Real Life Multimarker Monitoring in Patients With Heart Failure
Phase: NA
Conditions: Heart Failure
Sponsor: Bayer

Document Type: Study Protocol 
Official Title: 
Real Life Multimarker Monitoring in Patients with Heart Failure 
NCT Number: 
NCT03507439 
Document Date: 
21-FEB-2020

Integrated Clinical Study Protocol
No. 19167
21 Feb 2020
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Cover page of the integrated protocol
Real Life Multimarker Monitoring in Patients with Heart Failure
This protocol version is an integration of the following documents / sections:
Original protocol, Version 1.0, dated 06 Apr 2017
Amendment 1 (described in Section 15.1)
forming integrated protocol Version 2.0, dated 14 May 2018
Amendment 2 (described in Section 15.2)
forming integrated protocol Version 3.0, dated 06 Sep 2018
Amendment 3 (described in Section 15.3)
forming integrated protocol Version 4.0, dated 21 Feb 2020
Amendments not included in the consecutive numbering of amendments are 
local amendments not forming part of this integrated global protocol.

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1.
Title page - amended
Real Life Multimarker Monitoring in Patients with Heart Failure 
REALIsM-HF pilot study
Test drug:
Not applicable
Medical devices:
VitalPatch biosensor1
(VitalConnect1, USA) 
DynaPort Move Monitor (McRoberts, NL)
Clinical study phase:
Not applicable 
Date:
21 Feb 2020
Registration:
Not applicable
Version no.:
4.0
Sponsor’s study no.:
19167 
Sponsor:
Bayer AG, D-51368 Leverkusen, Germany
Sponsor’s medical expert:
Bayer AG
Aprather Weg 18a
42113 Wuppertal, Germany
Phone : 
E-mail : 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation.  Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed.  
Hence, the appearance of product names without these symbols does not imply that these names are not 
protected.
                                                
1 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)
PPD
PPD
PPD

21 Feb 2020 
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Signature of the sponsor's medically responsible person 
Page: 3 of 108 
The signatory agrees to the content of the final clinical study protocol as presented. 
Name: 
 
Date: 
2_ 4- _ 'FeJ.o .- z_ tJ 2. e
Role: 
 
Signature: 
PPD
PPD
PPD

21 Feb 2020 
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Name: 
Affiliation: 
Date: 
Signature: 
Signed copies of this signature page are stored in the sponsor's study file and i
center's investigator site file. 
In the protocol document, this page may remain unsigned. 
Signature of principal investigator 
The signatory agrees to the content of the final clinical study protocol as presented. 
 
PPD
PPD
PPD
PPD

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2.
Synopsis – amended
Title
Real Life Multimarker Monitoring in Patients with Heart Failure
Short title
REALIsM-HF pilot study
Clinical study phase
Exploratory study evaluating the clinical utility and feasibility of activity 
tracking in patients with HFrEF and HFpEF.
All medicinal products are used in accordance with the terms of the 
marketing authorization. Additional diagnostic or monitoring procedures 
do not pose more than minimal additional risk or burden to the safety of 
the subjects compared to normal clinical practice.
Study objective(s)
The study aims to explore two marketed devices providing a multi-marker 
monitoring including physical activity under real-life conditions in patients 
with HFpEF and HFrEF. It aims to identify potential novel endpoints for 
future HFpEF 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.
In addition, it is hypothesized that “subjective” items generated from 
patient experiences (PRO, QoL) in combination with an (objective) 
activity monitor would capture all relevant dimensions of exercise capacity 
in patients with HFpEF and HFrEF and thus can be used as patient centric 
approach in clinical studies.
Primary objective:

Measurement and quantification of daily physical activity (PA) in 
patients with HFpEF and HFrEF under real life conditions by 
activity tracker/belt and patch 
Secondary objectives:

Association between VitalPatch biosensor2 and DynaPort Move 
Monitor data (e.g. different levels of activity) to adverse 
events/clinical outcome data occurring during the study period

Assess the baseline level and longitudinal changes over time of 
heart rate, respiratory rate and ECG-derived parameters and the 
average of person-to-person physiological variability and the 
within-patient standard deviation between the baseline and 3-
month measurements.3
                                                
2 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)
3 Tissue impedance deleted as per Amendment 3 (Section 15.3)

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
Assess the feasibility of activity tracking with two devices 
(VitalPatch biosensor4 and DynaPort Move Monitor) in patients 
with heart failure

Correlation of activity data between VitalPatch biosensor4 data on 
activity and DynaPort Move Monitor 

Evaluate the relationship between physical activity levels, heart 
rate, respiratory rate and ECG-derived parameters and important
measures in HFpEF; such as quality of life (QoL), patient reported 
outcome (PRO), biomarkers, outcomes (e.g. clinical endpoints 
such as hospitalization for heart failure, cardiovascular death, 
emergency visits)5

Support the development of HFpEF specific questions (PRO) for 
testing/validating cross-sectional and longitudinally 

Determine the variability of device derived biomarkers between 
subjects and within subjects over time in order to validate such 
biomarkers for clinical use in the context of heart failure.

Evaluate hs-copeptin as potential biomarker 6,7

Correlation between patch monitor collected data and patient 
clinical data from the start of the study (e.g. echocardiography, 
weight gain/loss, NYHA, heart rate)

Explore the relationship between physical activity (PA), 6MWD, 
PRO, biomarkers, adverse events/clinical outcomes

Investigate the accuracy of patients’ self-reports (PRO, e.g. 
KCCQ) of time spent on PA in real life vs. objective assessment 
by the DynaPort Move Monitor and VitalPatch biosensor4
Medical Devices
Device 1
VitalPatch biosensor (VitalConnect, USA)4
Device 2
DynaPort Move Monitor (McRoberts, NL)
The devices will be provided by BAYER to sites and used according to 
their approved labeling.
Background treatment
During the study duration changes in treatment for HF and comorbidities 
should be based on clinical need. There is no change of the therapy 
required according to the protocol.
                                                
4 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)
5 tissue impedance deleted as per Amendment 3 (Section 15.3)
6 Transcutaneous thoracic impedance measurement and its correlation to biomarkers deleted as per Amendment 3 ((Section 
15.3)
7 Wording adapted as per Amendment 3 (Section 15.3)

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Indication
Heart failure with preserved ejection fraction (HFpEF) and Heart failure 
with reduced ejection fraction (HFrEF)
Diagnosis and main 
criteria for inclusion 
/exclusion
Female and male subjects with a diagnosis of heart failure with preserved 
ejection fraction (HFpEF; EF ≥ 45%) or reduced ejection fraction (HFrEF; 
EF ≤ 35%) will be enrolled.8
Study design
Multi-center, non-blinded, non-randomized, observatory prospective 
patient study
Methodology9
This study will comprise a screening phase of up to 9 days including an 
optional hospitalization period, an outpatient phase of approximately 12
weeks and a follow up telephone call after 6 months
Patients will be selected on the basis of their established diagnosis of 
HFrEF and HFpEF.
The patients will have site visits at week 0 (screening visit and visit 1 
within 9 days, during hospitalization phase or in ambulatory patients), 
week 1 after visit 1 / hospital discharge (visit 2; observational phase), week 
11 post visit 1 / discharge (visit 3, observational phase) and week 12 post 
visit 1 / discharge (visit 4, observational phase). 
In addition, one follow up phone call at 6 month post discharge will be 
made to assess patient safety, well-being and clinical status.
The VitalPatch10 heart failure patch will be applied at visit 1 / hospital 
discharge (first VitalPatch biosensor patch)10, at visit 2 (2nd patch, 3rd
patch will be subsequently applied by the patient at home), and at visit 3
(4th patch, 5th patch will be subsequently applied by the patient at home). 
The Dynaport MoveMonitor belt will be applied at visit 2 and visit 3. The 
6MWD test will be done at visit 1 / hospital discharge as well as visit 4 (12 
weeks post visit 1 / discharge). 
Transthoracic echocardiography will be performed at visit 1 (within ± 72 
hours).
The KCCQ questionnaire will be performed at visit 1 / prior to discharge, 
at week 3 after visit 1 / discharge, and at visit 4.
Daily and weekly PRO will be performed in parallel with the DynaPort 
MoveMonitor monitoring periods (visit 2, week 2-3) and visit 3 (week 11-
12).
Biomarkers reflecting cardiac structure and function will be examined as 
well as candidate biomarkers that may predict outcomes.
Daily physical activity (duration and intensity) will be recorded during 
repeated respective 5-day (Vital Patch) and 7-day (DynaPort 
MoveMonitor) time periods until 3 months after visit 1 / discharge from 
hospital.
                                                
8 Diagnosis extended as per Amendment 3 (Section 15.3)
9 Methodology adapted to new conduct specifications as per Amendment 3 (Section 15.3)

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Type of control
not applicable
Number of subjects
Due to the exploratory nature of this study, and to the multiplicity and the 
type of the observed parameters, the number of target subject was chosen 
to be comparable with other studies where a significant difference in PA 
was observed. The study will enroll enough subjects to have 80 subjects 
(HFpEF n=60, HFrEF n=20) who completed the main study, i.e. visit 4.
Primary variable(s)
Daily physical activity (amount, intensity, duration) obtained from the 
VitalPatch biosensor11 / DynaPort Move Monitor device
Time point/frame of 
measurement for 
primary variable(s)
Baseline level and longitudinal changes over time of physical activity and 
the average of person-to-person physiological variability and the within-
subject standard deviation between the baseline and 3-month post baseline
measurements.12
Plan for statistical 
analysis
Statistical analyses will be of explorative and descriptive nature. The study 
is not aimed to confirm or reject pre-defined hypotheses.
All variables will be analyzed descriptively with appropriate statistical 
methods: categorical variables by frequency tables (absolute and relative 
frequencies) and continuous variables by sample statistics (i.e. mean, 
standard deviation, minimum, median, quartiles and maximum). 
Continuous variables will be described by absolute value and as change 
from baseline per analysis time point, if applicable.
The variability of biomarkers assumed to be normal distributed will be 
analyzed using a linear mixed effect model with subject as random factor, 
and time as fixed factor, possibly including additional covariates as may 
result from the assessment at baseline for subject stratification or as 
required for clinical interpretation. Based on this model, point estimates 
(LS-Means) and exploratory 90% confidence intervals will be calculated 
for comparing baseline and 3 months data. For biomarkers assumed to be 
log-normal distributed, the logarithms of the biomarker concentration will 
be analyzed, and results will be reported as ratio for comparing baseline 
and 3 months data.
All analyses will be performed for the total study population (overall 
analysis). Subjects wearing at least once the VitalPatch biosensor11 system
and for which data was successfully collected over 5 days 13 will be 
included in the analysis.
Sample size and disposition information by analysis time point will be 
displayed in a frequency table.
                                                                                                                                                        
10 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)
11 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)
12 Adapted to reflect the extension on non-hospitalized subjects as per Amendment 3 (Section 15.3) 
13 Adapted to reflect the limitations of the VitalPatch biosensor system as per Amendment 3 (Section 15.3)

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Table of Contents
Cover page of the integrated protocol.................................................................................... 1
1.
Title page - amended......................................................................................................... 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of principal investigator......................................................................................... 4
2.
Synopsis – amended .......................................................................................................... 5
Table of Contents ..................................................................................................................... 9
Table of Tables ....................................................................................................................... 12
Table of Figures...................................................................................................................... 12
List of abbreviations............................................................................................................... 13
3.
Introduction - amended .................................................................................................. 15
4.
Study objectives - amended............................................................................................ 18
5.
Study design - amended.................................................................................................. 19
6.
Study population ............................................................................................................. 21
Inclusion criteria - amended........................................................................................... 21
6.1
Exclusion criteria - amended ......................................................................................... 22
6.2
Justification of selection criteria.................................................................................... 24
6.3
Withdrawal of subjects from study................................................................................ 25
6.4
6.4.1
Withdrawal ................................................................................................................. 25
6.4.2
Replacement ............................................................................................................... 26
Subject identification ..................................................................................................... 27
6.5
7.
Treatments....................................................................................................................... 27
Treatments to be administered....................................................................................... 27
7.1
Identity of study treatment............................................................................................. 27
7.2
Treatment assignment.................................................................................................... 27
7.3
Dosage and administration............................................................................................. 27
7.4
Blinding ......................................................................................................................... 27
7.5
Drug logistics and accountability................................................................................... 27
7.6
Treatment compliance.................................................................................................... 27
7.7
8.
Non-study therapy........................................................................................................... 27
Prior and concomitant therapy....................................................................................... 27
8.1
Post-study therapy.......................................................................................................... 28
8.2
9.
Procedures and variables ............................................................................................... 28
Tabular schedule of evaluations - amended................................................................... 28
9.1
Visit description - amended ........................................................................................... 30
9.2
Population characteristics .............................................................................................. 33
9.3
9.3.1
Demographic .............................................................................................................. 33
9.3.2
Medical history........................................................................................................... 33
Efficacy.......................................................................................................................... 33
9.4

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Pharmacokinetics / pharmacodynamics......................................................................... 33
9.5
Safety ............................................................................................................................. 33
9.6
9.6.1
Adverse events............................................................................................................ 33
Definitions............................................................................................................... 33
9.6.1.1
Classifications for adverse event assessment.......................................................... 34
9.6.1.2
9.6.1.2.1
Seriousness........................................................................................................... 34
9.6.1.2.2
Intensity................................................................................................................ 35
9.6.1.2.3
Causal relationship............................................................................................... 35
9.6.1.2.4
Action taken with study treatment ....................................................................... 36
9.6.1.2.5
Other specific treatment(s) of adverse events...................................................... 36
9.6.1.2.6
Outcome............................................................................................................... 36
Assessments and documentation of adverse events ................................................ 36
9.6.1.3
Reporting of serious adverse events - amended....................................................... 37
9.6.1.4
Expected adverse events.......................................................................................... 38
9.6.1.5
9.6.2
Pregnancies................................................................................................................. 38
9.6.3
Further safety – amended ........................................................................................... 38
Other procedures and variables...................................................................................... 39
9.7
9.7.1
VitalPatch biosensor/DynaPort Move Monitor devices - amended ........................... 39
9.7.2
Quality of life assessment/PRO - amended................................................................ 40
9.7.3
Six-minute walking distance ...................................................................................... 42
9.7.4
Laboratory parameters................................................................................................ 43
Appropriateness of procedures / measurements ............................................................ 43
9.8
10. Statistical methods and determination of sample size ................................................. 44
General considerations - amended................................................................................. 44
10.1
Analysis sets - amended................................................................................................. 44
10.2
Variables and planned statistical analyses..................................................................... 45
10.3
10.3.1
Analysis of demography, disease details, prior and concomitant medication and 
other baseline data ...................................................................................................... 45
10.3.2
Analysis of data within the hospitalization phase - amended..................................... 45
10.3.3
Analysis of primary and secondary outcomes............................................................ 46
Assessment of variability ........................................................................................ 46
10.3.3.1
Analysis of correlations - amended......................................................................... 47
10.3.3.2
10.3.4
Analysis of safety data................................................................................................ 47
Determination of sample size......................................................................................... 47
10.4
11. Data handling and quality assurance............................................................................ 48
Data recording................................................................................................................ 48
11.1
Monitoring ..................................................................................................................... 49
11.2
Data processing.............................................................................................................. 49
11.3
Missing data................................................................................................................... 50
11.4
Audit and inspection ...................................................................................................... 50
11.5
Archiving ....................................................................................................................... 50
11.6
12. Premature termination of the study.............................................................................. 50
13. Ethical and legal aspects................................................................................................. 51
Investigator(s) and other study personnel...................................................................... 51
13.1
Funding and financial disclosure - amended ................................................................. 51
13.2
Ethical and legal conduct of the study........................................................................... 52
13.3

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Subject information and consent.................................................................................... 52
13.4
Publication policy and use of data ................................................................................. 53
13.5
Compensation for health damage of subjects / insurance.............................................. 54
13.6
Confidentiality ............................................................................................................... 54
13.7
14. Reference list.................................................................................................................... 55
15. Protocol amendments...................................................................................................... 56
Amendment 1................................................................................................................. 56
15.1
15.1.1
Overview of changes to the study protocol ................................................................ 56
15.1.2
Changes to the protocol text....................................................................................... 57
Section 9.1 Time window added for conduct of echocardiography........................ 57
15.1.2.1
Section 9.2 Time window added for conduct of echocardiography........................ 58
15.1.2.2
Section 9.6.3 Time window added for conduct of echocardiography..................... 59
15.1.2.3
Section 6.2 Exclusion criterion for hemoglobin changed ....................................... 60
15.1.2.4
Section 2 Addition of weekly PRO......................................................................... 60
15.1.2.5
Section 9.1 Addition of weekly PRO...................................................................... 61
15.1.2.6
Section 9.2 Addition of weekly PRO...................................................................... 62
15.1.2.7
Section 9.7.2 Addition of weekly PRO................................................................... 63
15.1.2.8
Amendment 2................................................................................................................. 63
15.2
15.2.1
Overview of changes to the study protocol ................................................................ 63
15.2.2
Changes to the protocol text....................................................................................... 64
Section 1 Replacement of AVIVO MPM with VitalPatch Biosensor .................... 64
15.2.2.1
Section 2 Replacement of AVIVO MPM with VitalPatch Biosensor .................... 65
15.2.2.2
Section 3 Replacement of AVIVO MPM with VitalPatch Biosensor .................... 67
15.2.2.3
Section 4 Replacement of AVIVO MPM with VitalPatch Biosensor .................... 68
15.2.2.4
Section 5 Replacement of AVIVO MPM with VitalPatch Biosensor .................... 70
15.2.2.5
Section 6.1 Replacement of AVIVO MPM with VitalPatch Biosensor ................. 72
15.2.2.6
Section 9.1 Replacement of AVIVO MPM with VitalPatch Biosensor ................. 72
15.2.2.7
Section 9.2 Replacement of AVIVO MPM with VitalPatch Biosensor ................. 73
15.2.2.8
Section 9.6.1.4 Replacement of AVIVO MPM with VitalPatch Biosensor ........... 76
15.2.2.9
Section 9.7.1 Replacement of AVIVO MPM with VitalPatch Biosensor .............. 77
15.2.2.10
Section 9.7.2 Replacement of AVIVO MPM with VitalPatch Biosensor .............. 78
15.2.2.11
Section 10.1 Replacement of AVIVO MPM with VitalPatch Biosensor ............... 78
15.2.2.12
Section 10.2 Replacement of AVIVO MPM with VitalPatch Biosensor ............... 79
15.2.2.13
Section 10.3.2 Replacement of AVIVO MPM with VitalPatch Biosensor ............ 80
15.2.2.14
Section 10.3.3.2 Replacement of AVIVO MPM with VitalPatch Biosensor ......... 80
15.2.2.15
Section 13.2 Replacement of AVIVO MPM with VitalPatch Biosensor ............... 80
15.2.2.16
Section 16.1 Replacement of AVIVO MPM with VitalPatch Biosensor ............... 81
15.2.2.17
Amendment 3................................................................................................................. 82
15.3
15.3.1
Overview of changes to the study protocol ................................................................ 82
15.3.2
Changes to the protocol text....................................................................................... 83
Section 2 Extension of study population and simplification of study procedures .. 83
15.3.2.1
Section 4 Deletion of tissue impedance related objectives ..................................... 88
15.3.2.2
Section 5 Extension of study population and simplification of procedures............ 90
15.3.2.3
Section 6.1 Extension of study population.............................................................. 92
15.3.2.4
Section 6.2 Extension of study population.............................................................. 93
15.3.2.5
Section 9.1 Simplification of study procedures ...................................................... 94
15.3.2.6
Section 9.2 Simplification of study procedures ...................................................... 97
15.3.2.7

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Section 9.6.3 Simplification of study procedures ................................................. 102
15.3.2.8
Section 9.7.1 Removal of thoracic impedance measurement................................ 103
15.3.2.9
16. Appendices..................................................................................................................... 104
REALIsM-HF exploratory daily questionnaire to measure physical activity in heart 
16.1
failure - amended ......................................................................................................... 104
Table of Tables
Table 9–1: Tabulated overview on study procedures and variables collected during the study -
amended................................................................................................................. 29
Table of Figures
Figure 5-1: Study design - amended ........................................................................................ 19
Figure 9-1 Kansas City Cardiomyopathy Questionnaire score............................................... 42

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List of abbreviations
AE 
adverse event
AF
atrial fibrillation
BNP
B-type natriuretic peptide
CABG
Coronary artery bypass graft 
CRO
contract research organization
CRTD
Implantation of a cardiac resynchronization therapy device
DMP
data management plan
(e)CRF
(electronic) case report form
ECG
electrocardiogram
EDC
electronic data capture
EU
European Union
FPFV
first patient first visit
Gal 3
Galectin-3
GCP
good clinical practice
GDF 15
growth differentiation factor 15
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HF
heart failure
HFmrEF
heart failure with mid-range ejection fraction
HFpEF
heart failure with preserved ejection fraction
HFrEF
heart failure and reduced ejection fraction
HRV
heart rate variability 
hsTNT
high-sensitivity troponin T
ICH
International Conference of Harmonization
IEC
Independent ethics committee

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IGFBP7
insulin-like growth factor binding protein 7
INN
international nonproprietary name
IRB
institutional review board 
KCCQ
Kansas City Cardiomyopathy Questionnaire score
LPLV
last patient last visit
MedDRA
Medical Dictionary for Regulatory Activities
MPM
mobile patient monitoring
MRP
medical review plan
6MWD
six minute walking distance 
NT-proBNP
N-terminal propeptide of BNP
NYHA
New York Heart Association
PA
physical activity
PCI
Percutaneous coronary intervention
PRO
patient reported outcome
QoL
quality of life
QRP
quality review plan
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedure
sST2
Soluble suppression of tumorigenicity 2

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3.
Introduction - amended
Rationale and Background
Heart failure (HF) is known to be a major public health problem and a major cause of 
mortality and morbidity. It has a prevalence of up to 22% in elderly, and aging of population 
worldwide will result in a further rise in the HF prevalence by 50% over the next 10-15 years 
[1, 2]. 
Acute decompensated heart failure is constantly increasing in prevalence and is strongly 
associated with mortality and morbidity, including frequent hospitalizations [3, 4]. The high 
percentage (30 – 60%) of readmissions within 6 months is particularly noteworthy [5].
Heart failure with preserved ejection fraction (HFpEF) currently accounts for more than 50% 
of all HF cases and shows rising incidence [6], and outcomes among these patients are as poor 
as those with HF and reduced ejection fraction (HFrEF). Previous HF trials have focused 
primarily on reduction of CV mortality and/or readmission risk, whereas studies among 
hospitalized patients have largely focused on acute symptoms. Given the fact that patients 
with HFpEF are much older and have significant comorbidity burden compared to their peers 
with HFrEF, it is difficult to conceive that one drug or device can reduce mortality or 
hospitalization risk in these patients.[7] Though intensively managed, these patients remain 
symptomatic and have substantially reduced functional capacity and quality of life (QoL).
Improvement in mortality remains the gold standard outcome for HF clinical trials, and 
indeed many therapies in patients with HFrEF were able to reduce the risk of death. However, 
in HFpEF patients, the competing risk for death by complex comorbidities is substantial 
among these patients. Effectively targeting mechanisms related to HFpEF may improve 
underlying pathophysiology and subsequently patient status; however, this may be 
insufficient to alter overall mortality among HFpEF patients. Thus, in an older HFpEF 
population due to the competing risk for death, it may be prohibitively difficult to improve 
mortality as a singular goal of therapy. Reducing the risk of hospitalizations is an important 
consideration as they are associated with poor outcomes, high costs and impaired QoL. 
However, one of the major issues is that it may reflect regional practices [8]. 
Thus, alternate patient centric outcomes reflecting “patient journey” should be pursued as 
reasonable basis for drug approval in HFpEF. QoL/patient reported outcome (PRO) and 
exercise capacity is an increasingly recognized patient and caregiver concern and may present 
more pragmatic outcomes, but are currently not typically considered as primary endpoints for 
clinical trials in HF patients. 
The traditional approach for vital signs and biometrical data monitoring is based on in-
hospital spot-check measurements, which do not effectively characterize human physiology in 
real life environment. Current trends in the assessment of physical activity focus on the 
measures of amount and frequency of activities using activity monitors in real life 
environment. Biometrical data monitored from arrival to the hospital, throughout the hospital 
stay, and continued at home, based on new device technology offers a unique opportunity to 
explore these new endpoints in HF patients. In patients with HFpEF, small changes in 
physical activity are likely to be important effects of interventions aimed at enhancing 
physical activity and improvement of QoL. Therefore, in order for investigators to interpret 
the effect of interventions on physical activity, activity monitors that have been properly 
validated in these patient groups are needed.

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As these new digital technologies are technically validated but not yet fully clinically
validated, it is not clear whether clinical studies should harness the power of mobile health 
data to improve therapeutic outcomes and trial efficiency. These analytic devices need to be 
further evaluated for their clinical feasibility and the ability to identify clinically relevant 
changes. Furthermore, it is unlikely that an activity monitor can fully capture patients' 
experience of physical activity. For example, in chronic obstructive pulmonary disease 
patients, qualitative research has shown that patients experience symptoms while being active, 
or have to adapt their lifestyle, features that will unlikely be captured using activity monitors 
alone. Such a patient-centered concept should therefore include a PRO questionnaire in 
addition to tracking of physical activity. Conversely, a PRO questionnaire alone will also not 
allow assessment of physical activity patterns or detection of small changes in physical 
activity on a day-to-day basis. Unfortunately, the currently available PROs that aim to 
measure physical activity in HFpEF patients do not follow best practice as set out in the 
guidelines published by the US Food and Drug Administration (FDA).[9] Thus, in addition to 
testing the feasibility of activity tracking with two different devices, the present study aims to 
identify a set of non-redundant items for a potential PRO questionnaire in HFpEF. The data in
HFrEF will help generate hypotheses and aid in determining the feasibility of physical 
activity tracking with different devices in patients with HFrEF as well as HFpEF.
This study aims to explore two devices providing a multi-marker biometrical monitoring 
including daily activity under real-life conditions in patients with HFpEF and HFrEF. It aims 
to identify potential new endpoints for future HFpEF trials by exploring clinically relevant 
changes over time and correlations/associations with conventional endpoints and biomarkers. 
Furthermore, it aims to define the challenges and test the feasibility of this approach under 
real-life conditions.
It is hypothesized that “subjective” items generated from patient experiences (PRO) in 
combination with an (objective) activity monitor would capture all relevant dimensions of 
physical activity in patients with HFpEF.
The VitalPatch biosensor14 is a wearable, wireless physiological monitoring and arrhythmia 
detection system that is used by patients to aid clinicians in the identification, diagnosis and 
management of various clinical conditions, events and/or trends. It consists primarily of the 
wearable sensor (monitoring device) and a portable secured data transmitter (mobile phone 
with bluetooth and wireless connection). VitalPatch is manufactured by VitalConnect (USA), 
and is fully approved by the USA FDA, CE marked in the European Union, CMDR registered 
and ISO 13485 certified.14
The VitalPatch biosensor14 will be used to monitor patients’ cardiovascular status. The 
cardiac monitoring device will be worn as specified in Section 9.7.1.
The system is intended to continuously measure, record and store ECG data. The system can 
detect (but is not limited to) higher degree AV-blocks > I°, SVTs (e.g. atrial fibrillation [AF], 
atrial flutter, paroxysmal SVTs), ventricular ectopy, bradyarrhythmias, conduction disorders 
and heart rate variability. Apart from safety assessments, also the patient’s everyday physical 
activity (frequency, duration, intensity) will be tracked. 
                                                
14 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)

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Details of the cardiac monitoring and the device to be worn by the patient will be outlined in a 
manual that will be provided to all participating centers.
The DynaPort Move Monitor – the second activity tracker used in the present study -is a 
wearable device worn in an elastic strap on the lower back for ambulatory monitoring of 
physical activity for up to 7 days. DynaPort Move Monitor is manufactured by McRoberts 
BV (Netherlands). This device is US FDA approved, CE marked in the European Union and 
ISO 13485 certified.15 The DynaPort Move Monitor consists of three orthogonally mounted 
accelerometers, a tri-axial magnetometer, a temperature sensor and a barometer. 
Accelerometer data were collected at 100 Hz and stored on an internal flash memory drive.  
The DynaPort Move Monitor is attached centrally over the lower back with an elastic belt 
around the waist. The MoveMonitor distinguishes movement patterns (walking, shuffling, 
cycling, stair climbing) and body positions (standing, sitting, lying) during long-term 
measurements, and it measures the intensity (acceleration) at which movements such as 
walking are performed. The data collected will be uploaded to a secured cloud server, and the 
positions and accelerations of the 3 sensors will be analyzed with the MoveMonitor software. 
The software translates the recorded acceleration signals into basic activities (walking, 
shuffling, cycling, stair climbing) and postures (standing, sitting, lying) and quantifies the 
time spent in each of these activities or postures.
Benefit-risk assessment
The patients will not benefit from this study as they are treated according to standard of care 
and will receive no investigational drug. The devices, the questionnaires and the blood 
biomarkers will not have an influence on the treatment of the patients as these are only 
observational assessments which will have no effect on the well-being or disease progression 
of the patients.
Both devices have a CE mark and an FDA approval and are safe and well tolerated. All 
medicinal products are used in accordance with the terms of the marketing authorization.
The patients will have no direct individual therapeutic advantage from the participation in this 
clinical investigation, but their participation in the investigation is likely to contribute to 
benefits for specific patient groups.
All potential risks arising from the patients’ participation in the clinical investigation have 
been carefully assessed and found acceptable; they are outweighed by the foreseeable benefits 
for specific patient groups, especially for the population included in this study – patients with
HFpEF - in the development of an effective treatment for HFpEF.
Additional diagnostic or monitoring procedures do not pose more than minimal additional risk 
or burden to the safety of the subjects compared to normal clinical practice.
Therefore, the overall risk/benefit ratio is considered favorable for study participants.
Details of the cardiac monitoring and the devices to be worn by the patient will be outlined in 
a manual.

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4.
Study objectives - amended
Primary objective:

Measurement and quantification of daily physical activity (PA) in patients with
HFpEF and HFrEF under real life conditions by activity tracker/belt and patch
Secondary objectives:

Association between VitalPatch biosensor15 and DynaPort Move Monitor data (e.g. 
different levels of activity) to adverse events/clinical outcome data occurring during 
the study period

Assess the baseline level and longitudinal changes over time of heart rate, respiratory 
rate and ECG-derived parameters and the average of person-to-person physiological 
variability and the within-patient standard deviation between the baseline and 3-month 
measurements16

Assess the feasibility of activity tracking with two devices (VitalPatch biosensor15 and 
DynaPort Move Monitor) in patients with heart failure

Correlation of activity data between VitalPatch biosensor15 data on activity and 
DynaPort Move Monitor

Evaluate the relationship between physical activity levels, heart rate, respiratory rate 
and ECG-derived parameters and important measures in HFpEF; such as quality of 
life (QoL), patient reported outcome (PRO), biomarkers, outcomes (e.g. clinical 
endpoints such as hospitalization for heart failure, cardiovascular death, emergency 
visits)16

Support the development of HFpEF specific questions (PRO) for testing/validating 
cross-sectional and longitudinally 

Determine the variability of device derived biomarkers between subjects and within 
subjects over time in order to validate such biomarkers for clinical use in the context 
of heart failure

Evaluate hs-copeptin as potential biomarker 16

Correlation between patch monitor collected data and inpatient clinical data during 
hospital stay (e.g. echocardiography, weight gain/loss, NYHA, heart rate)

Explore the relationship between PA, 6MWD, PRO, biomarkers, adverse 
events/clinical outcomes

Investigate the accuracy of patients’ self-reports (PRO, e.g. KCCQ) of time spent on 
PA in real life vs. objective assessment by the DynaPort Move Monitor and VitalPatch 
biosensor17
                                                
15 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)
16 Tissue impedance deleted as per Amendment 3 (Section 15.3)
17 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)

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5.
Study design - amended
This is a non-randomized, multi-center, observatory prospective patient study. The study will 
be conducted in several centers in EU and non-EU.
Patients hospitalized due to heart failure as well as ambulatory patients with heart failure will 
be included in this study. Overall approx. 80 subjects have to complete at least all device 
monitoring periods:

Approx. 60 subjects with established diagnosis of heart failure with preserved ejection 
fraction (HFpEF; EF ≥ 45%) and 

Approx. 20 subjects with established diagnosis of heart failure with reduced ejection 
fraction (HFrEF; EF ≤ 35%).
All patients will receive the VitalPatch biosensor17 at 5 monitoring periods (5 patches each 
subject in total, monitoring period 5 days each period) and the DynaPort Move Monitor (belt) 
at 2 monitoring periods (7 day monitoring each period). Results from both devices are not 
visible to investigator and subjects to avoid bias on treatment decisions.
Biomarkers will be investigated during the hospital stay (only in case patient is hospitalized), 
at visit 1, and at visit 4. A 6-minute walking test will be performed at visit 1 / discharge and 
after 11-12 weeks.
Design overview
Figure 5-1:
Study design - amended18
Abbreviations: KCCQ = Kansas City Cardiomyopathy Questionnaire score; QS = Questionnaire for 
patient reported outcomes (daily and weekly); 6MWD = 6 minute walking distance; 
FUP = follow up visit
                                                
18 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2), simplification of number 
and timing of study-related procedures as per Amendment 3 (Section 15.3)
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Primary variables

Daily physical activity (amount, duration and intensity) obtained from the VitalPatch 
biosensor18 /DynaPort Move Monitor device
Secondary variables

6MWD

Other activity information obtained from the VitalPatch biosensor18 /DynaPort Move 
Monitor device such as sleep movements and patterns, sit-to stand behavior 
(DynaPort)

QoL as measured with the Kansas City Cardiomyopathy Questionnaire score 
(KCCQ)/PRO

Plasma/serum biomarkers 

Blood pressure and heart rate, cardiac function parameters measured by 
echocardiography

ECG derived readouts: heart rate variability (HRV) 

NYHA class
Results of the primary and secondary variables obtained at 3 months post-baseline (week 11-
12) versus baseline (visit 1).
Justification of the design
The open study design is considered acceptable and justified, because the variables of the 
study are objectively measured results that are unlikely to be subject to investigator or study 
patient induced bias.
Male and female patients will be enrolled into this study. There are no reasons to date (i.e.
safety reasons) to exclude women from these investigations.
The chosen study design is considered to be appropriate to establish a baseline for potential 
further objectives for the evaluation of efficacy of treatment responses in patients with heart 
failure, particularly HFpEF. The statistical analysis of this trial is performed in an exploratory 
manner.
This pilot study serves as a preparatory study designed to test the performance characteristics 
and capabilities of new measures, procedures, recruitment criteria, and operational strategies 
that are under consideration for use in a subsequent, larger, interventional study; cohort study 
is the appropriate study design for this pilot study. The aims and methods of this pilot study 
are aligned with the goals of potentially subsequent studies in BAYER’s target indications. 
The study will contribute to the development and design of future studies by clarifying and 
sharpening the research hypotheses to be studied, assessing the clinical utility of emerging 
readouts, identifying relevant factors that could create barriers to subsequent study 
completion, evaluating the acceptability of methods and instruments to participants, 
measuring the time required for study participation, and providing concrete estimates of the 
expected rates of missing data and participant attrition.

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In addition, the study aims to estimate baseline values and standard deviation of potential
pharmacodynamic outcome measures related to the physical activity (e.g. movement intensity, 
daily steps) to give information for sample size calculations in subsequent trials. Furthermore, 
the study will improve the understanding of study questionnaires or data collection tools
However, results from these kinds of studies can be influenced by unpredictable confounding 
factors.
End of study
The end of the study as a whole will be reached as soon as the last visit of the last subject has 
been reached in all centers in all participating countries (EU and non-EU).
6.
Study population
Inclusion criteria - amended
6.1
1. Written informed consent signed before any study-specific procedure
2. Men or women aged 45 years and older
3. Established diagnosis of chronic heart failure NYHA class II-IV
4. Worsening heart failure requiring hospitalization for the initiation of intensification of 
heart failure therapy with at least one of the following
o
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)
o
Radiographic evidence of pulmonary congestion (interstitial edema, 
pulmonary venous hypertension, vascular congestion, pleural effusion)
o
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 tolerated19, for at least 12 weeks
and at least one of the following
o
Hospitalization for heart failure within the past 12 months or
o
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)
                                                
19 Inclusion criteria extended to ambulatory subjects with chronic heart failure as per Amendment 3 (Section 15.3)

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5.
For HFrEF only
o
EF ≤ 35% assessed by any imaging modality (e.g. echocardiography, 
cardiac magnetic resonance, cine levocardiography) within 12 months prior 
to study inclusion 
6. For HFpEF only
o
EF ≥ 45% assessed by any imaging modality (e.g. echocardiography, 
cardiac magnetic resonance, cine levocardiography) within 12 months prior 
to study inclusion 
7. Willingness to wear the DynaPort Move Monitor accelerometer belt and VitalPatch
biosensor20 during the trial
8. 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 - amended
6.2
1. 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
2. Hemoglobin <8.0 g/dl21
3. Acute coronary syndrome or percutaneous coronary intervention within 3 months
prior to informed consent
4. Listing for heart transplantation and / or anticipated implantation of a ventricular assist 
device
5. Inability to exercise: wheelchair / scooter / walker dependent; dependent on 
supplemental oxygen
6. Known clinically significant persistent coronary ischemia (based on medical history, a 
preexisting or a recent clinical stress test)
7. 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
8. Occurrence of any of the following within 3 months prior to informed consent:
o
Myocardial infarction
o
Hospitalization for unstable angina
                                                
20 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)
21 Exclusion criterion modified to improve enrolment as per Amendment 3  (Section 15.3)

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o
Stroke or transient ischemic attack
o
Coronary artery bypass graft (CABG)
o
Percutaneous coronary intervention (PCI)
o
Implantation of a cardiac resynchronization therapy device (CRTD)
o
Major surgery (that could interfere with patients’ ability to exercise)
9. PCI, CABG or implantation of a CRTD planned between randomization and Visit 4
10. Subject who cannot tolerate placement of external patch monitor on chest in the 
proposed location (ECG lead II orientation)
11. Subject with known allergies or hypersensitivities to adhesives or hydrogels
12. deleted22
13. Severe uncorrected valvular heart disease
14. Known clinically relevant ventricular arrhythmias (sustained ventricular tachycardia, 
ventricular flutter or fibrillation)
15. Severe pulmonary disease with any of the following:
o
Requirement of continuous (home) oxygen or
o
History of chronic obstructive pulmonary disease ≥ GOLD III 
16. 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)
17. Any condition or therapy, which would make the patient unsuitable for the study, or 
life expectancy less than 12 months (e.g. active malignancy)
18. 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
19. 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 
devices23
20. Active myocarditis
21. Primary hypertrophic cardiomyopathy
22. Constrictive pericarditis or pericardial tamponade
23. 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) 
24. Previous participate in the study 
                                                
22 exclusion criterion deleted (referred to restrictions of the AVIVO patch) as per Amendment 3 (Section 15.3)
23 exclusion criterion specified as per Amendment 3 (Section 15.3)

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Justification of selection criteria
6.3
Bayer develops several investigational medicinal products for the indication HFpEF for which 
until now no successful treatment is available. Until now all endpoints failed and were not 
predictive for the outcome of the patient’s disease progression. Bayer intends to develop new 
endpoints and variables, which later might be useful to monitor pharmacodynamics effects 
and for the prediction of disease progression in interventional studies with new drugs. 
Digital device-derived biomarkers are of high interest regarding the identification of new 
potential endpoints, especially for patient populations where no predictable biomarkers are 
available. 
The new European guidelines (2016) for heart failure (HF) include the concept of HF with 
intermediate left ventricular ejection fraction (heart failure with mid-range ejection fraction,
HFmrEF), i.e. an LVEF between 40 and 49%.[1] However, a substantial heterogeneity may 
exist within patients with HFmrEF. In particular, this group may include both patients with de 
novo HF and patients with HF with previously reduced LVEF who have recovered their 
systolic function. Furthermore, considering the technical variability of echocardiographic 
assessment of ejection fraction as well as the biological variability, patients within the mid-
range ejection fraction may represent patients with HFpEF as well as HFrEF. For the purpose 
of this study, it is critical to study well defined patient groups with either HFpEF or HFrEF to 
avoid a relevant overlap between both groups.  Therefore, the inclusion criteria with respect to 
ejection fraction differ from current guidelines slightly. However, cut-off values used in the 
present study have also been used in several previous studies in patients with heart failure.
This study serves as a pilot study to identify a baseline for several digital biomarkers in
HFpEF patients. In parallel some HFrEF patients are included for which a baseline for some 
of the device readouts is already available derived from studies with implantable cardioverter-
defibrillator and cardiac resynchronization therapy devices. They serve as internal plausibility 
control.
Therefore, it is essential to include HFpEF and HFrEF patients in this study.

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Withdrawal of subjects from study
6.4
6.4.1
Withdrawal
Withdrawal criteria
An excessive rate of withdrawals (either patients discontinuing study medication or study 
withdrawal) can render the study non-interpretable. Therefore, un-necessary withdrawal of 
patients should be avoided, and all efforts should be taken to motivate patients to comply with 
all the study specific procedures and to be followed until the end of the trial to complete all 
study procedures and to detect the occurrence of cardiovascular events/assess the vital status. 
A patient has the right to withdraw from the study at any time and for any reason without 
prejudice to his or her future medical care by the physician or the institution. Patients who 
withdraw consent after enrolling will be evaluated to the time of withdrawal. If possible, the 
final assessment should be performed on all patients at the time of withdrawal. Patients 
should not be withdrawn from follow-up unless the patient explicitly withdraws consent to be
contacted. All efforts should therefore be made to minimize the number of patients who 
withdraw such consent as, in general, no further information on cardiovascular events and 
survival status may be collected after that point.
Patient will be withdrawn from the study for the following reasons:

At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a subject may decline to participate 
further.  The subject will not suffer any disadvantage as a result.

If, in the investigator's opinion, continuation of the study would be harmful to the 
patient's well-being,

At the specific request of the sponsor and in liaison with the investigator (e.g. obvious 
non-compliance, safety concerns).

Occurrence of adverse events or intercurrent diseases which the investigator judges 
unacceptable for continuation of participation in the study, or have from the 
investigator’s point of view, a negative impact on the patient’s individual risk-benefit 
ratio. (Investigators are obliged to reassess the patient’s individual risk-benefit ratio on 
a continuous basis. Factors like anticipated treatment effect, progression of underlying 
disease, occurrence of side effects and alternative treatment options have to be 
considered).

In case a patient is diagnosed while on study with any disease condition listed within 
the exclusion criteria,

Pertinent non-compliance with the conditions for the trial or instructions by the 
investigator.

Although not preferred, patient may interrupt their monitoring program of study due to 
reasonable circumstances/reasons at any time (e.g. hospitalization, safety reasons, and 
side effects). If an interruption lasts longer than 14 days in a row, it is at the discretion 
of the investigator to discontinue the study participation, and the Case Report Form 
(CRF) of the termination visit must be completed. In case program has to be 
interrupted for less than 14 days, activity monitoring has to be restarted.

Inclusion and exclusion criteria are being violated.

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The reason of discontinuation and the specific details must be recorded in the CRF. The 
investigator should determine one primary reason for discontinuation (only one choice is 
permitted).
All safety relevant data until removal will be collected and reported.
Any patient removed from the study due to an AE must be monitored until symptoms 
subside/stabilize or until there is a satisfactory explanation of the changes observed.
Data collected until the time a patient discontinues participation in the study will be handled 
in the same manner as data for patients completing the study.
Any decision for withdrawal of individual patients will be made after mutual agreement 
between the investigator and the sponsor.
Depending on the time point of withdrawal, a withdrawn subject is referred to as either 
“screening failure” or “dropout” as specified below:
Screening failure
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “dropout” (see below) is regarded a 
“screening failure”.  
The participation of an initial “screening failure” subject at a later time point is acceptable if 
he/she meets all selection criteria. 
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the subject to an unjustifiable health risk.  Also, for re-screening, the subject has to re-
sign the informed consent form, even if it was not changed after the subject’s previous 
screening.
Dropout
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been started one device monitoring period. 
General procedures
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject's 
medical records. 
The subject may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4.
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12 (Premature termination of the study).
6.4.2
Replacement
As far as possible patients who are considered as dropouts will be replaced until a number of 
at least 60 evaluable datasets for HFpEF patients and 20 for HFrEF patients has been reached. 

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Subject identification
6.5
The patient number is a 9-digit number consisting of:
Digits 1 to 5
= Unique center number
Digits 6 to 9
= Current patient number within the center
7.
Treatments
Treatments to be administered
7.1
Subjects will not be treated with an interventional drug.
Identity of study treatment
7.2
Not applicable.
Treatment assignment
7.3
Not applicable.
Dosage and administration
7.4
Not applicable.
Blinding
7.5
Not applicable.
Drug logistics and accountability
7.6
Not applicable.
Treatment compliance
7.7
Not applicable
8.
Non-study therapy
Prior and concomitant therapy
8.1
In accordance with standard local or international heart failure guidelines, all patients should 
be on standard HF therapy (an angiotensin-converting-enzyme inhibitor or angiotensin II 
receptor blocker, beta-blockers, mineralocorticoid receptor antagonist, angiotensin receptor-
neprilysin inhibitor, as applicable), unless contraindicated or (to the investigator’s knowledge) 
not tolerated. Concomitant therapy of comorbidities is allowed. During the study duration
change of the background medications for heart failure should be based on clinical need.
There is no change of the therapy required according to the protocol. All concomitant 
medication will be documented in the eCRF.
All medication taken 30 days before study start (initiated and stopped before study start) is 
termed prior medication. 
All medication taken after enrollment for any indication (either initiated before study start or 
during the study) is termed concomitant medication and has to be documented. Information to 

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be collected for medication includes: trade name or INN, start date, stop date/ongoing, dose, 
unit, frequency, application route and indication.
Post-study therapy
8.2
There is no defined post-study therapy. Patients will continue their usual medical treatments, 
unless otherwise decided by the attending physician.
9.
Procedures and variables
Tabular schedule of evaluations - amended
9.1
The investigator documents an initial visit, follow-up visits and the end of observation/final 
visit for each patient in the electronic case report form (eCRF). The end of observation visit 
will be documented after 12 weeks; a final follow-up call will be performed 6 months after 
visit 1 / discharge from hospital.24
Activities to be performed are summarized in the study flow chart in Table 9–1.
                                                
24 Adapted to reflect the option to include ambulatory patients as per Amendment 3 (Section 15.3)

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Table 9–1: Tabulated overview on study procedures and variables collected during 
the study - amended25
Study period
Screening phase
Observational phase
Safety FU 
call
Visit number
Scr1
1
2
3
4
5
Visit type
site
site
site
site
site

Screen 
assess
At discharge / 
ambulatory visit
Week after discharge / Visit 1
2
3
11
12
Day and allowed deviations -9  -1
0
9±2
16±2
77±2
84±2
6 months
±4 weeks
Signed informed consent form 
●
Inclusion / exclusion criteria
●
KCCQ
●
●
●
Daily and weekly PRO*
              
----1st----
----2nd----
Demographic data
●
Medical and surgical history
●
Height
●
Weight
●
●
●
●
12-lead ECG 
●
●
●
NYHA class
●
●
●
●
Blood pressure and heart rate
●
●
●
●
●
Adverse Events incl. 
healthcare resources
●
●
●
●
●
●
Concomitant medication
●
●
●
●
●
●
Echocardiography
  ●5
Six-minute walking distance  
●
●
DynaPort (for 7 days)2
start end
 ----1st----
----2nd----
VitalPatch26 (for 5 days)2
start end
--1st--
 2nd and 3rd 
   4th and 5th 
Blood sample for biomarkers3
●4
●
●
1 during hospitalization; alternatively, in ambulatory patients
2 DynaPort monitoring periods: For one week, after Visit 2 (Days 9-16) and from Visit 3 to Visit 4 (Days 
77-84)
  VitalPatch monitoring periods: first 5 days after hospital discharge / Visit 1 (Day 0-5), one week after 
Visit 2 (Day 9-16) and from Visit 3 to Visit 4 (Days 77-84)
3 central lab assessments: NTproBNP, hs-copeptin, hs-TNT, optionally: GDF15, IGFBP7, sST2, Gal3
* Concurrently evaluating PRO will be completed daily and weekly during DynaPort and VitalPatch
parallel monitoring period
4 only applicable to hospitalized patients
5 within ± 72 h of Visit 1 / discharge day
                                                
25 Adaption of timing and number of study related measurements to simplify procedures as per Amendment 3 (Section 15.3)
26 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)

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Visit description - amended
9.2
Enrollment / Screening Visit - amended
Patients hospitalized with worsening HF will be asked to participate in this study; 
alternatively, also ambulatory patients can be enrolled.27 The investigator will inform the 
patient about the study. This will include discussing the consent form and asking the patient to 
read and – when agreeing to participate – sign the informed consent.
The following activities will be performed at the enrollment/screening visit after signing 
patient informed consent:

Check for inclusion / exclusion criteria

Recording of
Demographic data (including weight and height)
Medical and surgical history
Concomitant medication
Adverse events (AEs) including the use of healthcare resources (e.g. HF 
hospitalizations and urgent visits for HF)28

Recording of a 12-lead ECG 

Measurement of blood pressure and heart rate

NYHA classification

Blood sampling for biomarkers only for hospitalized patients
Visit 1 (Day 0) - amended
This visit will take place up to 9 days after the screening visit, potentially at discharge from 
the hospital. The following activities will be performed:

Recording of 
Weight
Concomitant medication
AEs including the use of healthcare resources28

Recording of a 12-lead ECG 

Conduct of echocardiography within ± 72 h of discharge day

NYHA classification

Measurement of blood pressure and heart rate

Determination of 6MWD29

Completion of KCCQ
                                                
27 Adapted to reflect the option to include ambulatory patients as per Amendment 3 (Section 15.3)
28 Physical examination deleted to simplify study procedures as per Amendment 3 (Section 15.3)
29 6MWD shifted from Visit 2 to Visit 1 as per Amendment 3 (Section 15.3)

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
Blood sampling for biomarkers

Patients will get a VitalPatch biosensor attached to their chest, which they will wear 
for up to 5 days after Visit 1 / discharge from hospital27

Subjects will be informed how to wear and apply the VitalPatch biosensor 13
Outpatient Phase
Visit 2 (Day 9 ± 2 days) - amended
Patients will return to the clinic 9 days (± 2 days) after Visit 1 / discharge27. The following 
activities will be performed:

Recording of 
Weight
Concomitant medication
AEs including the use of healthcare resources

NYHA classification28, 29

Measurement of blood pressure and heart rate

The VitalPatch biosensor13 device attached at Visit 1 will be collected 

Subjects will receive another two VitalPatch biosensor patches which they will wear 
consecutively for up to 5 days each. One VitalPatch biosensor patch will be attached 
to the subject’s chest at the site, the other one has to be attached by the patient after 
removal of the first one after 5 days. Subjects will be informed how to wear and apply 
the VitalPatch biosensor.31

In addition, subjects will receive the DynaPort Move Monitor device which they will 
wear for 7 days. Subjects will be informed how to wear and apply the DynaPort 
MoveMonitor.

Instruction to patient to complete KCCQ (Day 16 ± 2 days) 

Completion of PRO daily and weekly during DynaPort Move Monitor and 
VitalPatch13 monitoring period.
Visit 3 (Day 77 ± 2 days) - amended
Patients will return to the clinic 77 days (± 2 days) after discharge. The following activities 
will be performed:

Recording of 
Concomitant medication
AEs including the use of healthcare resources28

Measurement of blood pressure and heart rate

Daily and weekly PRO during wearing of DynaPort Move Monitor and VitalPatch30
devices

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
The VitalPatch biosensor30 patches and the DynaPort Move Monitor device will be 
collected will be collected

Subjects will receive another two VitalPatch biosensor patches which they will wear 
consecutively for up to 5 days each. One VitalPatch biosensor patch will be attached 
to the subject’s chest at the site, the other one has to be attached by the patient after 
removal of the first one after 5 days.31

In addition, subjects will receive another DynaPort Move Monitor device which will 
be put on at the site and which will be worn for 7 days.31
Visit 4 (Day 84 ± 2 days) - amended
Patients will return to the clinic 84 days (± 2 days) after discharge. The following activities 
will be performed:

Recording of 
Weight
Concomitant medication
AEs including the use of healthcare resources28

Recording of a 12-lead ECG 

NYHA classification32

Measurement of blood pressure and heart rate

Determination of 6MWD

Completion of KCCQ/PRO

Blood sampling for biomarkers

The VitalPatch biosensor30 patches and the DynaPort Move Monitor device will be 
collected.
Follow-up visit (safety follow-up call)
Six months after discharge the investigator will phone the patient for a final safety follow-up. 
The following will be asked:

Concomitant medication

AEs including the use of healthcare resources
                                                
30 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)
31 Procedures for VitalPatch and DynaPort MoveMonitor simplified as per Amendment 3 (Section 15.3)
32 Second echocardiography deleted to simplify procedures as per Amendment 3 (Section 15.3)

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Population characteristics
9.3
9.3.1
Demographic
Male and female patients 45 years of age or older will be included into the study. 
Demographic characteristics (including sex, age in years, year of birth, height, weight, 
race/ethnicity) will be documented at Visit 1. The body mass index (BMI) will be calculated 
based on height and weight.
9.3.2
Medical history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

Start before signing of the informed consent 

Considered relevant for the subject’s study eligibility.
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 9.6.1.1.
Efficacy
9.4
Not applicable
Pharmacokinetics / pharmacodynamics
9.5
Not applicable
Safety
9.6
9.6.1
Adverse events
Definitions
9.6.1.1
Adverse Event (AE):
Any untoward medical occurrence (i.e. any unfavorable and unintended sign [including 
abnormal laboratory findings], symptom or disease) in a patient or clinical investigation 
subject after providing written informed consent for participation in the study. Therefore, an 
AE may or may not be temporally or causally associated with the use of a medicinal product.
A surgical procedure that was planned prior to the start of the study by any physician treating
the subject should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g. physical examination findings, symptoms, diseases, laboratory, ECG.

Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g. seasonal allergy without acute complaints).

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
Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events. This includes intercurrent illnesses.
Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a.
Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the subject was 
at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:
- The admission results in a hospital stay of less than 12 hours
- The admission is pre-planned
(e.g. elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures as described in Section 9.2)
- The admission is not associated with an AE 
(e.g. social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly / birth defect
f.
Is another serious or important medical event as judged by the investigator
Classifications for adverse event assessment
9.6.1.2
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.

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9.6.1.2.2
Intensity
The intensity of an AE is classified according to the following categories:
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living.
Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research participant.
Severe: A type of AE that requires intensive therapeutic intervention. The event interrupts 
usual activities of daily living, or significantly affects clinical status. The event possesses a 
significant risk of harm to the research participant and hospitalization may be required.
9.6.1.2.3
Causal relationship 
The relationship of an AE to the device must be assessed by the investigator based on all 
information available at the time of the completion of the CRF. 
The assessment is based on the question whether there was a “reasonable causal relationship”
to the device in question.
Possible answers are “yes” or “no”
An assessment of “no” would include:
1. The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.
or
2. Non-plausibility, e.g. the subject is struck by an automobile when there is no 
indication that wearing the device caused disorientation that may have caused the 
event.
An assessment of “yes” indicates that that the AE is reasonably associated with the use of the
device. 
Important factors to be considered in assessing the relationship of the AE to the device
include:

The temporal sequence from wearing the device: The event should occur after the 
device is applied. The length of time from wearing the device to event should be 
evaluated in the clinical context of the event.

Underlying, concomitant, intercurrent diseases: 
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have.

Concomitant medication or treatment: 
The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might have caused the event in question.

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
Exposure to physical and / or mental stresses: The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event.

The assessment is not possible.
Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedures is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedures.
Possible answers are “yes” or “no”
9.6.1.2.4
Action taken with study treatment 
Not applicable.
9.6.1.2.5
Other specific treatment(s) of adverse events
-
None
-
Remedial drug therapy
-
Other
9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 
-
Recovered/resolved
-
Recovering/resolving
-
Recovered/resolved with sequelae
-
Not recovered/not resolved
-
Fatal
-
Unknown
Assessments and documentation of adverse events
9.6.1.3
The investigator has to record on the respective AE CRF page, all adverse events occurring in 
the period between the signing of the informed consent and the end of the follow-up phase; 
after the end of the follow-up phase there is no requirement to actively collect AEs including 
deaths.  The type of information that should be assessed and recorded by the investigator for 
each AE is listed in Section 9.6.1.2. 
“Death” should not be recorded as an AE on the AE page. Instead, “death” is the outcome of 
underlying AE(s).
For all serious adverse events (SAEs) Bayer has to carry out a separate assessment for 
expectedness, seriousness and causal relationship regarding study procedures and Bayer 
drugs/devices.

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Reporting of serious adverse events - amended
9.6.1.4
The definition of serious adverse events (SAEs) is given in the Section 9.6.1.1. Each SAE 
must be followed up until resolution or stabilization by submission of updated reports to the 
designated recipient.
Any serious adverse events will be reported by the investigator to Bayer. Bayer will process 
these cases according to Bayer standard procedures and report as described below. In 
addition, all adverse events related to the VitalPatch biosensor33 or the DynaPort Move 
Monitor, which are both non-investigational devices in the Post-Marketing phase, will be 
reported by the investigator to the respective legal manufacturers, which would fulfill their 
reporting obligations to competent authorities and Notified bodies. 
In addition, for any adverse events related to any non-Bayer drugs/devices, investigators are 
recommended to use the national applicable system for reporting of spontaneous AEs.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs. This information, including all relevant contact 
details, is summarized in the investigator site file. This information will be updated as needed.
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs occurring during the period defined in Section 9.6.1.3 to the recipient detailed in the 
instructions for SAE reporting included in the Investigator File. For this, an AE page and the 
complementary SAE pages in the CRF must be completed for each SAE. 
SAEs occurring after the protocol-defined study period will be processed by the sponsor 
according to all applicable regulations.
Notification of the IECs / IRBs
Notification of the IECs/IRBs about suspected, unexpected, serious adverse reactions 
[SUSARs] is not applicable because there is no investigational product in this study.
Notification of the IECs/IRBs about all SAEs related to study procedure will be performed by 
Bayer and/or by the investigator according to all applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Reporting obligations for non-Bayer drugs/devices incl. VitalPatch biosensor33 and the 
DynaPort Move Monitor will be fulfilled by the respective Marketing Authorization 
holders/Manufacturers based on the information provided by the investigator via spontaneous 
reporting.
                                                
33 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)

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Sponsor’s notification of the investigational site
Notification of the investigational sites about suspected, unexpected, serious adverse reactions 
[SUSARs] is not applicable because there is no investigational product in this study. 
Notification of all investigational sites about all SAEs related to study procedure will be 
performed by Bayer according to all applicable regulations.
Expected adverse events
9.6.1.5
The expectedness of AEs for Bayer drugs/devices will be determined according to the 
applicable core company reference documents and according to all local regulations.
9.6.2
Pregnancies
The investigator must report to Bayer any pregnancy occurring in a female subject during her 
participation in this study. The outcome of the pregnancy should be followed up carefully, 
and any outcome of the mother and the child at delivery should be reported.
For a pregnancy in the partner of a male study subject, all efforts will be made to obtain 
similar information on course and outcome, subject to the partners consent.
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE.
9.6.3
Further safety – amended

Vital signs
Blood pressure, heart rate and body weight will be measured at time points given in the study 
flow charts in Table 9–1 as standard at the investigational site. 

Electrocardiogram/echocardiography
The standard 12-lead ECG will be evaluated by the investigator and the following parameters 
will be recorded in the eCRF: HR, PR interval, QRSD interval, QT interval (uncorrected). 
QTcB (QT interval frequency-corrected according to Bazett’s formula) will also be calculated 
but will not be valid for evaluation. The frequency-corrected QT interval will be calculated by 
data management according to the formulas of both Bazett and Fridericia.
All ECGs recorded during the study will be evaluated by a physician. He / she will document 
the diagnosis(es) including an overall assessment of the findings and their clinical relevance.
Any clinically relevant abnormality will be documented as an AE or SAE. Judgement 
normal/abnormal, including specification of abnormal findings
An echocardiography will be performed at Visit 1 / discharge from the hospital (within ± 72
hours).27

Physical examination 28
A general physical examination as routine at the center will not need to be performed, but a 
targeted exam might be triggered by symptoms. Abnormal physical examination findings are 
recorded either as medical history or as adverse events (see Section 9.6.1.1).

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
Laboratory evaluations
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g. clotted or hemolyzed) and to verify the results.  The 
results from such additional analyses may neither be included in the clinical database of this 
study nor evaluated further. If the results are relevant, the investigator will be informed to 
determine follow-up activities outside of this protocol.

Healthcare Resource Utilization 34
The use of Healthcare Resources in conjunction with AEs, in particular due to HF, needs to be 
documented, for example with regard to the time points or periods affected (e.g. 
hospitalizations for HF, urgent visits for HF to an emergency department or outpatient 
facility).
Other procedures and variables
9.7
9.7.1
VitalPatch biosensor35/DynaPort Move Monitor devices - amended
VitalPatch biosensor35
VitalPatch biosensor will be provided by Bayer to sites. Subjects will wear the VitalPatch 
biosensor for overall 5 periods of 5 days each (for details on time periods see Table 9–1).35
Parameters obtained from the VitalPatch biosensor35 are:

ECG and parameters derived from ECG, like e.g. heart rate, HRV, AF burden, 
arrhythmias etc.

Respiratory rate36

Skin temperature35

Step count35

Physical activity (duration and intensity)

Posture
DynaPort Move Monitor
DynaPort Move Monitor will be provided by Bayer to sites. Subjects will wear the DynaPort 
Move Monitor device for 2 periods of 7 days each (for details on time periods see Table 9–1).
                                                
34 Added as per Amendment 3 (Section 15.3)
35 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)
36 Thoracic impedance measurement is not supported by the VitalPatch device. Changed as per Amendment 3 (Section 15.3)

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Parameters obtained from the DynaPort Move Monitor device are:
1. Physical activity
o Type of activity
o Transitions between type of activity
o Steps
o Movement duration
o Movement frequency
o Movement intensity
2. Energy Expenditure
o Basal metabolic rate (BMR)
o Diet Induced Thermo Genesis (DIT)
o Activity-Related Energy Expenditure (AEE)
o Total Energy Expenditure (TEE)
o Physical Activity Ratio (PAR)
o Physical Activity Level (PAL)
3. Sleep Movements
o Going Out of Bed
o Night's Rest Detection
o Postures
o Movement Time
o Movement Intensity
o Transitions
9.7.2
Quality of life assessment/PRO - amended
Quality of life will be assessed using the KCCQ [10]. The total score will be documented. 
PRO will be completed daily and weekly during DynaPort Move Monitor and VitalPatch37
monitoring.
                                                
37 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)

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KCCQ
The KCCQ is the leading health-related quality-of-life measure for patients with HF. It was 
developed in the late 1990s to early 2000s by Dr. John Spertus at the Mid-America Heart 
Institute, Kansas City, MO, USA. It is a 23-item questionnaire that independently measures 
the impact of patients’ HF, or its treatment, on 7 distinct domains: 
1.
Symptom Frequency – the KCCQ Symptom scale quantifies the frequency of clinical 
symptoms in HF, including fatigue, shortness of breath, paroxysmal nocturnal 
dyspnea, and edema / swelling.
2.
Symptom Burden – the KCCQ Symptom burden scale quantifies the severity of 
clinical symptoms in HF, including fatigue, shortness of breath and edema / swelling.
3.
Physical Limitation – the KCCQ Physical limitation scale measures the limitations 
patients experience, due to their HF, in performing routine activities.
4.
Quality of Life – the KCCQ Quality of life scale is designed to reflect patients’ 
assessment of their quality of life, given the current status of their HF.
5.
Social Limitations – the KCCQ Social limitation scale quantifies the extent to which 
HF symptoms impair patients’ abilities to interact in social roles.
6.
Self-efficacy – numerous studies have underscored the importance of patients being 
engaged in the management of their disease. The KCCQ Self-efficacy scale quantifies 
patients’ perception of how to prevent HF exacerbations and manage complications 
when they arise.
7.
Symptoms Stability– unlike the other 5 domains that provide cross-sectional 
quantification of patients’ current status, the KCCQ Symptom stability domain 
measures recent changes in patients’ symptoms. As a measure of change, it is most 
interpretable as a baseline assessment of the stability of patients’ symptoms at the start 
of the study and thereafter.
In addition, there are 3 summary scores, a Total Symptom Score that combines the Symptom 
Frequency and the Symptom Burden scores, a Clinical Summary Score that combines the 
Total Symptom and Physical Limitation scores to replicate the NYHA classification; and an 
Overall Summary Score that includes the Total Symptom, Physical Limitation, Social 
Limitations, and Quality of Life scores (Figure 9-1).

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Figure 9-1
Kansas City Cardiomyopathy Questionnaire score
The exploratory daily QoL-Questionnaire is provided in Appendix 16.1.
KCCQ and PRO will be collected using electronic versions of the questionnaires on a tablet 
computer, which will be hand out to the patient for the duration of the study.
9.7.3
Six-minute walking distance
The walking distance after 6 minutes walking will be determined and documented.
The 6MWD test must be performed in accordance with the American Thoracic Society 
Guideline [11].
According to the guideline, the 6MWD test should be carried out indoors, along a long, flat, 
straight, enclosed corridor with hard surface that is seldom traveled. The walking course 
should be preferably 30 m in length, but not less than 25 m (longer walking courses should be 
shortened to 30 m). The length of the corridor and turnaround points should be marked. 
Patients will be instructed to walk alone, not run, from one end to the other end of the walking 
course, at their own pace, while attempting to cover as much ground as possible in 6 minutes. 
During the walk, patients are allowed to stop, lean against the wall and rest, but should 
resume walking as soon as they feel able to do so. The resting time will be included in the 6 
minutes. A “warm-up” period before the test should not be performed. The patients should sit 
at rest in a chair, located near the starting position, for at least 10 minutes before the test 
starts. Investigators should not walk with the patients. Moreover, only standardized phrases 
for encouragement must be used during the test. To allow reproducibility, standardized 
phrases should be used every minute according to the following pattern: After the first minute, 
tell the patient the following (in even tones): “You are doing well. You have 5 minutes to go.” 
When the timer shows 4 minutes remaining, tell the patient the following: “Keep up the good 
work. You have 4 minutes to go.”
Symptom 
Freauencv 
Symptom 
Burden 
Physical 
Limitations 
Quality of Life 
Social 
Limitations 
Self-efficacy 
Symptom 
Stability 
....__ 
I 
I 
Total 
Symptom 
Score 
Clinical 
Summary 
Score 
Overall 
Summary 
Score 

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When the timer shows 3 minutes remaining, tell the patient the following: “You are doing
well. You are halfway done.” When the timer shows 2 minutes remaining, tell the patient the 
following: “Keep up the good work. You have only 2 minutes left.”
When the timer shows only 1 minute remaining, tell the patient: “You are doing well. You 
have only 1 minute to go.” To reduce the variability of the 6MWD tests, it is of utmost 
importance that all 6MWD tests are performed under the same conditions, which must be the 
same as baseline conditions. Wheelchair or scooter dependent / supplemental oxygen patients 
or those on continuous oxygen for severe pulmonary disease are excluded from the study. The 
use of a cane is allowed in cane dependent patients, but then these patients need to use the 
same cane at every 6MWD test throughout the study. If a supplemental oxygen therapy 
should be implemented during the trial, if it is implemented already at baseline, the 
subsequent 6MWD test at Visit 4 / premature discontinuation visit has to be performed under 
the same “baseline” conditions (same flow of oxygen, same application route, and same way 
of carrying the oxygen bottle). The same applies if the need for walking aids should arise 
during the trial already at baseline. In that case the same walking aids should also be used at 
the Visit 4 / premature discontinuation test.
However, this should be avoided, and if not possible, at least the same conditions should be 
met in both 6MWD tests. For quality reasons, the inhalation of supplemental oxygen and the 
use of walking aids during the 6MWD tests must be documented in the eCRF.
9.7.4
Laboratory parameters
Blood samples will be collected as given in Table 9–1and the following biomarkers will be 
determined in plasma/serum by a central laboratory using validated assays platforms 
including appropriate quality controls:

NTproBNP

hs-Copeptin

hs-TNT
Further biomarkers may be tested:

GDF15

IGFBP7

sST2

Gal3
Details on the collection, processing, storage and shipment of biomarker samples will be 
provided in separate documents (e.g. sample handling sheets or lab manual). In addition to the 
biomarkers listed above, other biomarkers deemed relevant to gain further knowledge about 
the pathomechanisms of the disease may be measured, based on newly emerging data from 
other ongoing studies and / or literature data.
Appropriateness of procedures / measurements
9.8
All laboratory and safety parameters as well as the methods to measure them, are standard 
variables/ methods in clinical studies and/ or clinical practice. They are widely used and 
generally recognized as reliable, accurate and relevant.

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10.
Statistical methods and determination of sample size
General considerations - amended
10.1
All statistical details including calculated variables and proposed format and content of tables 
will be detailed in the Statistical Analysis Plan (SAP). The SAP will be finalized before study 
database lock. Statistical analysis will be performed using SAS or R; the versions used for 
both types of software will be specified in the SAP.
Statistical analyses will be of explorative and descriptive nature. The study is not aimed to 
confirm or reject pre-defined hypotheses; however, particular attention will be given to the 
ejection fraction (preserved versus reduced) as stratification factor.
All variables will be summarized with appropriate statistical methods: categorical variables 
by frequency tables (absolute and relative frequencies) and continuous variables by sample 
statistics (i.e. mean, standard deviation, minimum, median, quartiles and maximum). 
Continuous variables will be described by absolute value and as change from baseline per 
analysis time point, as applicable.
Data from VitalPatch38 and DynaPort devices is expected to include missing values, as result 
of compliance in wearing the device. The amount of missing data within a day cannot be 
predicted and will be an outcome of the study. Missing data within day will be assessed by 
vendors according their validated algorithms of data pre-processing and quality check. No 
imputation will be performed in case day monitoring did not pass quality checks. The amount 
of missing monitoring will be assessed prior each statistical analysis and in presence of 
outliers the exclusion of subjects’ data may occur. 
All analyses will be performed for the FAS population (overall analysis) and separately for 
each participating country if subject numbers are sufficient and if required for local reasons. 
Sample size and disposition information by analysis time point will be displayed in a
frequency table.
All therapies documented will be coded using the World Health Organization – Drug 
Dictionary. Medical history, any diseases and AEs will be coded using the latest Medical 
Dictionary for Regulatory Activities (MedDRA) version.
No interim analyses are planned. The final analysis will be performed after end of the study
which is the date the analytical dataset is completely available.
Analysis sets - amended
10.2
In absence of intervention and randomization the statistical analysis sets are defined on the 
base of a successful monitoring under the VitalPatch biosensor38 patch.  
Full analysis set (FAS)
The FAS population consists of all subjects that are included into the study and that are 
wearing at least one VitalPatch biosensor38 patch and for which data was successfully 
collected over the whole week. The FAS will be used to display baseline characteristics, 
assess parameter variability, correlative analyses.
                                                
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Safety analysis set (SAF)
The SAF population consists of all patients with a planned study procedure after signing the 
informed consent that are wearing at least one VitalPatch biosensor38 patch and for which 
data was successfully collected over the whole week will be included in the SAF. The SAF 
will be used to display safety analyses. 
Variables and planned statistical analyses
10.3
Given the descriptive nature of the study and the multivariate nature of the statistical approach 
used, all of the variables mentioned in section 9 are suitable to be analyzed.
In addition, variables including patient heart failure information (preserved vs reduced 
ejection fraction) or other clinical endpoints (e.g. re-hospitalization for heart failure, 
cardiovascular death, emergency visits) will be considered as well in the statistical analysis, 
possibly in interaction with other relevant parameters. 
10.3.1
Analysis of demography, disease details, prior and concomitant 
medication and other baseline data
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) will be presented for total and study part. Frequency tables for 
qualitative data will be provided. 
Unsupervised patient stratification at baseline will be carried out by means of the following 
multivariate techniques which allow the simultaneous analysis of many variables such as from 
demographics, disease history (MedDRA terms), co-morbidities, prior and concomitant 
medication, AEs, NYHA classification, ECG judgement, vital signs, KCCQ/PRO scores, and 
biomarkers (laboratory data). Continuous variables will be arbitrary discretized in tertiles or 
quartiles according their density distribution or according existing clinical ranges of 
normality. Multiple correspondence analyses will be used, subjects will be displayed in bi-
dimensional maps and the homogeneity of the population towards all the variables under 
assessment will be observed. If groups of subjects with specific co-occurrences for one or 
more parameters could be separated by the others in the bi-dimensional map (at 95% 
confidence ellipse) those will be flagged and eventually considered as separate population for 
the analysis. In the latter case, the parameter(s) responsible for the separation will be 
identified using the map of contribution of variable categories to the dimensions, and could be 
used as covariate in modeling. No additional investigations for comparative purposes will be 
performed.
10.3.2
Analysis of data within the hospitalization phase - amended
Data collected in the hospitalization phase for which records will be available until visit 1 
(from hospitalization and at hospital discharge, respectively) will be analyzed by means of 
multivariate techniques in order to describe changes and quantify the variability of changes in 
this early phase, and eventually identify subjects with extreme behavior in one or more of the
parameters under measurement. Changes in the parameters from 12-lead ECG, vital signs, 
KCCQ/PRO scores, and biomarkers will be described using multilevel Partial Least Square 
analysis. Such model allows conducting a paired analysis of subjects before and after 
hospitalization, hence to observe a potential effect of hospitalization on the observed 
parameters. If an effect will be observed, the parameters sensitive to hospitalization will be 

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assessed using linear mixed model as described in Section 10.3.3.1 but within the 
hospitalization time frame.
For VitalPatch39 data collected in this frame only the day to day variability will be of interest.
10.3.3
Analysis of primary and secondary outcomes
Assessment of variability
10.3.3.1
The variability between subjects and within subjects across time for each of the parameters of 
interest  will be described using a linear mixed model (LMM) with subject as random factor, 
and time as fixed factor, possibly including additional covariates as may result from the 
assessment at baseline for patient stratification or as required for clinical interpretation. 
In addition to effects and interactions of fixed effects parameters LMMs will be used to 
estimate simultaneously parameters of the variance and covariance components of random 
effects due to subjects. 
The LMM for the parameter of interest (Y) as selected among the molecular and digital 
biomarkers available (i.e. laboratory parameters and device generated digital data) will have 
the following base annotation:
Yst = β0 +  β1 · TIMEt + S0s + st
Where S is subject (random) and TIME represents visit, with baseline as reference.
The HF type (preserved/reduced) will be included in the model (here denoted as C), as 
random factor, and the effect on intercept or slope will be assessed:
Yst = β0 +  (β1 + C1s) · TIMEt + S0s + C0s + st
Where C1s will be the effect of HF type on the slope (e.g., if changes in physical activity are 
different between the two sub-populations) and C0s will be the effect on the intercept (e.g., if 
the two sub-populations have different baseline values).
Given the high number of parameters involved and the exploratory nature of the study, all of 
the possible models will not be addressed here, and the base model will be extended as 
appropriate depending on the specific question to address and the given subset of parameters 
involved.  
Testing of random effects and visualization of residuals will be performed in order to 
highlight single subjects (or sub-group) showing outstanding or peculiar characteristics.   
Estimates from the model will be used to quantify the ability of a parameter to measure 
clinically relevant changes over time. The intraclass correlation coefficient (ICC) will be used 
as key statistic when considering the relative proportion of within- and between-individual 
variation is the expected correlation among measurements from the same individual, it can 
indicate the degree of difference between individuals and will also be used as measure 
reliability (ability to reflect true between-individual differences). For any sample, the ICC will 
be calculated with estimates from LMMs of both between-individual variance and within-
individual variance, according the following: 
ICC = τ2 / (τ2+σ2)
                                                
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where τ2 is a commonly used symbol for between-individual variance (variance of S0s term in 
in the base model above) and σ2 for within-individual variance (variance of st in the base 
model). Then, ICC will be the proportion of total variance (τ2+σ2) attributable to between-
individual differences (τ2). 
In addition, point estimates (LS-Means) and exploratory 90% confidence intervals will be 
calculated for comparing baseline and 3 months data by HF type (preserved/reduced), and 
may include intermediate time points if available. 
Analysis of correlations - amended
10.3.3.2
Given the high degree of collinearity expected within each set of data, multivariate 
approaches will be considered in order to take in account the covariance structure and 
properly assess simultaneously the correlation of variables within and between datasets 
consisting of multiple variables, such as digital or biomarker datasets. 
The relationship between variables as obtained from a given source or technology will be 
assessed by means of Canonical Correlation. This analysis allows investigating the 
relationship between two multivariate sets of variables, such as the one obtained using the 
VitalPatch biosensor40 or DynaPort Move Monitor device, and another one as obtained from 
other contexts, such as contexts defined by the following data sets: i) echocardiography 
parameters set, ii) 12-lead ECG parameters set, and iii) a composite set including biomarkers, 
6MWD score, KCCQ total score, and vital signs (blood pressure, heart rate). Such model will 
possibly indicate which combination of the many parameters observed using the device will 
better reflect a clinical context as given by ECG, KCCQ, or other data. 
The correlation of digital biomarkers and AEs or concomitant medication (CM) will be tested 
by means of partial least square analysis (PLS-DA). The Y-matrix to use for PLS-DA 
regression can be – depending on the resulting complexity – i) a joint matrix of AEs and 
CMs; ii) grouping variable identifying subjects with similar AE and CMs (the latter obtained
by multiple correspondence analysis and kernel based clustering). Such model will possibly 
indicate which combination of the many parameters observed using the device will better 
reflect a clinical profile as obtained from observed frequencies in AEs and CMs.
10.3.4
Analysis of safety data
The SAF population will be used to display safety analyses.
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) or frequency tables will be provided as applicable.
Determination of sample size
10.4
Due to the exploratory nature of this study, the number and the diversity of parameters used to 
measure physical activity, or which could affect this outcome in “real-life” conditions, no 
modeling for power estimation was performed. The number of subjects was set to be 
comparable to other studies which involved the assessment of physical activity on daily life 
(activity monitoring) and where a significant difference in PA was observed (60 subject in 
                                                
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average). Also considering the expected variability due to measurement under unstandardized 
conditions [12] a number of 80 subjects (HFpEF n=60, HFrEF n=20) who completed the main 
study (i.e. visit 4) was defined as target. 
11.
Data handling and quality assurance
Data recording
11.1
The data collection tool for this study will be eCRF; a validated electronic data capture system 
called RAVE.  Subject data necessary for analysis and reporting will be entered/transmitted 
into a validated database or data system (CIE/TOSCA; SAS).  
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based EDC software system RAVE, which Bayer has licensed 
from Medidata Solutions Worldwide.  RAVE has been validated by Medidata Solutions 
Worldwide and Bayer for use in its clinical studies.  RAVE allows for the application of 
software logic to set-up data entry screens and data checks to ensure the completeness and 
accuracy of the data entered by the site personnel.  Bayer extensively applies the logic to 
ensure data are complete and reflect the clinical data requirements of the study.  Data queries 
resulting from the application of the software logic are resolved by the site personnel.  The 
data are stored at a secure host facility maintained by Medidata Solutions Worldwide and 
transferred on a periodic basis to Bayer's internal computer system via a secure Virtual Private 
Network.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software.  All internal Bayer and external investigator site personnel seeking 
access must go through a thorough RAVE training process before they are granted access to 
RAVE for use in Bayer's clinical studies. Training records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made. This information is available both at the investigator’s site and at Bayer. Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
subjects enrolled in this study.
Source documentation
The site must implement processes to ensure availability of all required source 
documentation.  A source document checklist (not part of this protocol) will be used at the 
site to identify the source data for key data points collected and the monitor will work with the 
site to complete this.
It is the expectation of the sponsor that all data entered into the CRF has source 
documentation available at the site.  

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Data recorded from screening failures
At minimum, the following data should be recorded in the CRF:

Demographic information (subject number; year of birth / age; sex; if applicable race / 
ethnicity)

Date of informed consent

Relevant inclusion/exclusion criteria

Reason for premature discontinuation

Date of last visit  
These data will be transferred to the respective database.
For screening failures with an SAE, the following data should be collected in the CRF in 
addition to the data specified above:

All information related to the SAE such as: 
- The SAE itself
- Concomitant medication
- Medical history
- Other information needed for SAE complementary page
Monitoring
11.2
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements.  When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete.  
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes). 

Safety and rights of subjects are being protected

Study is conducted in accordance with the currently approved protocol 

Any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
Data processing
11.3
Data will be collected as described in Section 11.1. Clinical data management will be 
performed in accordance with applicable sponsor’s standards and data cleaning procedures.  
This is applicable for data recorded on CRF as well as for data from other sources (e.g. IVRS, 
laboratory, ECG, PRO, adjudication committees).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.

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Missing data 
11.4
Missing data will not be replaced.
Audit and inspection
11.5
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible.  The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues.  Audits and inspections may occur at any time during or after 
completion of the study.
Archiving
11.6
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice.  Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g. relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. centers]) at any time, which may be due but not limited to the following reasons: 

If risk-benefit ratio becomes unacceptable owing to, for example,
- Safety findings from this study (e.g. SAEs)

If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.
The investigator has the right to close his/her center at any time.

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For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties.  Final decision 
on the closure must be in writing.

All affected institutions (e.g. IEC(s)/IRB(s); study center; head of study center) must 
be informed as applicable according to local law.

All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor.  The investigator will retain all other documents until 
notification is given by the sponsor for destruction.

In the event of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner.
Details for individual subject's withdrawal can be found in Section 6.4.1.
13.
Ethical and legal aspects
Investigator(s) and other study personnel
13.1
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate.  This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g. ethics committee, sponsor) before subject 
recruitment may start at the respective center.  Likewise, all amendments to the protocol must 
be signed by the principal investigator and must have received all required external approvals 
before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
The global sponsor of this study is identified on the title page of this protocol.  If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
Funding and financial disclosure - amended
13.2
Funding
This study will be funded by its sponsor.
Collaborator of this study is VitalConnect Inc., 224 Airport Parkway Suite 300, San Jose, 
California 95110, USA.41
                                                
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Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements.  All relevant documentation will be filed in the 
trial master file.
Ethical and legal conduct of the study
13.3
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the 
Declaration of Helsinki.  The study will also be carried out in keeping with applicable local 
law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and also forwarded to the sponsor.  The responsible unit (e.g. 
IEC/IRB, head of the study center/medical institution) must supply to the sponsor, upon 
request, a list of the IEC/IRB members involved in the vote and a statement to confirm that 
the IEC/IRB is organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.  
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC/IRB/sponsor approval/favorable opinion.  As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor.  Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
Subject information and consent
13.4
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent form provided by the sponsor or the study center.  A sample 
subject information and informed consent form is provided as a document separate to this 
protocol.
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject, prior to his/her entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.

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Each subject will be informed about the following aspects of premature withdrawal:
Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.  
The subject’s data that have been collected until the time of withdrawal will be retained 
and statistically analyzed in accordance with the statistical analysis plan. 
Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the statistical analysis plan.  The subject has the right to object to the 
generation and processing of this post-withdrawal data. The subject’s oral objection may 
be documented in the subject’s source data.
Each subject will have ample time and opportunity to ask questions.
Only if the subject voluntarily agrees to sign the informed consent form and has done so, may 
he/she enter the study. Additionally, the investigator will personally sign and date the form.  
The subject will receive a copy of the signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution.
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject´s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
1. If the subject is not capable of providing a signature, a verbal statement of consent can 
also be given in the presence of an impartial witness (independent of the sponsor and 
the investigator).  This is to be documented by a signature from the informing 
physician as well as by a signature from the witness.
The informed consent form and any other written information provided to subjects will be 
revised whenever important new information becomes available that may be relevant to the 
subject’s consent, or there is an amendment to the protocol that necessitates a change to the 
content of the subject information and / or the written informed consent form.  The 
investigator will inform the subject / legal representative or proxy consenter of changes in a 
timely manner and will ask the subject to confirm his/her participation in the study by signing 
the revised informed consent form.  Any revised written informed consent form and written 
information must receive the IEC/IRB`s approval / favorable opinion in advance of use.
Publication policy and use of data
13.5
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs.  
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study.  However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 

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publication manuscript before its submission.  To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.
Compensation for health damage of subjects / insurance
13.6
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
Confidentiality
13.7
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the sponsor.  Only the subject number will be recorded 
in the CRF, and if the subject name appears on any other document (e.g. pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor.  Study findings 
stored on a computer will be stored in accordance with local data protection laws.  As part of 
the informed consent process, the subjects will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the subject’s identity will remain confidential.
The investigator will maintain a list to enable subjects to be identified.

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14.
Reference list 
1.
Yancy et al., 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy 
for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of 
Heart Failure: A Report of the American College of Cardiology Foundation/American 
Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure 
Society of America. Circulation. 2016 Sep 27;134(13):e282-93
2.
Tiller D et al. Prevalence of symptomatic heart failure with reduced and with normal 
ejection fraction in an elderly general population-the CARLA study. PLoS ONE 2013; 
8(3):e59225.
3.
Teerlink JR et al. Acute decompensated heart failure update. Curr Cardiol Rev. 
2015;11(1):53-62. 
4.
Gheorghiade M et al. Rationale and Design of the Multicenter Randomized Double Blind 
Placebo Controlled Study to Evaluate the Efficacy of Vasopressin Antagonism in Heart 
Faiilure: Outcome Study with Tolvaptan (EVEREST). J Card Fail 2005;11(4):260-9. 
5.
Palazzuoli A et al. Loop diuretics in acute heart failure: beyond the decongestive relief 
for the kidney. Crit Care. 2015 3;19:296. 
6.
Paulus WJ, van Ballegoij JJM. Treatment of heart failure with normal ejection fraction: 
an inconvenient truth! J Am Coll Cardiol 2010; 55(6):526–37. 
7.
Vaduganathan M, Michel A, Hall K, Mulligan C, Nodari S, Shah SJ, Senni M, Triggiani 
M, Butler J, Gheorghiade M. Spectrum of epidemiological and clinical findings in 
patients with heart failure with preserved ejection fraction stratified by study design: a 
systematic review. Eur J Heart Fail. 2016 Jan;18(1):54-65. doi: 10.1002/ejhf.442.
8.
Krum H, Hopper I. The Ongoing Evolution of Optimal Clinical Endpoints for Heart 
Failure Trials. JACC Heart Fail. 2015 Aug;3(8):615-7. doi: 10.1016/j.jchf.2015.04.010. 
9.
Psotka MA, von Maltzahn R, Anatchkova M, Agodoa I, Chau D, Malik FI, Patrick DL, 
Spertus JA, Wiklund I, Teerlink JR. Patient-Reported Outcomes in Chronic Heart 
Failure: Applicability for Regulatory Approval. JACC Heart Fail. 2016 Oct;4(10):791-
804. doi: 10.1016/j.jchf.2016.04.010.
10. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the 
Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart 
failure. J Am Coll Cardiol. 2000;35(5):1245-1255
11. STATEMENT OF THE AMERICAN THORACIC SOCIETY: Guidelines for the Six-
Minute Walk Test Am J Respir Crit Care Med Vol 166. pp 111–117, 2002
12. Demeyer H, Burtin C, Van Remoortel H, Hornikx M, Langer D, Decramer M, Gosselink 
R, Janssens W, Troosters T. Standardizing the analysis of physical activity in patients 
with COPD following a pulmonary rehabilitation program. Chest. 2014 Aug;146(2):318-
27. doi: 10.1378/chest.13-1968.

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15.
Protocol amendments
Amendment 1
15.1
Amendment 1 is dated 14 May 2018.
15.1.1
Overview of changes to the study protocol
This amendment was written to clarify issues with the sites and to improve the enrollment 
rate.
Modification 1: Time window added for conduct of echocardiography
Description of the modification of the study plan: A time window of ‘within ± 72 of discharge 
day’ was added for the conduct of the echocardiography in Visit 1.
Rationale for introducing the modification:
To clarify an issue with the sites
List of all CSP sections affected by this modification: Sections 9.1, 9.2, 9.6.3
Modification 2: Exclusion criterion for hemoglobin changed
Description of the modification of the study plan: The exclusion criterion for hemoglobin was 
changed from <11.0 g/dl to <10.0 g/dl.
Rationale for introducing the modification:
To reflect the ‘real world’ condition of HF patients as most patients’ average hemoglobin is 
<10 g/dl, especially for acutely decompensated patients.
List of all CSP sections affected by this modification: Section 6.2
Modification 3: Addition of weekly PRO
Description of the modification of the study plan: In addition to daily PRO already planned in 
the protocol, weekly PRO was added to Visits 2 and 3.
Rationale for introducing the modification:
To clarify an issue with the sites
List of all CSP sections affected by this modification: Sections 2, 9.1, 9.2, 9.7.2

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15.1.2
Changes to the protocol text
In this section on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version.
As applicable, changes to the protocol text are highlighted as follows:
Editing of an existing portion
Comparative presentation of “old text” versus “new 
text”, with “old text” referring to the most recent 
previous protocol version. Deletions are crossed out in 
the “old text”. Additions are underlined in the “new 
text”.
Tables / figures / sections
The term “amended” is added to the caption/heading.
Corrections of typos or omissions are not highlighted.
Section 9.1 Time window added for conduct of echocardiography
15.1.2.1
This section was changed as a result of Modification 1.
Old text 
(…)
Table 1: Tabulated overview on study procedures and variables collected during the study
Study period
Hospitalization 
phase
Outpatient phase
Safety 
FU call
Visit number
Scr1
1
2
3
4
5
Visit type
site
site
site
site

Screen 
assess
At hospital 
discharge
Week after discharge
1
2
3
11
12
Day and allowed deviations
0
9±2
16±2
23±2
77±2
84±2
6 months
±4 weeks
(…)
Echocardiography
●
●
Six-minute walking distance  
●
●
DynaPort (for 7 days)2
startend
     
     ----1st----
     ----2nd----
AVIVO (for 7 days)2
start end
  ---1st-----2nd----3rd----4th--           ----5th----
Blood sample for biomarkers3
●
●
●
●
1 within 72 hours after hospitalization
2 DynaPort monitoring periods: Second week after hospital discharge (Days 7-14) and Week 11 to 12 
(Days 77-84)
  AVIVO monitoring periods: up to 7 days during the hospital stay, first week after hospital discharge 
(Day 0-7), during weeks 2 and 3 (Day 7-14, Day 17-23) and Week 11 to 12 (Days 77-84)
3 central lab assessments: NTproBNP, hs-copeptin, hs-TNT, optionally: GDF15, IGFBP7, sST2, Gal3
* Concurrently evaluating PRO will be completed daily during DynaPort and AVIVO parallel monitoring 
period
I 
I 
I 
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New text
(…)
Table 1: Tabulated overview on study procedures and variables collected during the study
Study period
Hospitalization 
phase
Outpatient phase
Safety 
FU call
Visit number
Scr1
1
2
3
4
5
Visit type
site
site
site
site

Screen 
assess
At hospital 
discharge
Week after discharge
1
2
3
11
12
Day and allowed deviations
0
9±2
16±2
23±2
77±2
84±2
6 months
±4 weeks
(…)
Echocardiography
●4
●
Six-minute walking distance  
●
●
DynaPort (for 7 days)2
startend
     
     ----1st----
     ----2nd----
AVIVO (for 7 days)2
start end
  ---1st-----2nd----3rd----4th--           ----5th----
Blood sample for biomarkers3
●
●
●
●
1 within 72 hours after hospitalization
2 DynaPort monitoring periods: Second week after hospital discharge (Days 7-14) and Week 11 to 12 
(Days 77-84)
  AVIVO monitoring periods: up to 7 days during the hospital stay, first week after hospital discharge 
(Day 0-7), during weeks 2 and 3 (Day 7-14, Day 17-23) and Week 11 to 12 (Days 77-84)
3 central lab assessments: NTproBNP, hs-copeptin, hs-TNT, optionally: GDF15, IGFBP7, sST2, Gal3
* Concurrently evaluating PRO will be completed daily during DynaPort and AVIVO parallel monitoring 
period
4 within ± 72 of discharge day
Section 9.2 Time window added for conduct of echocardiography
15.1.2.2
This section was changed as a result of Modification 1.
Old text 
(…)
Visit 1 (Day 0)
At discharge from the hospital the following activities will be performed:

Recording of 
Weight
Concomitant medication
AEs

Physical examination

Recording of a 12-lead ECG 
-
I 
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
Conduct of echocardiography 

Measurement of blood pressure and heart rate
(…)
New text
(…)
Visit 1 (Day 0)
At discharge from the hospital the following activities will be performed:

Recording of 
Weight
Concomitant medication
AEs

Physical examination

Recording of a 12-lead ECG 

Conduct of echocardiography within ± 72 of discharge day

Measurement of blood pressure and heart rate
Section 9.6.3 Time window added for conduct of echocardiography
15.1.2.3
This section was changed as a result of Modification 1.
Old text 
(…)

Electrocardiogram/echocardiography
The standard 12-lead ECG will be evaluated by the investigator and the following parameters 
will be recorded in the eCRF: HR, PR interval, QRSD interval, QT interval (uncorrected). 
QTcB (QT interval frequency-corrected according to Bazett’s formula) will also be calculated 
but will not be valid for evaluation. The frequency-corrected QT interval will be calculated by 
data management according to the formulas of both Bazett and Fridericia.
All ECGs recorded during the study will be evaluated by a physician. He / she will document 
the diagnosis(es) including an overall assessment of the findings and their clinical relevance.
Any clinically relevant abnormality will be documented as an AE or SAE. Judgement 
normal/abnormal, including specification of abnormal findings
An echocardiography will be performed at discharge from the hospital and on Day 84.
(…)
New text
(…)

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
Electrocardiogram/echocardiography
The standard 12-lead ECG will be evaluated by the investigator and the following parameters 
will be recorded in the eCRF: HR, PR interval, QRSD interval, QT interval (uncorrected). 
QTcB (QT interval frequency-corrected according to Bazett’s formula) will also be calculated 
but will not be valid for evaluation. The frequency-corrected QT interval will be calculated by 
data management according to the formulas of both Bazett and Fridericia.
All ECGs recorded during the study will be evaluated by a physician. He / she will document 
the diagnosis(es) including an overall assessment of the findings and their clinical relevance.
Any clinically relevant abnormality will be documented as an AE or SAE. Judgement 
normal/abnormal, including specification of abnormal findings
An echocardiography will be performed at discharge from the hospital (within ± 72 of 
discharge day) and on Day 84.
(…)
Section 6.2 Exclusion criterion for hemoglobin changed
15.1.2.4
This section was changed as a result of Modification 2.
Old text 
1. 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
2. Hemoglobin <11.0 g/dl
(…)
New text
1. 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
2. Hemoglobin <10.0 g/dl
(…)
Section 2 Addition of weekly PRO
15.1.2.5
This section was changed as a result of Modification 3.
Old text 
(…)
Methodology
(…)
Daily PRO will be performed daily in parallel with the DynaPort Move Monitor monitoring periods 
(visit 2, week 1-2) and visit 3 (week 11-12)
(…)

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New text
(…)
Daily and weekly PRO will be performed in parallel with the DynaPort Move Monitor monitoring 
periods (visit 2, week 1-2) and visit 3 (week 11-12)
(…)
Section 9.1 Addition of weekly PRO
15.1.2.6
This section was changed as a result of Modification 3.
Old text 
(…)
Table 1: Tabulated overview on study procedures and variables collected during the study
Study period
Hospitalization 
phase
Outpatient phase
Safety 
FU call
Visit number
Scr1
1
2
3
4
5
Visit type
site
site
site
site

Screen 
assess
At hospital 
discharge
Week after discharge
1
2
3
11
12
Day and allowed deviations
0
9±2
16±2
23±2
77±2
84±2
6 
months
±4 weeks
Signed informed consent form 
●
Inclusion / exclusion criteria
●
KCCQ
●
●
●
Daily PRO*
         
----1st----
----2nd----
(…)
* Concurrently evaluating PRO will be completed daily during DynaPort and AVIVO parallel monitoring
period

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New text
(…)
Table 1: Tabulated overview on study procedures and variables collected during the study
Study period
Hospitalization 
phase
Outpatient phase
Safety 
FU call
Visit number
Scr1
1
2
3
4
5
Visit type
site
site
site
site

Screen 
assess
At hospital 
discharge
Week after discharge
1
2
3
11
12
Day and allowed deviations
0
9±2
16±2
23±2
77±2
84±2
6 
months
±4 weeks
Signed informed consent form 
●
Inclusion / exclusion criteria
●
KCCQ
●
●
●
Daily and weekly PRO*
         
----1st----
----2nd----
(…)
* Concurrently evaluating PRO will be completed daily and weekly during DynaPort and AVIVO 
parallel monitoring period
Section 9.2 Addition of weekly PRO
15.1.2.7
This section was changed as a result of Modification 3.
Old text 
(…)
Visit 2 (Day 9 ± 2 days)
(…)

Instruction to patient to complete KCCQ (Day 16 ± 2 days) 

Completion of PRO daily during DynaPort Move Monitor and AVIVO parallel 
monitoring period.
(…)
Visit 3 (Day 77 ± 2 days)
(…)

Measurement of blood pressure and heart rate

daily PRO during wearing of DynaPort Move Monitor and AVIVO MPM devices
(…)
New text
(…)

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Visit 2 (Day 9 ± 2 days)
(…)

Instruction to patient to complete KCCQ (Day 16 ± 2 days) 

Completion of PRO daily and weekly during DynaPort Move Monitor and AVIVO 
parallel monitoring period.
(…)
Visit 3 (Day 77 ± 2 days)
(…)

Measurement of blood pressure and heart rate

Daily and weekly PRO during wearing of DynaPort Move Monitor and AVIVO MPM 
devices
(…)
Section 9.7.2 Addition of weekly PRO
15.1.2.8
This section was changed as a result of Modification 3.
Old text 
Quality of life will be assessed using the KCCQ [10]. The total score will be documented. 
PRO will be completed daily during DynaPort Move Monitor and AVIVO MPM parallel 
monitoring.
(…)
New text
Quality of life will be assessed using the KCCQ [10]. The total score will be documented. 
PRO will be completed daily and weekly during DynaPort Move Monitor and AVIVO MPM 
parallel monitoring.
(…)
Amendment 2
15.2
Amendment 2 is dated 06 Sep 2018.
15.2.1
Overview of changes to the study protocol
This amendment was issued to address the discontinuation of AVIVO Mobile Patient 
Monitoring (MPM) devices by Medtronic Inc. for commercial and clinical trial use effective 
September 20, 2018. These devices will be replaced by VitalConnect VitalPatch biosensors 
for use in this study. 

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Modification 1: Replacement of AVIVO MPM with VitalPatch Biosensor
Description of modification to the study plan: 
Medtronic AVIVO Mobile Patient Monitoring systems will be replaced by VitalConnect 
VitalPatch biosensors for use in this study.
Rationale for introducing the modification: 
Effective on 20-Sep-2018, AVIVO MPM devices utilized in the study will be discontinued by 
the manufacturer Medtronic. The VitalPatch biosensor manufactured by VitalConnect will 
serve as a replacement monitoring device. As a result of this change, the monitoring period
for each device will decrease from 7 to 5 days. Step count and skin temperature are the only 
additional parameters that will be collected with the VitalPatch biosensor as this data was not 
available with the AVIVO MPM patches. With the exception of these two additional 
parameters, all data collected, analyzed and reported in the context of this study will remain 
unaffected by this change. The VitalPatch biosensor is USA FDA approved, CE Marked in 
EU, ISO 13485 certified and Canada CMDR registered. 
List of all CSP sections affected by this modification: Sections 1, 2, 3, 4, 5, 6.1, 9.1, 9.2, 
9.6.1.4, 9.7.1, 9.7.2, 10.1, 10.2, 10.3.2, 10.3.3.2, 13.2, and 16.1
15.2.2
Changes to the protocol text
In this section on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version.
As applicable, changes to the protocol text are highlighted as follows:
Editing of an existing portion
Comparative presentation of “old text” versus “new 
text”, with “old text” referring to the most recent 
previous protocol version. Deletions are crossed out in 
the “old text”. Additions are underlined in the “new 
text”.
Tables / figures / sections
The term “amended” is added to the caption/heading.
Corrections of typos or omissions are not highlighted.
Section 1 Replacement of AVIVO MPM with VitalPatch Biosensor 
15.2.2.1
This section was changed as a result of Modification 1.  
Old text
(…)
Medical devices:
AVIVO Mobile Patient Monitoring System (MPM) (Medtronic, 
USA) 
DynaPort Move Monitor (McRoberts, NL)
(…)

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New text
(…)
Medical devices:
VitalPatch biosensor
(VitalConnect, USA) 
DynaPort Move Monitor (McRoberts, NL)
(…)
Section 2 Replacement of AVIVO MPM with VitalPatch Biosensor
15.2.2.2
This section was changed as a result of Modification 1. 
Old text
(…)
Secondary objectives:

Association between AVIVO MPM and DynaPort Move Monitor data (e.g. different levels of 
activity) to adverse events/clinical outcome data occurring during the study period

Assess the baseline level and longitudinal changes over time of tissue impedance, heart rate, 
respiratory rate and ECG-derived parameters and the average of person-to-person 
physiological variability and the within-patient standard deviation between the baseline and 3-
month measurements.

Assess the feasibility of activity tracking with two devices (AVIVO MPM system and 
DynaPort Move Monitor) in patients with heart failure
Correlation of activity data between AVIVO MPM data on activity and DynaPort Move Monitor  
(…) 

Explore longitudinal changes in transcutaneous thoracic impedance measurement (AVIVO 
MPM) and thus as a surrogate of fluid status in patients with acute HF and after stabilization 
(…)

Investigate the accuracy of patients’ self-reports (PRO, e.g. KCCQ) of time spent on PA in 
real life vs. objective assessment by the DynaPort Move Monitor and AVIVO MPM
(…)
Medical Devices
Device 1
AVIVO MPM system (Medtronic, USA) 
Device 2
DynaPort Move Monitor (McRoberts, NL)
The devices will be provided by BAYER to sites and used according 
to their approved labeling.
(…)

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The AVIVO heart failure patch will be applied after successful screening (first AVIVO patch), after 
discharge (2nd Patch), at visit 2 (3rd patch), at week 2 after discharge (patch 4) and visit 3. The Dynport 
MoveMonitor belt will be applied at visit 2 and visit 3. The 6MWD test will be done at visit 2 (first 
week after discharge) as well as week 12 post discharge (visit 4).
(…)
Primary variable(s)
Daily physical activity (amount, intensity, duration) obtained from the 
AVIVO MPM/DynaPort Move Monitor device
(…)
All analyses will be performed for the total study population (overall analysis). Subjects wearing at 
least once the AVIVO MPM system and for which data was successfully collected over a whole week 
will be included in the analysis. 
(…)
New text
(…)
Secondary objectives:

Association between VitalPatch biosensor and DynaPort Move Monitor data (e.g. different 
levels of activity) to adverse events/clinical outcome data occurring during the study period

Assess the baseline level and longitudinal changes over time   of tissue impedance, heart rate, 
respiratory rate and ECG-derived parameters and the average of person-to-person 
physiological variability and the within-patient standard deviation between the baseline and 3-
month measurements.

Assess the feasibility of activity tracking with two devices (VitalPatch biosensor and 
DynaPort Move Monitor) in patients with  heart failure
Correlation of activity data between VitalPatch biosensor data on activity and DynaPort Move 
Monitor  
(…)

Explore longitudinal changes in transcutaneous thoracic impedance measurement (VitalPatch 
biosensor) and thus as a surrogate of fluid status in patients with acute HF and after 
stabilization 
(…)

Investigate the accuracy of patients’ self-reports (PRO, e.g. KCCQ) of time spent on PA in 
real life vs. objective assessment by the DynaPort Move Monitor and VitalPatch biosensor
(…)
Medical Devices

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Device 1
VitalPatch biosensor (VitalConnect, USA) 
Device 2
DynaPort Move Monitor (McRoberts, NL)
The devices will be provided by BAYER to sites and used according 
to their approved labeling.
(…)
The VitalPatch heart failure patch will be applied after successful screening (first VitalPatch biosensor
patch), after discharge (2nd Patch), at visit 2 (3rd patch), at week 2 after discharge (patch 4) and visit 3. 
The Dynport Move Monitor belt will be applied at visit 2 and visit 3. The 6MWD test will be done at 
visit 2 (first week after discharge) as well as week 12 post discharge (visit 4).
(…)
Primary variable(s)
Daily physical activity (amount, intensity, duration) obtained from the 
VitalPatch biosensor/DynaPort Move Monitor device
(…)
All analyses will be performed for the total study population (overall analysis). Subjects wearing at 
least once the VitalPatch biosensor system and for which data was successfully collected over a whole 
week will be included in the analysis. 
(…)
Section 3 Replacement of AVIVO MPM with VitalPatch Biosensor 
15.2.2.3
This section was changed as a result of Modification 1. 
Old text 
(…)
The AVIVO Mobile Patient Management (MPM) System is a wearable, wireless 
physiological monitoring and arrhythmia detection system that is used by patients to aid 
clinicians in the identification, diagnosis and management of various clinical conditions, 
events and/or trends. It consists primarily of the wearable sensor (monitoring device) and the 
transmitter (portable data transmission device).
The AVIVO MPM will be used to monitor patients’ cardiovascular status. The cardiac 
monitoring device will be worn as specified in Section 9.7.1.
(…)
The system is CE marked and US FDA cleared. Apart from safety assessments, also the 
patient’s everyday physical activity (frequency, duration, intensity) will be tracked. 
Details of the cardiac monitoring and the device to be worn by the patient will be outlined in a 
manual that will be provided to all participating centers.
The DynaPort Move Monitor – the second activity tracker used in the present study -is a 
wearable device worn in an elastic strap on the lower back for ambulatory monitoring of 

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physical activity for up to 7 days. The DynaPort Move Monitor consists of three orthogonally 
mounted accelerometers, a tri-axial magnetometer, a temperature sensor and a barometer.
(…)
New text
(…)
The VitalPatch biosensor is a wearable, wireless physiological monitoring and arrhythmia 
detection system that is used by patients to aid clinicians in the identification, diagnosis and 
management of various clinical conditions, events and/or trends. It consists primarily of the 
wearable sensor (monitoring device) and a portable secured data transmitter (mobile phone 
with bluetooth and wireless connection). VitalPatch is manufactured by VitalConnect (USA), 
and is fully approved by the USA FDA, CE marked in the European Union, CMDR registered 
and ISO 13485 certified.
The VitalPatch biosensor will be used to monitor patients’ cardiovascular status. The cardiac 
monitoring device will be worn as specified in Section 9.7.1.
(…)
Details of the cardiac monitoring and the device to be worn by the patient will be outlined in a 
manual that will be provided to all participating centers.
The DynaPort Move Monitor – the second activity tracker used in the present study -is a 
wearable device worn in an elastic strap on the lower back for ambulatory monitoring of 
physical activity for up to 7 days. DynaPort Move Monitor is manufactured by McRoberts 
BV (Netherlands). This device is US FDA approved, CE marked in the European Union and 
ISO 13485 certified. The DynaPort Move Monitor consists of three orthogonally mounted 
accelerometers, a tri-axial magnetometer, a temperature sensor and a barometer.
(…)
Section 4 Replacement of AVIVO MPM with VitalPatch Biosensor  
15.2.2.4
This section was changed as a result of Modification 1. 
Old text 
(…)
Secondary objectives:

Association between AVIVO MPM and DynaPort Move Monitor data (e.g. different 
levels of activity) to adverse events/clinical outcome data occurring during the study 
period

Assess the baseline level and longitudinal changes over time of tissue impedance, 
heart rate, respiratory rate and ECG-derived parameters and the average of person-to-
person physiological variability and the within-patient standard deviation between the 
baseline and 3-month measurements

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
Assess the feasibility of activity tracking with two devices (AVIVO MPM system and 
DynaPort Move Monitor) in patients with heart failure

Correlation of activity data between AVIVO MPM data on activity and DynaPort 
Move Monitor
(…)

Explore longitudinal changes in transcutaneous thoracic impedance measurement 
(AVIVO MPM) and thus as a surrogate of fluid status in patients with acute HF and 
after stabilization
(…)

Investigate the accuracy of patients’ self-reports (PRO, e.g. KCCQ) of time spent on 
PA in real life vs. objective assessment by the DynaPort Move Monitor and AVIVO 
MPM
(…)
New text
(…)
Secondary objectives:

Association between VitalPatch biosensor and DynaPort Move Monitor data (e.g. 
different levels of activity) to adverse events/clinical outcome data occurring during 
the study period

Assess the baseline level and longitudinal changes over time of tissue impedance, 
heart rate, respiratory rate and ECG-derived parameters and the average of person-to-
person physiological variability and the within-patient standard deviation between the 
baseline and 3-month measurements

Assess the feasibility of activity tracking with two devices (VitalPatch biosensor and 
DynaPort Move Monitor) in patients with heart failure

Correlation of activity data between VitalPatch biosensor data on activity and 
DynaPort Move Monitor
(…)

Explore longitudinal changes in transcutaneous thoracic impedance measurement 
(VitalPatch biosensor) and thus as a surrogate of fluid status in patients with acute HF 
and after stabilization
(…)

Investigate the accuracy of patients’ self-reports (PRO, e.g. KCCQ) of time spent on 
PA in real life vs. objective assessment by the DynaPort Move Monitor and VitalPatch 
biosensor
(…)

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Section 5 Replacement of AVIVO MPM with VitalPatch Biosensor
15.2.2.5
This section was changed as a result of Modification 1.
Old text
(…)
All patients will receive AVIVO MPM system at 5 monitoring periods (5 patches each subject 
in total, monitoring period 7 days each period) and the DynaPort Move Monitor (belt) at 2 
monitoring periods (7 day monitoring each period). Results from both devices are not visible 
to investigator and subjects to avoid bias on treatment decisions.
(…)
Figure 5-1:
Study design 
(…)
Primary variables

Daily physical activity (amount, duration and intensity) obtained from the AVIVO 
MPM /DynaPort Move Monitor device
Secondary variables

6MWD

Other activity information obtained from the AVIVO MPM /DynaPort Move Monitor 
device such as sleep movements and patterns, sit-to stand behavior (DynaPort)
(…)
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New text
(…)
All patients will receive VitalPatch biosensor at 5 monitoring periods (5 patches each subject 
in total, monitoring period 5 days each period) and the DynaPort Move Monitor (belt) at 2 
monitoring periods (7 day monitoring each period). Results from both devices are not visible 
to investigator and subjects to avoid bias on treatment decisions.
(…)
Figure 5-1:
Study design - amended
(…)
Primary variables

Daily physical activity (amount, duration and intensity) obtained from the VitalPatch 
biosensor /DynaPort Move Monitor device
Secondary variables

6MWD

Other activity information obtained from the VitalPatch biosensor /DynaPort Move 
Monitor device such as sleep movements and patterns, sit-to stand behavior 
(DynaPort)
(…)
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Section 6.1 Replacement of AVIVO MPM with VitalPatch Biosensor
15.2.2.6
This section was changed as a result of Modification 1. 
Old text
(…)
7.
Willingness to wear the DynaPort Move Monitor accelerometer belt and AVIVO 
MPM during the trial
(…)
New text
(…)
7.
Willingness to wear the DynaPort Move Monitor accelerometer belt and VitalPatch 
biosensor during the trial
(…)
Section 9.1 Replacement of AVIVO MPM with VitalPatch Biosensor
15.2.2.7
This section was changed as a result of Modification 1.
Old text
(…)
Table 1: Tabulated overview on study procedures and variables collected during the study –
amended
Study period
Hospitalization 
phase
Outpatient phase
Safety 
FU call
Visit number
Scr1
1
2
3
4
5
Visit type
site
site
site
site

Screen 
assess
At hospital 
discharge
Week after discharge
1
2
3
11
12
Day and allowed deviations
0
9±2
16±2
23±2
77±2
84±2
6 months
±4 weeks
(…)
AVIVO (for 7 days)2
start end
  ---1st-----2nd----3rd----4th--           ----5th----
(…)1- -

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1 within 72 hours after hospitalization
2 DynaPort monitoring periods: Second week after hospital discharge (Days 7-14) and Week 11 to 12 
(Days 77-84)
  AVIVO monitoring periods: up to 7 days during the hospital stay, first week after hospital discharge 
(Day 0-7), during weeks 2 and 3 (Day 7-14, Day 17-24) and Week 11 to 12 (Days 77-84)
3 central lab assessments: NTproBNP, hs-copeptin, hs-TNT, optionally: GDF15, IGFBP7, sST2, Gal3
* Concurrently evaluating PRO will be completed daily and weekly during DynaPort and AVIVO
parallel monitoring period
4 within ± 72 of discharge day
(…)
New text
(…)
Table 1: Tabulated overview on study procedures and variables collected during the study –
amended
Study period
Hospitalization 
phase
Outpatient phase
Safety 
FU call
Visit number
Scr1
1
2
3
4
5
Visit type
site
site
site
site

Screen 
assess
At hospital 
discharge
Week after discharge
1
2
3
11
12
Day and allowed deviations
0
9±2
16±2
23±2
77±2
84±2
6 months
±4 weeks
(…)
VitalPatch (for 5 days)2
start end
  ---1st-----2nd----3rd----4th--           ----5th----
(…)
1 within 72 hours after hospitalization
2 DynaPort monitoring periods: Second week after hospital discharge (Days 7-14) and Week 11 to 12 
(Days 77-84)
  VitalPatch monitoring periods: up to 5 days during the hospital stay, first 5 days after hospital 
discharge (Day 0-5), during weeks 2 and 3 (Day 7-12, Day 12-17) and Week 11 to 12 (Days 77-
82)
3 central lab assessments: NTproBNP, hs-copeptin, hs-TNT, optionally: GDF15, IGFBP7, sST2, Gal3
* Concurrently evaluating PRO will be completed daily and weekly during DynaPort and VitalPatch
parallel monitoring period
4 within ± 72 of discharge day
(…)
Section 9.2 Replacement of AVIVO MPM with VitalPatch Biosensor
15.2.2.8
This section was changed as a result of Modification 1. 
Old text
(…)
I- -

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Enrollment / Screening Visit 
(…)

Eligible patients will be included in the study and will wear the AVIVO MPM patch
for up to 7 days during the hospital stay
(…)
Visit 1 (Day 0) - amended
(…)

A new AVIVO MPM patch will be attached to subject`s chest, which they will wear 
for 7 days after discharge from hospital (may be expanded until Days 9±2).

Subjects will be informed how to wear and apply the AVIVO MPM.
(…)
Visit 2 (Day 9 ± 2 days) - amended
(…)

The AVIVO MPM patch device will be collected 

In addition subjects will receive the DynaPort Move Monitor device which they will 
also wear for 7 days. Subjects will be informed how to wear and apply the DynaPort 
Move Monitor.

Subjects will receive another 2 AVIVO MPM patches which they will wear 
consecutively for 7 days each. One AVIVO MPM patch will be attached to the 
subject`s chest at the site, the other one has to be attached by the patient after removal 
of the first one after 7 days. 

Instruction to patient to complete KCCQ (Day 16 ± 2 days) 

Completion of PRO daily and weekly during DynaPort Move Monitor and AVIVO 
parallel monitoring period.
(…)
Visit 3 (Day 77 ± 2 days) - amended
(…)

daily and weekly PRO during wearing of DynaPort Move Monitor and AVIVO MPM
devices

The AVIVO patches will be collected

Subjects will receive another AVIVO MPM patch and the DynaPort Move Monitor 
device which they will wear for 7 days. The AVIVO MPM patch will be placed on 
subject`s chest and DynaPort Move Monitor belt will be put on at the site.
(…)

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Visit 4 (Day 84 ± 2 days)
(…)
The AVIVO MPM patch and the DynaPort Move Monitor device will be collected.
(…)
New text
(…)
Enrollment / Screening Visit – amended
(…)

Eligible patients will be included in the study and will wear the VitalPatch biosensor
for up to 5 days during the hospital stay
(…)
Visit 1 (Day 0) - amended
(…)

A new VitalPatch biosensor will be attached to subject`s chest, which they will wear 
for 5 days after discharge from hospital 

Subjects will be informed how to wear and apply the VitalPatch biosensor.
(…)
Visit 2 (Day 9 ± 2 days) - amended
(…)

The VitalPatch biosensor device will be collected 

In addition subjects will receive the DynaPort Move Monitor device which they will 
wear for 7 days. Subjects will be informed how to wear and apply the DynaPort Move 
Monitor.

Subjects will receive another 2 VitalPatch biosensor patches which they will wear 
consecutively for 5 days each. One VitalPatch biosensor patch will be attached to the 
subject`s chest at the site, the other one has to be attached by the patient after removal 
of the first one after 5 days. 

Instruction to patient to complete KCCQ (Day 16 ± 2 days) 

Completion of PRO daily and weekly during DynaPort Move Monitor and VitalPatch 
monitoring period.
(…)
Visit 3 (Day 77 ± 2 days) - amended
(…)

daily and weekly PRO during wearing of DynaPort Move Monitor and VitalPatch
devices

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
The VitalPatch biosensor patches will be collected

Subjects will receive another VitalPatch biosensor patch and the DynaPort Move 
Monitor device which they will wear for 5 and 7 days, respectively. The VitalPatch 
biosensor will be placed on subject`s chest and DynaPort Move Monitor belt will be 
put on at the site.
(…)
Visit 4 (Day 84 ± 2 days) - amended
(…)
The VitalPatch biosensor patch and the DynaPort Move Monitor device will be collected.
(…)
Section 9.6.1.4 Replacement of AVIVO MPM with VitalPatch 
15.2.2.9
Biosensor 
This section was changed as a result of Modification 1. 
Old text
(…)
Any serious adverse events will be reported by the investigator to Bayer. Bayer will process 
these cases according to Bayer standard procedures and report as described below. In 
addition, all adverse events related to the AVIVO Mobile Patient Management (MPM) 
System or the DynaPort Move Monitor, which are both non-investigational devices in the 
Post-Marketing phase, will be reported by the investigator to the respective legal 
manufacturers, which would fulfill their reporting obligations to competent authorities and 
Notified bodies. 
(…)
Reporting obligations for non-Bayer drugs/devices incl. AVIVO Mobile Patient Management 
(MPM) System and the DynaPort Move Monitor will be fulfilled by the respective Marketing 
Authorization holders/Manufacturers based on the information provided by the investigator 
via spontaneous reporting.
(…)
New text
(…)
Any serious adverse events will be reported by the investigator to Bayer. Bayer will process 
these cases according to Bayer standard procedures and report as described below. In 
addition, all adverse events related to the VitalPatch biosensor or the DynaPort Move 
Monitor, which are both non-investigational devices in the Post-Marketing phase, will be 
reported by the investigator to the respective legal manufacturers, which would fulfill their 
reporting obligations to competent authorities and Notified bodies. 
(…)

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Reporting obligations for non-Bayer drugs/devices incl. VitalPatch biosensor and the 
DynaPort Move Monitor will be fulfilled by the respective Marketing Authorization 
holders/Manufacturers based on the information provided by the investigator via spontaneous 
reporting.
(…)
Section 9.7.1 Replacement of AVIVO MPM with VitalPatch Biosensor
15.2.2.10
This section was changed as a result of Modification 1. 
Old text
(…)
9.7.1
AVIVO MPM/DynaPort Move Monitor devices
AVIVO MPM system
AVIVO MPM system will be provided by Bayer to sites. Subjects will wear the AVIVO 
MPM patch for overall 5 periods of 7 days each (for details on time periods see Table 1).
Parameters obtained from the AVIVO MPM patch are:
•
ECG and parameters derived from ECG, like e.g. heart rate, HRV, AF burden, 
arrhythmias etc.
•
Respiratory rate
•
Transcutaneous thoracic impedance = fluid status
•
Physical activity (duration and intensity)
•
Posture
(…)
New text
(…)
9.7.1
VitalPatch biosensor/DynaPort Move Monitor devices - amended
VitalPatch biosensor
VitalPatch biosensor will be provided by Bayer to sites. Subjects will wear the VitalPatch 
biosensor for overall 5 periods of 5 days each (for details on time periods see Table 1).
Parameters obtained from the VitalPatch biosensor are:
•
ECG and parameters derived from ECG, like e.g. heart rate, HRV, AF burden, 
arrhythmias etc.
•
Respiratory rate
•
Transcutaneous thoracic impedance = fluid status

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•
Skin temperature
•
Step count
•
Physical activity (duration and intensity)
•
Posture
(…)
Section 9.7.2 Replacement of AVIVO MPM with VitalPatch Biosensor
15.2.2.11
This section was changed as a result of Modification 1. 
Old text
(…)
Quality of life will be assessed using the KCCQ [10]. The total score will be documented. 
PRO will be completed daily and weekly during DynaPort Move Monitor and AVIVO MPM
parallel monitoring.
(…)
New text
(…)
Quality of life will be assessed using the KCCQ [10]. The total score will be documented. 
PRO will be completed daily and weekly during DynaPort Move Monitor and VitalPatch
monitoring.
(…)
Section 10.1 Replacement of AVIVO MPM with VitalPatch Biosensor
15.2.2.12
This section was changed as a result of Modification 1. 
Old text
(…)
Data from AVIVO and DynaPort devices is expected to include missing values, as result of 
compliance in wearing the device.
(…)
New text
(…)
Data from VitalPatch and DynaPort devices is expected to include missing values, as result of 
compliance in wearing the device.
(…)

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Section 10.2 Replacement of AVIVO MPM with VitalPatch Biosensor
15.2.2.13
This section was changed as a result of Modification 1.
Old text
(…)
10.2
Analysis sets 
In absence of intervention and randomization the statistical analysis sets are defined on the 
base of a successful monitoring under the AVIVO MPM patch.  
Full analysis set (FAS)
The FAS population consists of all subjects that are included into the study and that are 
wearing at least one AVIVO MPM patch and for which data was successfully collected over 
the whole week. The FAS will be used to display baseline characteristics, assess parameter 
variability, correlative analyses. 
Safety analysis set (SAF)
The SAF population consists of all patients with a planned study procedure after signing the 
informed consent that are wearing at least one AVIVO MPM patch and for which data was 
successfully collected over the whole week will be included in the SAF. The SAF will be 
used to display safety analyses.
(…)
New text
(…)
10.2
Analysis sets - amended
In absence of intervention and randomization the statistical analysis sets are defined on the 
base of a successful monitoring under the VitalPatch biosensor patch.  
Full analysis set (FAS)
The FAS population consists of all subjects that are included into the study and that are 
wearing at least one VitalPatch biosensor patch and for which data was successfully collected 
over the whole week. The FAS will be used to display baseline characteristics, assess 
parameter variability, correlative analyses. 
Safety analysis set (SAF)
The SAF population consists of all patients with a planned study procedure after signing the 
informed consent that are wearing at least one VitalPatch biosensor patch and for which data 
was successfully collected over the whole week will be included in the SAF. The SAF will be 
used to display safety analyses.
(…)

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Section 10.3.2 Replacement of AVIVO MPM with VitalPatch Biosensor
15.2.2.14
This section was changed as a result of Modification 1. 
Old text
(…)
For AVIVO data collected in this frame only the day to day variability will be of interest.
(…)
New text
(…)
For VitalPatch data collected in this frame only the day to day variability will be of interest.
(…)
Section 10.3.3.2 Replacement of AVIVO MPM with VitalPatch 
15.2.2.15
Biosensor
This section was changed as a result of Modification 1. 
Old text
(…)
This analysis allows investigating the relationship between two multivariate sets of variables, 
such as the one obtained using the AVIVO MPM or DynaPort Move Monitor device, and 
another one as obtained from other contexts, such as contexts defined by the following data 
sets: i) echocardiography parameters set, ii) 12-lead ECG parameters set, and iii) a composite 
set including biomarkers, 6MWD score, KCCQ total score, and vital signs (blood pressure, 
heart rate).
(…)
New text
(…)
This analysis allows investigating the relationship between two multivariate sets of variables, 
such as the one obtained using the VitalPatch biosensor or DynaPort Move Monitor device, 
and another one as obtained from other contexts, such as contexts defined by the following 
data sets: i) echocardiography parameters set, ii) 12-lead ECG parameters set, and iii) a 
composite set including biomarkers, 6MWD score, KCCQ total score, and vital signs (blood 
pressure, heart rate).
(…)
Section 13.2 Replacement of AVIVO MPM with VitalPatch Biosensor
15.2.2.16
This section was changed as a result of Modification 1. 
Old text
(…)

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Funding
This study will be funded by its sponsor.
Collaborator of this study is Medtronic Inc., Patient Monitoring & Diagnostics, 8200 Coral 
Sea Street, NE Mounds View, Minnesota 55112, USA.
(…)
New text
(…)
Funding
This study will be funded by its sponsor.
Collaborator of this study is VitalConnect Inc., 224 Airport Parkway Suite 300, San Jose, 
California 95110, USA.
(…)
Section 16.1 Replacement of AVIVO MPM with VitalPatch Biosensor
Old text
(…)

Provide a brief high-level outline of how the PRO items can be used to: 
o
Validate activity monitoring data from wearable devices (AVIVO patch
and DynaPort Move Monitor)
(…)
New text
(…)

Provide a brief high-level outline of how the PRO items can be used to: 
o
Validate activity monitoring data from wearable devices (VitalPatch 
biosensor and DynaPort Move Monitor)
(…)
Section 16.1 Replacement of AVIVO MPM with VitalPatch Biosensor
15.2.2.17
This section was changed as a result of Modification 1. 
Old text
(…)

Provide a brief high-level outline of how the PRO items can be used to: 

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o
Validate activity monitoring data from wearable devices (AVIVO patch
and DynaPort Move Monitor)
(…)
New text
(…)

Provide a brief high-level outline of how the PRO items can be used to: 
o
Validate activity monitoring data from wearable devices (VitalPatch 
biosensor and DynaPort Move Monitor)
(…)
Amendment 3
15.3
Amendment 3 is dated 21 Feb 2020.
15.3.1
Overview of changes to the study protocol
This amendment was issued to open the recruitment of the study to additional patients, 
especially patients with chronic heart failure (CHF) who show up in an unplanned outpatient 
visit but need no hospitalization, and to generally facilitate the conduct of the study at the 
sites.
Modification 1: Extension of the study population
Description of modification to the study plan: 
In- and exclusion criteria were modified to allow participation of a wider range of patients 
with heart failure. 
Rationale for introducing the modification: 
Ambulatory, stable patients were added to the study population to also gain further insights 
into this group, in comparison to the hospitalized patients with worsening heart failure. The 
data generated is meant to be used as reference for future clinical development projects across 
various different heart failure subpopulations, to cover the complete clinical spectrum and 
various characteristics of the patient journey.
In addition, entry criteria were adjusted to match the situation of the subjects in scope.
Specifically, the exclusion criterion for hemoglobin was changed from <10.0 g/dL to 
<8.0 g/dL . Low hemoglobin values are commonly observed due to dilution of the blood from 
excess fluid. Through application of standard diuretic therapy, it is expected that hemoglobin 
levels will quickly recover, and hemoglobin will not have an impact on exercise capacity.
List of all CSP sections affected by this modification: Sections 2, 5, 6.1, 6.2.
Modification 2: Simplification of number and timing of study-related procedures
Description of modification to the study plan: 
The number of timing of the following measurements was aligned and - in some cases -
reduced: physical exam, echocardiography, blood samples for biomarkers, vital patch 
application.

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Rationale for introducing the modification: 
Following the exchange of the AVIVO patch versus the VitalPatch in amendment 2 and 
limitations provided by the new device, adaptions of the timing of the planned measurements 
became necessary to facilitate the conduct of the study. In addition, the study team revisited 
procedures with limited value for the envisaged study objectives and optimized workflows for 
enhanced feasibility.
List of all CSP sections affected by this modification: Sections 2, 4, 5, 9.1, 9.2, 9.6.3, 9.7.1.
15.3.2
Changes to the protocol text
In this section on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version.
As applicable, changes to the protocol text are highlighted as follows:
Editing of an existing portion
Comparative presentation of “old text” versus “new 
text”, with “old text” referring to the most recent 
previous protocol version. Deletions are crossed out in 
the “old text”. Additions are underlined in the “new 
text”.
Tables / figures / sections
The term “amended” is added to the caption/heading.
Corrections of typos or omissions are not highlighted.
Section 2 Extension of study population and simplification of study 
15.3.2.1
procedures
This section was changed as a result of Modification 1 and 2 (tissue impedance was provided 
by the AVIVO patch but is not measured by the VitalPatch anymore).
Old text
Study objective(s)
The study aims to explore two marketed devices providing a multi-marker 
monitoring including physical activity under real-life conditions in patients 
with HFpEF and HFrEF. It aims to identify potential new endpoints for future 
HFpEF 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.
[…]
Secondary objectives:
[…]

Assess the baseline level and longitudinal changes over time  of tissue 
impedance, heart rate, respiratory rate and ECG-derived parameters 
and the average of person-to-person physiological variability and the 
within-patient standard deviation between the baseline and 3-month 
measurements.

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[…]

Evaluate the relationship between physical activity levels, tissue 
impedance, heart rate, respiratory rate and ECG-derived parameters 
and important measures in HFpEF; such as quality of life (QoL), 
patient reported outcome (PRO), biomarkers, outcomes (e.g. clinical 
endpoints such as hospitalization for heart failure, cardiovascular 
death, emergency visits)
[…]

Evaluate hs-copeptin as potential biomarker 

Explore longitudinal changes in transcutaneous thoracic impedance 
measurement (VitalPatch biosensor) and thus as a surrogate of fluid 
status in patients with acute  HF and after stabilization 

Correlate blood based biomarkers of congestion (e.g. NTproBNP/hs-
copeptin) with functional marker (impedance)
New text
Study objective(s)
The study aims to explore two marketed devices providing a multi-marker 
monitoring including physical activity under real-life conditions in patients 
with HFpEF and HFrEF. It aims to identify potential novel endpoints for 
future HFpEF 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.
[…]
Secondary objectives:
[…]

Assess the baseline level and longitudinal changes over time of heart 
rate, respiratory rate and ECG-derived parameters and the average of 
person-to-person physiological variability and the within-patient 
standard deviation between the baseline and 3-month measurements.
[…]

Evaluate the relationship between physical activity levels, heart rate, 
respiratory rate and ECG-derived parameters and important measures 
in HFpEF; such as quality of life (QoL), patient reported outcome 
(PRO), biomarkers, outcomes (e.g. clinical endpoints such as 
hospitalization for heart failure, cardiovascular death, emergency 
visits)
[…]

Evaluate hs-copeptin as potential biomarker 
Further changes were introduced as a result of Modification 1 (extension of study population).

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Old text
Diagnosis and main 
criteria for inclusion 
/exclusion
Female and male subjects with a diagnosis of acute decompensated heart 
failure with preserved ejection fraction (HFpEF; EF ≥ 45%) or acute 
decompensated heart failure with reduced ejection fraction (HFrEF; EF ≤ 
35%) will be enrolled.
New text
Diagnosis and main 
criteria for inclusion 
/exclusion
Female and male subjects with a diagnosis of heart failure with preserved 
ejection fraction (HFpEF; EF ≥ 45%) or reduced ejection fraction (HFrEF; 
EF ≤ 35%) will be enrolled.

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Further changes were introduced as a result of Modification 2 (simplification of study related 
procedures).
Old text:
Methodology
This study will compromise a hospital phase of approximately 5.5 days 
including the screening period, an outpatient phase of approximately 11
week (depending on duration of hospital phase) and a follow up telephone 
call after 6 months
Patients will be selected on the basis of their established diagnosis of
HFrEF and HFpEF.
The patients will have site visits at weeks 0 (screening visit and baseline
visit 1 during in hospitalization phase), week 1 after hospital discharge 
(visit 2; outpatient phase), week 11 post discharge (visit 3, outpatient 
phase) and week 12 post discharge (visit 4, outpatient phase). 
In addition, one follow up phone call at 6 month post discharge will be 
made to assess patient safety, well-being and clinical status.
The VitalPatch heart failure patch will be applied after successful 
screening (first VitalPatch biosensor patch), after discharge (2nd Patch), at 
visit 2 (3rd patch), at week 2 after discharge (patch 4) and visit 3. The 
Dynport MoveMonitor belt will be applied at visit 2 and visit 3. The 
6MWD test will be done at visit 2 (first week after discharge) as well as 
week 12 post discharge (visit 4). 
Transthoracic echocardiography will be performed prior to hospital 
discharge at visit 1 and visit 4.
The KCCQ questionnaire will be performed at visit 1 prior to discharge, 
week 2 after discharge and at visit 4.
Daily and weekly PRO will be performed in parallel with the DynaPort 
Move Monitor  monitoring periods (visit 2, week 1-2) and visit 3 (week 
11-12).
Biomarkers reflecting cardiac structure and function will be examined as 
well as candidate biomarkers that may predict outcomes.
Daily physical activity (duration and intensity) will be recorded during 
repeated 7-day time periods until 3 months after discharge from hospital.

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New text
Methodology
This study will comprise a screening phase of up to 9 days including an 
optional hospitalization period or, alternatively starting after an 
unscheduled outpatient visit; an outpatient phase of approximately 12
weeks and a follow up telephone call after 6 months
Patients will be selected on the basis of their established diagnosis of
HFrEF and HFpEF.
The patients will have site visits at week 0 (screening visit and visit 1
within 9 days, during hospitalization phase or in ambulatory patients), 
week 1 after visit 1 / hospital discharge (visit 2; observational phase), week 
11 post visit 1 / discharge (visit 3, observational phase) and week 12 post 
visit 1 / discharge (visit 4, observational phase). 
In addition, one follow up phone call at 6 months post discharge will be 
made to assess patient safety, well-being and clinical status.
The VitalPatch heart failure patch will be applied after successful 
screening (first VitalPatch biosensor patch), at visit 2 (2nd patch, 3rd patch
will be subsequently applied by the patient at home), and at visit 3 (4th
patch, 5th patch will be subsequently applied by the patient at home). The 
DynaPort MoveMonitor belt will be applied at visit 2 and visit 3. The 
6MWD test will be done at visit 1 / hospital discharge) as well as visit 4 
(12 weeks post visit 1 / discharge). 
Transthoracic echocardiography will be performed at visit 1 (within ± 72 
hours).
The KCCQ questionnaire will be performed at visit 1 / prior to discharge, 
week 3 after visit 1 / discharge and at visit 4.
Daily and weekly PRO will be performed in parallel with the DynaPort 
MoveMonitor  monitoring periods (visit 2, week 1-2) and visit 3 (week 11-
12).
Biomarkers reflecting cardiac structure and function will be examined as 
well as candidate biomarkers that may predict outcomes.
Daily physical activity (duration and intensity) will be recorded during 
repeated respective 5-day (VitalPatch) and 7-day (DynaPort 
MoveMonitor) time periods until 3 months after visit 1 / discharge from 
hospital.
Old text
Time point/frame of 
measurement for 
primary variable(s)
Baseline level and longitudinal changes over time of physical activity and 
the average of person-to-person physiological variability and the within-
subject standard deviation between the baseline and 3-month post
discharge measurements.

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New text
Time point/frame of 
measurement for 
primary variable(s)
Baseline level and longitudinal changes over time of physical activity and 
the average of person-to-person physiological variability and the within-
subject standard deviation between the baseline and 3-month post baseline
measurements.
Old text
Plan for statistical 
analysis
[…]
All analyses will be performed for the total study population (overall 
analysis). Subjects wearing at least once the VitalPatch biosensor11 system 
and for which data was successfully collected over a whole week will be 
included in the analysis.
New text
Plan for statistical 
analysis
[…]
All analyses will be performed for the total study population (overall 
analysis). Subjects wearing at least once the VitalPatch biosensor11 system 
and for which data was successfully collected over 5 days will be included 
in the analysis.
Section 4 Deletion of tissue impedance related objectives
15.3.2.2
This section was changed as a result of Modification 2 (tissue impedance was provided by the 
AVIVO patch, but is not measured by the VitalPatch anymore).
Old text
Secondary objectives:
[…]

Assess the baseline level and longitudinal changes over time of tissue impedance, 
heart rate, respiratory rate and ECG-derived parameters and the average of person-to-
person physiological variability and the within-patient standard deviation between the 
baseline and 3-month measurements
[...]

Evaluate the relationship between physical activity levels, tissue impedance, heart rate, 
respiratory rate and ECG-derived parameters and important measures in HFpEF; such 
as quality of life (QoL), patient reported outcome (PRO), biomarkers, outcomes (e.g. 
clinical endpoints such as hospitalization for heart failure, cardiovascular death, 
emergency visits)

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[…]

Evaluate hs-copeptin as potential biomarker 

Explore longitudinal changes in transcutaneous thoracic impedance measurement 
(VitalPatch biosensor) and thus as a surrogate of fluid status in patients with acute HF 
and after stabilization 

Correlate blood based biomarkers of congestion (e.g. NTproBNP/hs-copeptin) with 
functional marker (impedance) 

Correlation between patch monitor collected data and inpatient clinical data during 
hospital stay (e.g. echocardiography, weight gain/loss, NYHA, heart rate)

Explore the relationship between PA, 6MWD, PRO, biomarkers, adverse 
events/clinical outcomes
New text
Secondary objectives:
[…]

Assess the baseline level and longitudinal changes over time of heart rate, respiratory 
rate and ECG-derived parameters and the average of person-to-person physiological 
variability and the within-patient standard deviation between the baseline and 3-month 
measurements
[...]

Evaluate the relationship between physical activity levels, heart rate, respiratory rate 
and ECG-derived parameters and important measures in HFpEF; such as quality of 
life (QoL), patient reported outcome (PRO), biomarkers, outcomes (e.g. clinical 
endpoints such as hospitalization for heart failure, cardiovascular death, emergency 
visits)
[...]

Evaluate hs-copeptin as potential biomarker 

Correlation between patch monitor collected data and inpatient clinical data during 
hospital stay (e.g. echocardiography, weight gain/loss, NYHA, heart rate)

Explore the relationship between PA, 6MWD, PRO, biomarkers, adverse 
events/clinical outcomes

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Section 5 Extension of study population and simplification of 
15.3.2.3
procedures
This section was changed as a result of Modification 1 and Modification 2.
Old text
This is a non-randomized, multi-center, observatory prospective patient study. The study will 
be conducted in several centers in EU and non-EU.
Patients hospitalized due to acute heart failure will be included in this study. Overall 80 
subjects have to complete at least all device monitoring periods:

60 subjects with acute decompensated heart failure with preserved ejection fraction 
(HFpEF; EF ≥ 45%) and 

20 subjects with acute decompensated heart failure with reduced ejection fraction 
(HFrEF; EF ≤ 35%).
[…]
Biomarkers will be investigated during the hospital stay and at the visits 2 and 4. A 6-minute 
walking test will be performed at baseline (first week after discharge) and after 11-12 weeks.
Design overview
Figure 5-1:
Study design
Abbreviations: HHF = heart failure hospitalization; 6MWD = 6-minute walking distance test, 
                      PRO = patient reported outcome; FU = follow up visit
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New text
This is a non-randomized, multi-center, observatory prospective patient study. The study will 
be conducted in several centers in EU and non-EU.
Patients hospitalized due to heart failure as well as ambulatory patients with heart failure will 
be included in this study. Overall approx. 80 subjects have to complete at least all device 
monitoring periods:

Approx. 60 subjects with established diagnosis of heart failure with preserved ejection 
fraction (HFpEF; EF ≥ 45%) and 

Approx. 20 subjects with established diagnosis of heart failure with reduced ejection 
fraction (HFrEF; EF ≤ 35%).
[…]
Biomarkers will be investigated during the hospital stay (only in case patient is hospitalized),
at visit 1, and at visit 4. A 6-minute walking test will be performed at visit 1 / discharge and 
after 11-12 weeks.
Design overview
Figure 5-1:
Study design
Abbreviations: KCCQ = Kansas City Cardiomyopathy Questionnaire score; QS = Questionnaire for 
patient reported outcomes (daily and weekly); 6MWD = 6 minute walking distance; 
FUP = follow up visit
Old text
Secondary variables

[…]

Plasma/serum biomarkers 

Blood pressure and heart rate, cardiac function parameters measured by 
echocardiography
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
Tissue impedance

ECG derived readouts: heart rate variability (HRV) 

NYHA class
Results of the primary and secondary variables obtained at 3 months post-discharge (week 11-
12) versus baseline (first week after discharge).
New text
Secondary variables

[…]

Plasma/serum biomarkers 

Blood pressure and heart rate, cardiac function parameters measured by 
echocardiography

ECG derived readouts: heart rate variability (HRV) 

NYHA class
Results of the primary and secondary variables obtained at 3 months post-baseline (week 11-
12) versus baseline (visit 1).
Section 6.1 Extension of study population
15.3.2.4
This section was changed as a result of Modification 1.
Old text
4. Worsening heart failure requiring hospitalization within the last 72 hours for the 
initiation of intensification of heart failure therapy with at least one of the following 
o
BNP ≥ 100 pg/mL or NT-proBNP ≥ 400 pg/mL (sinus rhythm) or
o
BNP ≥ 300 pg/mL or NT-proBNP ≥ 1200 pg/mL (atrial fibrillation)
o
Radiographic evidence of pulmonary congestion (interstitial edema, 
pulmonary venous hypertension, vascular congestion, pleural effusion)
o
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)
5. For HFrEF only
o
EF ≤ 35% assessed by any imaging modality (e.g. echocardiography, 
cardiac magnetic resonance, cine levocardiography) within 3 months prior 
to study inclusion 

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6. For HFpEF only
o
EF ≥ 45% assessed by any imaging modality (e.g. echocardiography, 
cardiac magnetic resonance, cine levocardiography) within 3 months prior 
to study inclusion 
New text
4. Worsening heart failure requiring hospitalization for the initiation of intensification of 
heart failure therapy with at least one of the following 
o
BNP ≥ 100 pg/mL or NT-proBNP ≥ 400 pg/mL (sinus rhythm) or
o
BNP ≥ 300 pg/mL or NT-proBNP ≥ 1200 pg/mL (atrial fibrillation)
o
Radiographic evidence of pulmonary congestion (interstitial edema, 
pulmonary venous hypertension, vascular congestion, pleural effusion)
o
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 one of the following
o
Hospitalization for heart failure within the past 12 months or
o
BNP ≥ 100 pg/mL or NT-proBNP ≥ 400 pg/mL (sinus rhythm) or
o
BNP ≥ 300 pg/mL or NT-proBNP ≥ 1200 pg/mL (atrial fibrillation)
5. For HFrEF only
o
EF ≤ 35% assessed by any imaging modality (e.g. echocardiography, 
cardiac magnetic resonance, cine levocardiography) within 12 months prior 
to study inclusion 
6. For HFpEF only
o
EF ≥ 45% assessed by any imaging modality (e.g. echocardiography, 
cardiac magnetic resonance, cine levocardiography) within 12 months prior 
to study inclusion 
Section 6.2 Extension of study population 
15.3.2.5
This section was changed as a result of Modification 1.
Old text
2. Hemoglobin <10.0 g/dl
[…]

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11. Subject with known allergies or hypersensitivities to adhesives or hydrogels
12. Subject with implantable devices with active minute ventilation sensors
13. Severe uncorrected valvular heart disease
[…]
19. Patients who regularly (> 1x per week) swim or do water aerobics
New text
2. Hemoglobin <8.0 g/dl
[…]
11. Subject with known allergies or hypersensitivities to adhesives or hydrogels
12. deleted
13. Severe uncorrected valvular heart disease
[…]
19. 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
Section 9.1 Simplification of study procedures
15.3.2.6
This section was changed as a result of Modification 2.
Old text
The investigator documents an initial visit, follow-up visits and the end of observation/final 
visit for each patient in the electronic case report form (eCRF). The end of observation visit 
will be documented after 12 weeks; a final follow-up call will be performed 6 months after 
discharge from hospital.
Activities to be performed are summarized in the study flow chart in Table 1.

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Table 1: Tabulated overview on study procedures and variables collected during the study -
amended
Study period
Hospitalization
phase
Outpatient phase
Safety 
FU call
Visit number
Scr1
1
2
3
4
5
Visit type
site
site
site
site

Screen 
assess
At hospital
discharge
Week after discharge
1
2
3
11
12
Day and allowed deviations
0
9±2
16±2
23±2
77±2
84±2
6 months
±4 weeks
Signed informed consent form 
●
Inclusion / exclusion criteria
●
KCCQ
●
●
●
Daily and weekly PRO*
----1st----
----2nd----
Demographic data
●
Medical and surgical history
●
Physical exam
●
●
●
●
●
Height
●
Weight
●
●
●
●
12-lead ECG 
●
●
●
NYHA class
●
●
●
●
Blood pressure and heart rate
●
●
●
●
●
Adverse events
●
●
●
●
●
●
Concomitant medication
●
●
●
●
●
●
Echocardiography
  ●4
●
Six-minute walking distance  
●
●
DynaPort (for 7 days)2
start end
     
     ----1st----
    ----2nd----
VitalPatch (for 5 days)2
start end
  ---1st-----2nd----3rd----4th--           ----5th----
Blood sample for biomarkers3
●
●
●
●
1 within 72 hours after hospitalization
2 DynaPort monitoring periods: Second week after hospital discharge (Days 7-14) and Week 11 to 12 
(Days 77-84)
  VitalPatch monitoring periods: up to 5 days during the hospital stay, first 5 days after hospital 
discharge (Day 0-5), during weeks 2 and 3 (Day 7-12, Day 12-17) and Week 11 to 12 (Days 77-
82)
3 central lab assessments: NTproBNP, hs-copeptin, hs-TNT, optionally: GDF15, IGFBP7, sST2, Gal3
* Concurrently evaluating PRO will be completed daily and weekly during DynaPort and VitalPatch
parallel monitoring period
4 within ± 72 h of discharge day
New text
The investigator documents an initial visit, follow-up visits and the end of observation/final 
visit for each patient in the electronic case report form (eCRF). The end of observation visit 
will be documented after 12 weeks; a final follow-up call will be performed 6 months after 
visit 1 / discharge from hospital.
Activities to be performed are summarized in the study flow chart in Table 9-1.

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Table 9–1: Tabulated overview on study procedures and variables collected during 
the study - amended
Study period
Screening phase
Observational phase
Safety FU 
call
Visit number
Scr1
1
2
3
4
5
Visit type
site
site
site
site
site

Screen 
assess
At discharge / 
ambulatory visit
Week after discharge / Visit 1
2
3
11
12
Day and allowed deviations
-9  -1
0
9±2
16±2
77±2
84±2
6 months
±4 weeks
Signed informed consent form 
●
Inclusion / exclusion criteria
●
KCCQ
●
●
●
Daily and weekly PRO*
              
----1st----
----2nd----
Demographic data
●
Medical and surgical history
●
●Height
●
Weight
●
●
●
●
12-lead ECG 
●
●
●
NYHA class
●
●
●
●
Blood pressure and heart rate
●
●
●
●
●
Adverse Events incl. 
healthcare resources
●
●
●
●
●
●
Concomitant medication
●
●
●
●
●
●
Echocardiography
  ●5
Six-minute walking distance  
●
●
DynaPort (for 7 days)2
start end
     
 ----1st----
----2nd----
VitalPatch (for 5 days)2
start end
---1st---
 2nd and 3rd 
   4th and 5th 
Blood sample for biomarkers3
●4
●
●
1 within 4 days after hospitalization; alternatively, in ambulatory patients
2 DynaPort monitoring periods: For one week, after Visit 2 (Days 9-16) and from Visit 3 to Visit 4 (Days 
77-84)
  VitalPatch monitoring periods: first 5 days after hospital discharge / Visit 1 (Day 0-5), one week after 
Visit 2 (Day 9-16) and from Visit 3 to Visit 4 (Days 77-84)
3 central lab assessments: NTproBNP, hs-copeptin, hs-TNT, optionally: GDF15, IGFBP7, sST2, Gal3
* Concurrently evaluating PRO will be completed daily and weekly during DynaPort and VitalPatch
parallel monitoring period
4 only applicable to hospitalized patients
5 within ± 72 h of Visit 1 / discharge day

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Section 9.2 Simplification of study procedures
15.3.2.7
This section was changed as a result of Modification 2.
Old text
Enrollment / Screening Visit - amended
Within 72 hours after hospitalization patients with acute HF will be asked to participate in this 
study. The investigator will inform the patient about the study. This will include discussing 
the consent form and asking the patient to read and – when agreeing to participate – sign the 
informed consent.
The following activities will be performed at the enrollment/screening visit after signing 
patient informed consent:

Check for inclusion / exclusion criteria

Recording of 
Demographic data (including weight and height)
Medical and surgical history
Concomitant medication
Adverse events (AEs)

Physical examination

Recording of a 12-lead ECG 

Measurement of blood pressure and heart rate

NYHA classification

Blood sampling for biomarkers

Eligible patients will be included in the study and will wear the VitalPatch biosensor 
for up to 5 days during the hospital stay
Visit 1 (Day 0)
At discharge from the hospital the following activities will be performed:

Recording of
Weight
Concomitant medication
AEs

Physical examination

Recording of a 12-lead ECG 

Conduct of echocardiography within ± 72 h of discharge day 

NYHA classification

Measurement of blood pressure and heart rate

Completion of KCCQ

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
Blood sampling for biomarkers

A new VitalPatch biosensor will be attached to subject`s chest, which they will wear 
for 5 days after discharge from hospital

Subjects will be informed how to wear and apply the VitalPatch biosensor
Outpatient visits
Visit 2 (Day 9 ± 2 days)
Patients will return to the clinic 9 days (± 2 days) after discharge. The following activities will 
be performed:

Recording of 
Weight
Concomitant medication
AEs

Physical examination

NYHA classification

Measurement of blood pressure and heart rate

Determination of 6MWD

Blood sampling for biomarkers

The VitalPatch biosensor device will be collected 

Subjects will receive another two VitalPatch biosensor patches which they will wear 
consecutively for 5 days each. One VitalPatch biosensor patch will be attached to the 
subject`s chest at the site, the other one has to be attached by the patient after removal 
of the first one after 5 days.

In addition subjects will receive the DynaPort Move Monitor device which they will 
wear for 7 days.  Subjects will be informed how to wear and apply the DynaPort 
MoveMonitor.

Instruction to patient to complete KCCQ (Day 16 ± 2 days) 

Completion of PRO daily and weekly during DynaPort Move Monitor and VitalPatch 
monitoring period.
Visit 3 (Day 77 ± 2 days)
Patients will return to the clinic 77 days (± 2 days) after discharge. The following activities 
will be performed:

Recording of 
Concomitant medication
AEs

Physical examination

Measurement of blood pressure and heart rate

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
daily and weekly PRO during wearing of DynaPort Move Monitor and VitalPatch 
devices

The VitalPatch biosensor patches will be collected

Subjects will receive another VitalPatch biosensor patch and the DynaPort Move 
Monitor device which they will wear for 5 and 7 days, respectively. The VitalPatch 
biosensor will be placed on subject`s chest and DynaPort Move Monitor belt will be 
put on at the site.
Visit 4 (Day 84 ± 2 days) - amended
Patients will return to the clinic 84 days (± 2 days) after discharge. The following activities 
will be performed:

Recording of 
Weight
Concomitant medication
AEs

Physical examination

Recording of a 12-lead ECG 

NYHA classification

Conduct of echocardiography

Measurement of blood pressure and heart rate

Determination of 6MWD

Completion of KCCQ/PRO

Blood sampling for biomarkers

The VitalPatch biosensor patch and the DynaPort Move Monitor device will be 
collected.

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Follow-up visit (safety follow-up call)
Six months after discharge the investigator will phone the patient for a final safety follow-up. 
The following will be asked:

Concomitant medication

AEs
New text
Enrollment / Screening Visit - amended
Patients hospitalized with worsening HF will be asked to participate in this study; 
alternatively, also ambulatory patients can be enrolled. The investigator will inform the 
patient about the study. This will include discussing the consent form and asking the patient to 
read and – when agreeing to participate – sign the informed consent.
The following activities will be performed at the enrollment/screening visit after signing 
patient informed consent:

Check for inclusion / exclusion criteria

Recording of 
Demographic data (including weight and height)
Medical and surgical history
Concomitant medication
Adverse events (AEs) including the use of healthcare resources (e.g. HF 
hospitalizations and urgent visits for HF

Physical examination

Recording of a 12-lead ECG 

Measurement of blood pressure and heart rate

NYHA classification

Blood sampling for biomarkers only for hospitalized patients
Visit 1 (Day 0)
This visit will take place up to 9 days after the screening visit, potentially at discharge from 
the hospital. The following activities will be performed:

Recording of 
Weight
Concomitant medication
AEs including the use of healthcare resources

Recording of a 12-lead ECG 

Conduct of echocardiography within ± 72 h of discharge day 

NYHA classification

Measurement of blood pressure and heart rate

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
Determination of 6MWD

Completion of KCCQ

Blood sampling for biomarkers

Patients will get a VitalPatch biosensor attached to their chest, which they will wear 
for up to 5 days after Visit 1 / discharge from hospital

Subjects will be informed how to wear and apply the VitalPatch biosensor
Outpatient visits
Visit 2 (Day 9 ± 2 days) - amended
Patients will return to the clinic 9 days (± 2 days) after Visit 1 / discharge. The following 
activities will be performed:

Recording of 
Weight
Concomitant medication
AEs including the use of healthcare resources

NYHA classification

Measurement of blood pressure and heart rate

Blood sampling for biomarkers

The VitalPatch biosensor device attached at Visit 1 will be collected 

Subjects will receive another two VitalPatch biosensor patches which they will wear 
consecutively for up to 5 days each. One VitalPatch biosensor patch will be attached 
to the subject`s chest at the site, the other one has to be attached by the patient after 
removal of the first one after 5 days. Subjects will be informed how to wear and apply 
the VitalPatch biosensor.

In addition subjects will receive the DynaPort Move Monitor device which they will 
wear for 7 days.  Subjects will be informed how to wear and apply the DynaPort 
MoveMonitor.

Instruction to patient to complete KCCQ (Day 16 ± 2 days) 

Completion of PRO daily and weekly during DynaPort Move Monitor and VitalPatch 
monitoring period.
Visit 3 (Day 77 ± 2 days)
Patients will return to the clinic 77 days (± 2 days) after discharge. The following activities 
will be performed:

Recording of 
Concomitant medication
AEs including the use of healthcare resources

Measurement of blood pressure and heart rate

Daily and weekly PRO during wearing of DynaPort Move Monitor and VitalPatch30
devices

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
The VitalPatch biosensor patches will be collected

Subjects will receive another two VitalPatch biosensor patches which they will wear 
consecutively for up to 5 days each. One VitalPatch biosensor patch will be attached 
to the subject’s chest at the site, the other one has to be attached by the patient after 
removal of the first one after 5 days. 

In addition, subjects will receive another DynaPort Move Monitor device which will 
be put on at the site and which will be worn for 7 days.
Visit 4 (Day 84 ± 2 days)
Patients will return to the clinic 84 days (± 2 days) after discharge. The following activities 
will be performed:

Recording of 
Weight
Concomitant medication
AEs including the use of healthcare resources

Recording of a 12-lead ECG 

NYHA classification

Measurement of blood pressure and heart rate

Determination of 6MWD

Completion of KCCQ/PRO

Blood sampling for biomarkers

The VitalPatch biosensor patches and the DynaPort Move Monitor device will be 
collected.
Follow-up visit (safety follow-up call)
Six months after discharge the investigator will phone the patient for a final safety follow-up. 
The following will be asked:

Concomitant medication

AEs including the use of healthcare resources
Section 9.6.3 Simplification of study procedures
15.3.2.8
This section was changed as a result of Modification 2.
Old text

Electrocardiogram/echocardiography
[…]
An echocardiography will be performed at discharge from the hospital (within ± 72 of 
discharge day) and on Day 84.

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
Physical examination
A general physical examination as routine at the center will be performed at time points given 
in Table 1. Abnormal physical examination findings are recorded either as medical history or 
as adverse events (see Section 9.6.1.1).
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g. clotted or hemolyzed) and to verify the results.  The 
results from such additional analyses may neither be included in the clinical database of this 
study nor evaluated further.  If the results are relevant, the investigator will be informed to 
determine follow-up activities outside of this protocol.
New text
[…]
An echocardiography will be performed at Visit 1 / discharge from the hospital (within 
± 72 hours).

Physical examination
A general physical examination as routine at the center will not need to be performed, but a 
targeted exam might be triggered by symptoms. Abnormal physical examination findings are 
recorded either as medical history or as adverse events (see Section 9.6.1.1).

Laboratory evaluations
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g. clotted or hemolyzed) and to verify the results.  The 
results from such additional analyses may neither be included in the clinical database of this 
study nor evaluated further.  If the results are relevant, the investigator will be informed to 
determine follow-up activities outside of this protocol.

Healthcare Resource Utilization 
The use of Healthcare Resources in conjunction with AEs, in particular due to HF, needs to be 
documented, for example with regard to the time points or periods affected (e.g. 
hospitalizations for HF, urgent visits for HF to an emergency department or outpatient 
facility).
Section 9.7.1 Removal of thoracic impedance measurement
15.3.2.9
This section was changed as a result of Modification 2.
Old text
VitalPatch biosensor
VitalPatch biosensor will be provided by Bayer to sites. Subjects will wear the VitalPatch 
biosensor for overall 5 periods of 5 days each (for details on time periods see Table 1).

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Parameters obtained from the VitalPatch biosensor are:

ECG and parameters derived from ECG, like e.g. heart rate, HRV, AF burden, 
arrhythmias etc.

Respiratory rate

Transcutaneous thoracic impedance  = fluid status

Skin temperature

Step count 

Physical activity (duration and intensity)

Posture
New text
VitalPatch biosensor
VitalPatch biosensor will be provided by Bayer to sites. Subjects will wear the VitalPatch 
biosensor for overall 5 periods of 5 days each (for details on time periods see Table 9-1). 
Parameters obtained from the VitalPatch biosensor are:

ECG and parameters derived from ECG, like e.g. heart rate, HRV, AF burden, 
arrhythmias etc.

Respiratory rate

Skin temperature

Step count 

Physical activity (duration and intensity)

Posture
16.
Appendices
REALIsM-HF exploratory daily questionnaire to measure physical 
16.1
activity in heart failure - amended
Daily Patient-Reported Outcome Diary Items for REALIsM-HF Study
Objectives

Develop patient-reported outcome (PRO) items that can be administered as a daily 
diary in the REALIsM-HF pilot study

Provide a brief high-level outline of how the PRO items can be used to: 

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o
Validate activity monitoring data from wearable devices (VitalPatch 
biosensor42 and DynaPort Move Monitor)
o
Measure symptom severity
o
Facilitate the calculation of responder definitions/MIDs for activity and 
symptom data

We hypothesized that “subjective” items generated from patient experiences (PRO, 
QoL) in combination with an (objective) activity monitor would capture all relevant 
dimensions of exercise capacity in patients with HFpEF and HFrEF and thus can be 
used as patient centric approach in clinical studies.
INSTRUCTIONS: We would like to know about your physical activities and heart failure 
symptoms in the past 24 hours. Physical activities are all activities that require “movement of 
your body,” such as walking, housework, and lifting objects. Please complete this 
questionnaire in the evening before going to bed. Please select the response that best applies 
to your physical activities and symptoms in the past 24 hours.

24 hour interval captures nighttime symptoms, such as orthopnea and PND

Shorter instructions are ideal for daily assessment

Need to develop a training module for use in hospital 
                                                
42 Replacement of AVIVO MPM with VitalPatch Biosensor as per Amendment 2 (Section 15.2)

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ITEM
RESPONSE SCALE
How much time did you spend carrying or lifting 
objects in the past 24 hours? 
Did not carry or lift objects
1-10 minutes
11-30 minutes
31-60 minutes
Greater than 60 minutes 
How much time did you spend walking outside of 
the house in the past 24 hours? 
Did not walk outside of the house
1-10 minutes
11-30 minutes
31-60 minutes
Greater than 60 minutes 
How much time did you spend walking in general 
(in any location) in the past 24 hours?
Did not walk outside of the house
1-10 minutes
11-30 minutes
31-60 minutes
Greater than 60 minutes
How much time did you spend doing housework 
or chores in the past 24 hours? 
Did not do housework or chores
1-10 minutes
11-30 minutes
31-60 minutes
Greater than 60 minutes
How many flights of stairs did you climb in the 
past 24 hours? 
Did not climb stairs
1 flight of stairs
2 flights of stairs
3 flights of stairs
4 flights of stairs
5 flights of stairs
6 flights of stairs
7 flights of stairs
8 flights of stairs
9 flights of stairs
10 or more flights of stairs 
How much time did you spend exercising in the 
past 24 hours? 
Did not exercise
1-10 minutes
11-30 minutes
31-60 minutes
Greater than 60 minutes 
In general, how physically active were you in the 
past 24 hours?
Not active at all
A little active
Somewhat active
Very active
Extremely active 

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ITEM
RESPONSE SCALE
Please rate your worst tiredness at rest (when 
NOT doing physical activities) in the past 24 
hours  
Not Tired At All 0 1 2 3 4 5 6 7 8 9 10 Extremely 
Tired
Please rate your worst tiredness during 
physical activities in the past 24 hours
Not Tired At All 0 1 2 3 4 5 6 7 8 9 10 Extremely 
Tired
Please rate your worst shortness of breath at 
rest (when NOT doing physical activities) in the 
past 24 hours
No Shortness of Breath 0 1 2 3 4 5 6 7 8 9 10 
Extreme Shortness of Breath
Please rate your worst shortness of breath 
during physical activities in the past 24 hours
No Shortness of Breath 0 1 2 3 4 5 6 7 8 9 10 
Extreme Shortness of Breath
Please rate the worst swelling in your legs, 
ankles, or feet in the past 24 hours
No Swelling 0 1 2 3 4 5 6 7 8 9 10 Extreme 
Swelling
In general, how bad were your heart failure 
symptoms in the past 24 hours? 
No Symptoms 0 1 2 3 4 5 6 7 8 9 10 Extreme 
Symptoms
INSTRUCTIONS
Now we would like for you to think about how your 
physical activities and symptoms have changed 
since you were discharged from the hospital. 
How have your physical activities changed 
since you were discharged from the hospital?
Very much more physically active
Much more physically active 
A little more physically active
No change in physical activities
A little less physically active
Much less physically active
Very much less physically active 
How has your feeling of tiredness changed 
since you were discharged from the hospital? 
Very much improved
Much improved
Minimally improved
No change
Worse
Much Worse
Very much worse
How has your shortness of breath changed 
since you were discharged from the hospital?
Very much improved
Much improved
Minimally improved
No change
Worse
Much Worse

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ITEM
RESPONSE SCALE
Very much worse 
How has your swelling in your legs, ankles, or 
feet changed since you were discharged from 
the hospital?
Very much improved
Much improved
Minimally improved
No change
Worse
Much Worse
Very much worse 
USE OF DIARY ITEMS TO VALIDATE ACTIVITY MONITOR

Compare 1 week of activity monitor data with physical activity items from 1 week of 
diary monitoring

Average diary data over 7 day period (must have ≥ 4 days to calculate a value)

Physical Activity Diary Scores
o
Overall activity including carrying/lifting, walking outside, walking 
general, climbing stairs, housework, and exercise (average across items)
o
Individual item scores including general physical activity item

Examine correlations between the activity monitor movement data and the physical 
activity diary scores
USE OF DIARY ITEMS TO CALCULATE RESPONDER DEFINITIONS

Calculate average activity/symptom scores associated with change on anchor measures

Anchor measures
o
General physical activity item (1 unit change on weekly average score)
o
Physical activity impression of change item (2 unit change)
o
Fatigue impression of change item (2 unit change)
o
Shortness of breath impression of change item (2 unit change)
o
Swelling impression of change item (2 unit change)

Address using data from each weekly interval