under investigation, or determine changes in its administration regimen or in the conduct
of the research, for example:
-
A qualitative change or increase in an expected SAE/EAGD/EAID, which is considered clinically
relevant.
-
Unexpected SAEs that occur after the completion of a clinical investigation and are notified by
the investigator to the sponsor.
-
New developments related to the conduct of the research or the development of the
investigational device and that are likely to affect the safety of the subjects.
-
Any recommendations from the data monitoring committee, which are relevant to the safety of
the subjects.
This relevant information must be notified as soon as possible and no later than 7 calendar days after
the promoter has become aware of it. Furthermore, if additional information is obtained that is relevant,
it must be notified as quickly as possible.
Page 37 of 42

14.4.7 Monitoring of adverse events
Monitoring of AEs, especially those that could not be classified as “unrelated” due to the relationship
with the product under investigation, is necessary until the reference level is reached or the subject
remains stable. If a clear explanation is found, it should be entered in the CRD. If the type of AA requires
the assistance of another person, the subject will be referred to the local hospital, and information about
the subject's progress should also be recorded in the corresponding CRD, even if the subject has
withdrawn from the clinical investigation for safety reasons. . Follow-up of AEs will continue until
resolution, with confirmation if the subject remains stable, or until follow-up is no longer possible.
Follow-up will be necessary for both subjects who attend the participants' clinic and those who are
referred to their local hospitals for further treatment.
The safety parameter will be defined as the adverse events that occur, including those leading to
withdrawal from the study.
14.4.8 Adverse Events Associated with the Investigational Device
In this study the safety information will be given in the user manual. No relevant adverse effects are
anticipated.
15 Suspension or early termination of CI
15.1 Termination and Discontinuation Criteria
The research will be completed when all research subjects have completed all the visits established in
the clinical research plan.
However, research can be stopped prematurely:
-
For security reasons.
-
If the planned recruitment data is not met
-
If the research is not being carried out in accordance with the standards of Good Clinical
Practice (GCP).
15.2 Completion of the investigation
The end of the research is defined as the moment in which the last subject has completed the last visit,
in accordance with REGULATION (EU) No. 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE
COUNCIL of April 16, 2014 on clinical trials and medical devices. for human use, and repealing Directive
2001/20/EC.
15.2.1 Monitoring and care plan for subjects after the completion of the clinical
research
Page 38 of 42

Once the study is completed, the subject will continue with their treatment following the usual protocol,
or, if they wish, using our platform by obtaining a license from it.
16 Publishing policy
The results of the research will be made public according to the channels accepted by the scientific
community, maintaining in all cases the confidentiality and rights of the participants.
16.1 Preparation of the final clinical research report
Once the recruitment of the last subject is completed, the statistical analysis of the results will be carried
out and the final report of the clinical investigation will be prepared.
16.2 Clinical evaluation plan
The analysis of the results and the final report will be part of the development of the Clinical Evaluation
Plan (CEP) described in section A of annex XIV of regulation 2017/745, which is being developed as part
of the technical documentation for obtaining the marking. CE of the product as a medical device.
Page 39 of 42

17 Literature
Brahmbhatt, D. H., & Cowie, M. R. (2019). Remote Management of Heart Failure: An Overview of
Telemonitoring Technologies. Cardiac Failure Review, 5(2), 86–92.
https://doi.org/10.15420/cfr.2019.5.3
Brooke, J. (1995). SUS: A quick and dirty usability scale. Usability Eval. Ind., 189.
Calvo-López, M., Tolós, R. A., Expósito, J. M., Gruosso, D., Andrea, R., Roque, M., Falces, C., Yago, G.,
Araguas, J. S., Pastor, N., Sitges , M., & Garza, M. S. la. (2023). Cardio4Health Study, a Cardiac
Telerehabilitation Pilot Program Aimed at Patients After an Ischemic Event: Cross-sectional
Study. JMIR Cardio, 7(1), e44179. https://doi.org/10.2196/44179
Castillo Padrós, M. R., Mosquera Peña, M., Benítez Rosario, M., Riveira Fraga, M. C., Garrido Bernet, B., &
García García, R. M. (2022). New attention and care strategies in the context of a pandemic:
Development of a telematic symptom monitoring system in patients with advanced diseases
(AvanzaT). Palliative Medicine, 29(3), 171–179.
https://doi.org/10.20986/medpal.2022.1319/2022
Garin, O., Soriano, N., Ribera, A., Ferrer, M., Pont, À., Alonso, J., & Permanyer, G. (2008). Validation of the
Spanish version of the Minnesota Living with Heart Failure Questionnaire. Spanish Journal of
Cardiology, 61(3), 251–259. https://doi.org/10.1157/13116652
Guidi, G., Pollonini, L., Dacso, C. C., & Iadanza, E. (2015). A multi-layer monitoring system for clinical
management of Congestive Heart Failure. BMC Medical Informatics and Decision Making, 15
Suppl 3(Suppl 3), S5. https://doi.org/10.1186/1472-6947-15-S3-S5
Jaarsma, T., Arestedt, K. F., Mårtensson, J., Dracup, K., & Strömberg, A. (2009). The European Heart
Failure Self-care Behaviour scale revised into a nine-item scale (EHFScB-9): A reliable and valid
international instrument. European Journal of Heart Failure, 11(1), 99–105.
https://doi.org/10.1093/eurjhf/hfn007
Koehler, F., Winkler, S., Schieber, M., Sechtem, U., Stangl, K., Böhm, M., Boll, H., Baumann, G., Honold,
M., Koehler, K., Gelbrich, G., Kirwan, B.-A., Anker, S. D., & Telemedical Interventional Monitoring
in Heart Failure Investigators. (2011). Impact of remote telemedical management on mortality
Page 40 of 42

and hospitalizations in ambulatory patients with chronic heart failure: The telemedical
interventional monitoring in heart failure study. Circulation, 123(17), 1873–1880.
https://doi.org/10.1161/CIRCULATIONAHA.111.018473
Koulaouzidis , G. , Iakovidis , D. K. , & Clark , A. L. (2016). Telemonitoring predicts in advanced heart
failure admissions. International Journal of Cardiology, 216, 78–84.
https://doi.org/10.1016/j.ijcard.2016.04.149
Lee, S., Chu, Y., Ryu, J., Park, Y. J., Yang, S., & Koh, S. B. (2022). Artificial Intelligence for Detection of
Cardiovascular-Related Diseases from Wearable Devices: A Systematic Review and
Meta-Analysis. Yonsei Medical Journal, 63(Suppl), S93–S107.
https://doi.org/10.3349/ymj.2022.63.S93
Lewis, J. R. (1992). Psychometric Evaluation of the Post-Study System Usability Questionnaire: The
PSSUQ. Proceedings of the Human Factors Society Annual Meeting, 36(16), 1259–1260.
https://doi.org/10.1177/154193129203601617
McDonagh, T. A., Metra, M., Adamo, M., Gardner, R. S., Baumbach, A., Böhm, M., Burri, H., Butler, J.,
Čelutkienė, J., Chioncel, O., Cleland, J. G. F., Coats, A. J. S., Crespo-Leiro, M. G., Farmakis, D.,
Gilard, M., Heymans, S., Hoes, A. W., Jaarsma, T., Jankowska, E. A., … ESC Scientific Document
Group. (2021). 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart
failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart
failure of the European Society of Cardiology (ESC) With the special contribution of the Heart
Failure Association (HFA) of the ESC. European Heart Journal, 42(36), 3599–3726.
https://doi.org/10.1093/eurheartj/ehab368
Ortega Suárez, F. J., Sánchez Plumed, J., Pérez Valentín, M. A., Pereira Palomo, P., Muñoz Cepeda, M. A.,
& Lorenzo Aguiar, D. (2011). Validation of the simplified medication adherence questionnaire
(SMAQ) in kidney transplant patients on tacrolimus therapy. Nephrology (Madrid), 31(6),
690–696.
Rector, T. S. (n.d.). FDA Medical Device Development Tool (MDDT) Qualification Package for the
Minnesota Living with Heart Failure Questionnaire (MLHFQ).
Roque, N. A., & Boot, W. R. (2018). A New Tool for Assessing Mobile Device Proficiency in Older Adults:
Page 41 of 42

The Mobile Device Proficiency Questionnaire. Journal of Applied Gerontology: The Official
Journal of the Southern Gerontological Society, 37(2), 131–156.
https://doi.org/10.1177/0733464816642582
Sanchez, U., Pastor, N., Ruiz, M., Amorós, J., & Morrison, D. (2020). Observational Pilot Study of Remote
Telemonitoring of Heart Failure Patients in Torrevieja Hospital.
Schiff, G. D., Fung, S., Speroff, T., & McNutt, R. A. (2003). Decompensated heart failure: Symptoms,
patterns of onset, and contributing factors. The American Journal of Medicine, 114(8), 625–630.
https://doi.org/10.1016/s0002-9343(03)00132-3
Tripoliti, E. E., Papadopoulos, T. G., Karanasiou, G. S., Naka, K. K., & Fotiadis, D. I. (2017). Heart Failure:
Diagnosis, Severity Estimation and Prediction of Adverse Events Through Machine Learning
Techniques. Computational and Structural Biotechnology Journal, 15, 26–47.
https://doi.org/10.1016/j.csbj.2016.11.001
Page 42 of 42