A Study to Investigate the Association of Real-world Sensor-derived Biometric Data With Clinical Parameters and Patient-reported Outcomes for Monitoring Disease Activity in Patients With Chronic Obstructive Pulmonary Disease (COPD)
Phase: NA
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

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Company substance code 
INN  
MS202559_0001 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
4/67 
 
 
9.7.2 
Statistical Methods ..............................................................................34 
9.7.3 
Sequence of Analyses .........................................................................37 
9.8 
Quality Control ...................................................................................37 
9.9 
Limitations of the Research Methods .................................................38 
9.10 
Other Aspects ......................................................................................39 
9.10.1 
Ethical Conduct of the Study ..............................................................39 
9.10.2 
Independent Ethics Committee or Institutional Review Board ..........39 
9.10.3 
Monitoring ..........................................................................................40 
9.10.4 
Health Authorities ...............................................................................40 
9.10.5 
Quality Assurance ...............................................................................41 
9.10.6 
Medical Device Supply, Accountability and Handling ......................41 
9.10.7 
Archiving ............................................................................................41 
10 
Protection of Human Participants .......................................................42 
10.1 
Participant Information and Informed Consent ..................................42 
10.2 
Participant Identification and Privacy ................................................42 
11 
Management and Reporting of Adverse Events and Device 
Deficiencies ........................................................................................43 
11.1 
Definition of (Serious) Adverse Events and other safety related 
events ..................................................................................................43 
11.2 
Severity of Adverse Events ................................................................45 
11.3 
Causality Assessment .........................................................................45 
11.4 
Recording of Adverse Events .............................................................46 
11.5 
Safety Data Collection for Reporting .................................................47 
11.6 
Safety Reporting to the Competent Authorities and IEC/IRBs. .........49 
12 
Plans for Disseminating and Communicating Study Results .............49 
12.1 
Study Report .......................................................................................49 
12.2 
Publication ..........................................................................................50 
13 
References ...........................................................................................50 
14 
Appendices .........................................................................................53 
14.1 
Additional Information .......................................................................53 
14.1.1 
End of the Study Questionnaire ..........................................................53 
14.1.2 
Mapping of Objectives, Outcomes and Variables ..............................56 
14.2 
Signature Pages and Responsible Persons for the Study ....................66 

Company substance code 
INN  
MS202559_0001 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
5/67 
 
 
Signature Page – Protocol Lead .........................................................................................66 
Signature Page – Coordinating Investigator ......................................................................67 
 
2 
List of Abbreviations  
AE 
Adverse Event 
AECOPD 
Acute Exacerbation of COPD 
BfArM 
Bundesinstitut for Arzneimittel und Medizinprodukte 
BGA 
Blood Gas Analysis 
CAT 
COPD Assessment Test 
CBC 
Complete Blood Count 
CDB 
Clinical Database 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
eCRF 
Electronic Case Report Form 
CRP 
C-Reactive Protein 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
FEV1 
Forced Expiratory Volume in 1 second 
FVC 
Forced Vital Capacity 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
IAP 
Integrated Analysis Plan 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LOCF 
Last Observation Carried Forward 
LTE 
Long Term Evolution (Phone) 
MCID 
Minimal Clinically Important Difference 
MDR 
Medical Device Regulation 
MPDG 
Medizinprodukterecht-Durchführungsgesetz 
PRO 
Patient Reported Outcomes 
RPM 
Remote Patient Monitoring 

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Company substance code 
INN  
MS202559_0001 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
7/67 
 
 
4 
Abstract  
Title 
A study to investigate the association of real-world sensor-derived 
biometric data with clinical parameters and patient-reported outcomes 
for monitoring disease activity in patients 
Rationale and 
background 
Remote patient monitoring (RPM) using wearable sensors has the 
potential to improve Chronic Obstructive Pulmonary Disease (COPD) 
patients' treatment and outcome by providing patients and physicians 
with early actionable insights, therefore reducing, or preventing 
exacerbations and increasing the quality of life. Previous published 
studies on sensor-based remote patient monitoring in patients with 
COPD suggest that such an approach is scientifically feasible and 
clinically promising, especially for decreasing the number of 
hospitalizations associated with exacerbations and improving overall 
outcome. 
The purpose of this study (designated as “Sonstige Klinische Prüfung” 
(other clinical study) as per Art. 82 Regulation (EU) 2017/745 /§3 No. 
4 MPDG) is to generate biometric sensor-derived data, correlate them 
to clinical parameters and patient reported outcomes and develop 
predictive models for COPD exacerbations and patients’ disease 
status as a basis for a future RPM solution for patients with COPD.  
Research question and 
objectives 
Primary Objectives: 
1. To describe the distribution of sensor collected data on 
physical activity, heart rate, heart rate variability, 
temperature, respiration rate, cough frequency, and sleep 
pattern, by severity of COPD exacerbations. 
2. To predict moderate or severe COPD exacerbations by 
building a statistical model employing sensor-derived data 
and demographic and medical covariates. 
Secondary Objectives: 
3. To evaluate the correlation of sensor collected data with  
a) patients’ self-assessed health status and symptoms (CAT) 
at baseline and study end,  
b) lung function and lab values at baseline and study end, 
c) and with history of mild, moderate and severe 
exacerbations at study end.   
4. Sensor derived data may be related to the CAT score, 
therefore, an additional objective is to investigate whether 
changes in physical activity, heart rate, heart rate variability, 
temperature, respiration rate, cough frequency, and sleep 
pattern in the 3-month observation period, are associated with 
changes of the patient self-assessed symptoms (CAT).  
5. To predict the CAT score and changes thereof by building a 
statistical model employing sensor-derived data and 
demographic and medical covariates. 

Company substance code 
INN  
MS202559_0001 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
8/67 
 
 
Study Design 
This multicenter, prospective cohort study will be conducted at 11 
sites in Germany, a cohort of participants with COPD GOLD stage II-
IV will be followed for 3 months.  
During the Baseline visit each enrolled participant will be provided 
with a wearable device which records ECG, temperature and 
movement via an accelerometer and a connected smartphone and 
trained on the use of these devices. A study digital application is 
provided with the smartphone for the participants to fill in a daily 
COPD symptoms’ questionnaire (CAT), label activities or events 
relevant for the interpretation of sensor signals, and receive 
notifications/reminders.  
During the 3-month observation period the participants will attend 
visits at sites as per routine clinical practice in case of exacerbations 
or regular COPD check-ups. At all visits at the study sites, 
assessments will be performed as per physician’s judgement and 
routine clinical practice. 
At the end of the 3-month observation period, the participants will 
return the devices to the site during a regular COPD related visit 
scheduled at 3 months (± 14 days) after the baseline visit (Day 0).  
Additionally, a calibration cohort of non-COPD participants will be 
enrolled in an internal medicine center in Germany. The participants 
will use the wearable device during a 2-week observation period.   
Population 
Key Inclusion criteria: 
For participants with COPD: 
• Participants ≥40 and ≤80 years at baseline 
• Diagnosis of COPD stage II to IV (documented post-
bronchodilator Forced Expiratory Volume in 1 second 
(FEV1)/ Forced Vital Capacity (FVC) < 0.7 and FEV1 < 80% 
predicted)  
• History of moderate or severe exacerbations (≥2 moderate 
exacerbations or ≥1 severe exacerbations in any 12-month 
time window during last 3 years prior to inclusion and ≥1  
moderate or severe exacerbations in the last 12 months prior 
to inclusion, considering that the last 12 months may reflect 
lower exacerbation rate due to Covid-19 measures) 
For participants in the calibration cohort: 
• Participants ≥40 and ≤80 years at baseline 
Key Exclusion criteria: 
For participants with COPD: 
• Participants with a cardiac pacemaker, defibrillators, or other 
implanted electronic devices 
• Participants with known allergies or sensitivity to silicon or 
hydrogel 
• Less than 6 weeks since previous moderate/severe 
exacerbation  

Company substance code 
INN  
MS202559_0001 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
9/67 
 
 
For participants in the calibration cohort:  
• Participants with a cardiac pacemaker, defibrillators, or other 
implanted electronic devices 
• Participants with known allergies or sensitivity to silicon or 
hydrogel 
• Diagnosis of pulmonary disease including, but not limited to 
COPD, asthma, pulmonary fibrosis, with impact on the lung 
function and exercise capacity 
Outcomes 
The primary outcome, COPD exacerbations during observation 
period will be defined as follows:   
• For moderate/severe exacerbation requiring a physician’s 
intervention, emergency room visit or hospitalization, the severity, 
date of the exacerbation, and the duration of the exacerbation will 
be recorded via eCRF.  
• For mild exacerbations: self-reported; treated by the participant 
without intervention by a physician will be documented in the 
patient application labeling section (days with added treatment). 
Secondary outcomes will be defined as follows: 
• Patients' health status and symptoms at baseline (Day 0) and study 
end will be measured as the summary score across items of the 
CAT questionnaire that consists of 8-items in which participants 
can choose a score from 0 to 5, for each visit.   
• Lung function will be assessed using plethysmography and lab 
values including complete blood count (CBC) with differential, 
blood gas analyses (BGA), procalcitonin and CRP will be assessed 
as per standard practice at baseline (Day 0) and at study end.   
• Number, date of onset and duration of mild, moderate, and severe 
exacerbations, respectively, during the observation period. 
• During the observation period the CAT score will be obtained on 
a daily basis. Daily summary score across items of the CAT 
questionnaire will be computed. 
• Patients' health status and symptoms at baseline (Day 0) will be 
measured as the summary score across items of the CAT 
questionnaire that consists of 8-items in which participants can 
choose a score from 0 to 5. During the observation period the CAT 
score will be obtained via a digital application on a daily basis.   
Key Variables 
Variables measured with the Vivalink wearable device (including, but 
not limited to):  
• Physical activity  
• Heart rate 
• Temperature   
• Respiration rate 
Self-measured Variables: 
• Data on Self-reported COPD symptoms will be collected via the 
CAT questionnaires using the participant app 

Company substance code 
INN  
MS202559_0001 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
10/67 
 
 
• Self-reported activities (e.g., coughing, sports, sleeping) as 
collected by the participant app 
• Self-reported satisfaction to the study, collected via end of study 
questionnaire 
Covariates will be collected from patient records (status at the time of 
Day 0, closest record prior to): 
• Demographics, Body mass index, Smoking status  
• Relevant medical history, comorbidities, current medication 
including COPD treatment at baseline 
• Date of diagnosis of COPD and COPD severity (GOLD stage) 
• Number of moderate or severe exacerbations prior to baseline visit 
(at Day 0, moderate/severe exacerbation visit and End of study visit): 
• Current body plethysmography parameters  
• Current (capillary) pO2, O2 saturation and pCO2  
Several biomarkers at the time of baseline depending on availability  
Data Sources 
The data source used for this study will consist of patients charts from 
11 sites (mainly pulmonology private practices) in Germany as well 
as from a device, which will get handed out to the participant.  
The data informing this study will be extracted from patient medical 
records using eCRF directly in an electronic data capture system. In 
addition, a patient reported outcomes (PRO) questionnaire (COPD 
assessment tool [CAT], filled in by the participant electronically), and 
a wearable device (adhesive patch device with sensors) will be used 
for data collection.  
Study Size 
Sample size required to show a sensitivity of ≥0.85 for a model 
predicting moderate to severe COPD exacerbations was estimated to 
be 67 participants including a drop-out rate of 10%. The study will 
also observe 10 participants in the calibration cohort for 2 weeks. The 
number of participants for this cohort is chosen on an exploratory 
basis. 
Data Analysis 
Sensor collected data on physical activity, heart rate, heart rate 
variability, temperature, respiration rate, cough frequency, sleep 
pattern, at baseline, and shortly prior (14 days prior to, 7 days prior) 
to, during an exacerbation and after an exacerbation (8 to 14 days 
after, 2 weeks after, 3 weeks after, up to 4 weeks after an exacerbation) 
will be reported as mean (SD) and/or median (Interquartile Range) for 
continuous variables and counts and frequency (%) for categorical 
variables.  
A statistical model employing sensor collected data to predict COPD 
exacerbations will be built as follows:  
As input to the model a number of algorithms (e.g. self-learning 
algorithms) for obtaining derived parameters such as cough 
frequency, physical activities and sleep pattern will be developed first 
using the label dataset obtained via the app.  

Company substance code 
INN  
MS202559_0001 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
11/67 
 
 
Different machine learning algorithms will be evaluated, and their 
performance will be assessed by estimating their accuracy, specificity, 
sensitivity, and area under ROC metrics.  

Company substance code 
INN  
MS202559_0001 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
12/67 
 
 
5 
Amendments and Updates  
The following amendments and updates to the protocol were implemented. 
Protocol 
Number 
Date 
Section of 
Study 
Protocol 
Amendment or update 
Reason 
3.0 
01 MAR 
2023 
throughout 
Changed the number of study 
centers from “up to 10” to “11”. 
To achieve enrolment more than 
anticipated study centers need 
to be activated. 
2.0 
21 OCT 2022 
9.2.1 
Added capability of giving signed 
informed consent to in-
/exclusion criteria. 
EC request 
 
 
9.2.4 
“Data collection via App (labeling 
events and activities)” added to 
Table 5: Planned Assessments 
Calibration Cohort  
Correction of oversight. 
 
 
9.10.1 
Addition of Section 9.10.1 
Ethical Conduct of the Study 
EC request to add a statement 
of compliance  
 
 
9.10.6 
Addition of Section 9.10.6 
Medical Device Supply, 
Accountability and Handling 
EC request to add a description 
on the accountability of the 
device. 
 
 
10.1 
Deleted possibility to delegate 
patient informed consent taking 
EC request to clarify that 
informed consent is given 
exclusively by investigators. 
 
 
throughout 
Correction of typos and spelling 
of units 
Correction of oversights. 
6 
Milestones  
Not applicable as no existing databases are used. 
7 
Rationale and Background  
Chronic Obstructive Pulmonary Disease (COPD) is a progressive life-threatening lung disease 
with no curative treatment available (Christenson 2022). According to the World Health 
Organization (WHO), COPD is currently the fourth, and will soon become the third, most frequent 
cause of death worldwide (WHO 2022; Quaderi 2018). It is also associated with high costs for 
treating and managing patients (Sullivan 2000). The Global Burden of Disease Study reports a 
prevalence of 251 million cases of COPD globally in 2016.  
COPD exacerbations are defined as an acute worsening of respiratory symptoms that result in 
additional therapy (GOLD 2022). Exacerbations usually cause further damage to the lungs, lead 
to more rapid progression, and carry a substantial mortality risk (Rhodes 2022). Hence, frequency 
of exacerbations is an important efficacy endpoint in COPD clinical studies and pharmacological 
therapy of COPD is used to reduce frequency and severity of exacerbations. Exacerbations are 
classified by severity into severe, moderate and mild. The Global Initiative for Chronic Obstructive 
Lung Disease (GOLD) consortium defines these as severe if they require hospitalization, moderate 
if they require added drug treatment from the group of systemic corticosteroids and antibiotics 
which requires a physician’s interaction, and mild if they can be treated by the patient by an 
additional (inhaled) drug without intervention of a physician (Vogelmeier 2017). The main target 

Company substance code 
INN  
MS202559_0001 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
13/67 
 
 
of all therapeutic approaches are the severe and moderate exacerbations. Limited knowledge exists 
on the importance of mild exacerbations. 
Most patients with COPD experience chronic respiratory symptoms and limitations to their daily 
lives such as chest tightness and shortness of breath, chronic cough and excessive mucus, activity 
and exercise limitations and impaired physical functioning (Kessler 2011; Landis 2014). The 
COPD Assessment Test (CAT) was developed according to the Food and Drug Administration’s 
(FDA) patient reported outcome development guidance, and it is a short digital or paper tool that 
can be used to assess the symptoms of COPD (Jones 2013). 
Since its launch in 2009, CAT has been used globally, with >90 approved and linguistically 
validated translations. Furthermore, clinical and observational studies, as well as randomized 
controlled trials, have used CAT as a measure of health-related quality of life (HRQoL) and clinical 
efficacy, respectively (Müllerová 2019). 
The CAT has also been incorporated in the GOLD combined assessment to establish a threshold 
at which patients become symptomatic to justify and guide in the selection of treatment (Jones 
2013) and is used in routine clinical practice. The score is higher in people with more frequent 
exacerbation and it changes with the onset and recovery from an exacerbation (Al Rajeh 2020, 
Zimmermann 2020). The 8 items of the CAT questionnaire provide a scoring range of 0 to 40. A 
2-point change in the CAT score has been established as the Minimally Clinically Important 
Difference (MCID, Kon 2014). Importantly, the CAT closely reflects the functional status of 
patients with COPD (Gulart 2017).  
Remote patient monitoring using wearable sensors has the potential to improve treatment and 
outcomes of patients with COPD by providing patients and physicians with early actionable 
insights, therefore reducing, or preventing exacerbations and increasing the quality of life. 
Previous published studies on sensor-based remote patient monitoring in patients with COPD 
suggest that such an approach is scientifically feasible and clinically promising, especially for 
decreasing the number of hospitalizations associated with exacerbations and improving overall 
outcome (Pedone 2013; McLean 2011; Isaranuwatchai 2018). 
The purpose of this study (designated as “Sonstige Klinische Prüfung” [other clinical study] as per 
Art. 82 Regulation [EU] 2017/745 /§3 No. 4 Medizinprodukterecht-Durchführungsgesetz 
[MPDG]) is to generate biometric sensor-derived data, evaluate their correlation to clinical 
parameters and patient reported outcomes (PRO) and develop a predictive model for COPD 
exacerbations as well as for monitoring current disease status and changes thereof. In the this study 
the participants will receive a wearable device (Vivalink) with sensors that will measure heart rate, 
heart rate variability, respiration patterns, temperature, and physical activity. The analysis of this 
data will help to understand the utility of remote patient monitoring using a multimodal sensor 
approach and contribute to the development of a future remote patient monitoring solution. The 
purpose of this study is not to evaluate, validate, nor register the device itself, the device merely 
serves as a means for collecting the targeted sensor-derived data. 
Specifically, this study aims at predicting 2 target outcomes: acute exacerbations of COPD 
(AECOPDs) as defined by the GOLD initiative, and the CAT score as a proxy for patients’ disease 
status. The start of an exacerbation within a patient, regardless of how many exacerbations the 
patient may have experienced before, will be predicted based on sensor data preceding the 

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CCI

Company substance code 
INN  
MS202559_0001 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
16/67 
 
 
by the study protocol but will be determined as per normal clinical practice, and decision to 
prescribe a particular medication is fully independent from the decision to enroll the participant in 
the study. No medication or other therapeutic measure will be provided to the participants as part 
of the study. 
A calibration cohort with non-COPD participants will be included and followed for 2 weeks. 
See Figure 1 for a graphical design overview. 
Figure 1 
Design Overview for COPD Cohort 
 
Note: Exacerbation visit(s) could take place at any time point during the observation period, based on the occurrence 
of exacerbations. 
COPD Cohort 
Participants will be enrolled consecutively, in pulmonology practices and/or outpatient hospital 
settings during the regular scheduled clinical visits. The Baseline visit (Day 0) can take place once 
the participant provides written informed consent to participate in the study. Enrolled participants 
with COPD will be followed for a 3-month observation period.  
During the Baseline visit each enrolled participant will be provided with a Vivalink wearable 
device and a connected phone and trained on the how to use these devices. The participants should 
wear the Vivalink device continuously, day and night (except for charging times and situations 
described in the instructions for use), during the observation period to ensure recording of ECG, 
accelerometer, and temperature data.   
A study digital application is installed on the phone provided with the Vivalink wearable device 
for the participants to fill in the CAT questionnaire, label activities or events relevant for the 
interpretation of sensor signals, receive notifications/reminders and visualize their progress with 
study related activities.  
The CAT questionnaire will be filled in by each participant at home, once per day, every day 
during the observation period electronically using the study digital application. The validated 
translation of the CAT questionnaire in German will be incorporated as an electronic questionnaire 
in the software application for the study participants. The participants will be trained during the 
baseline visit how to use the study application to fill in the CAT questionnaire.  

Company substance code 
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MS202559_0001 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
17/67 
 
 
The study digital application will be used also for the labeling of activities relevant for 
interpretation of data collected with the wearable device. The application will contain a predefined 
list of options: coughing, coughing with sputum production, spray use, non-scheduled spray use, 
eating, going to bed, waking up, walking, climbing stairs, and physical exercise that can be easily 
selected to indicate when such an event/activity occurs. The participants will be trained to use the 
application to correctly label events and activities. Participants will be requested to label at least 5 
events per day, every day during the observation period. 
The digital study application will also provide participants automated notifications/reminders 
related to the Vivalink device (e.g. to charge or to wear the device), to fill in the CAT questionnaire, 
and to input labeling information. Participants will be encouraged to fulfill these daily tasks by 
reminders and notifications triggered once data is not entered as requested. A dashboard with 
compliance data will be provided to the participants allowing them to have an overview of 
outstanding tasks and their performance to fill out questionnaires, wear the device, and label events 
to encourage them to be compliant. 
A help line will be set up to assist participants in case of questions or issues regarding use of the 
Vivalink device or the digital application.  
During the 3-month observation period the participants will attend visits at sites as per routine 
clinical practice in case of exacerbations, regular COPD check-ups, or other medical issues or 
events. At all visits at the study sites, assessments will be performed as per physician’s judgement 
and documented as part of the routine clinical practice. 
At the end of the 3-month observation period the participants will return the devices to the site 
during a regular COPD related visit scheduled at 3 months (± 14 days) after the baseline visit 
(Day 0). This will be the End of Study and assessments will be performed as per clinical practice.  
In cases, when the End of Study does not align with an intended COPD related visit as per routine 
clinical practice, an End of Study visit will be scheduled at 3 months (± 14 days) after the baseline 
visit (Day 0) for the return of the devices. The assessments performed at this visit should be aligned 
with the clinical practice for a regular COPD related visit and costs shall be covered by the sponsor 
of the study.  
In cases when the End of Study visit cannot be performed on site, the participants will be contacted 
via phone and provided with instructions to return the devices.  
Death also defines End of Study. Although data from an End of Study visit will not be available, 
data from the patient will be used for analyses.  
Calibration Participants Cohort 
Participants will be enrolled in an internal medicine center in Germany. No additional procedures 
are required for establishing eligibility except for physician’s judgement as described in the 
inclusion criteria (see Section 9.2.1). The Baseline visit (Day 0) can take place once the participants 
provided written consent to participate in the study. During the Baseline visit the enrolled 
participants will receive the following: the Vivalink wearable device (adhesive patch device with 

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ECG, accelerometer, temperature sensor), a connected phone, and training on how to use these 
devices. 
The participants should wear the Vivalink device continuously, day and night, during a 2-week 
observation period in order to ensure recording of ECG, accelerometer and temperature data.   
A study digital application is provided on the phone provided with the Vivalink device for the 
participants to label activities or events relevant for the interpretation of sensor signals and receive 
notifications/reminders. The application will contain a predefined list of options. The participants 
will be trained to use the application to correctly label as many such events as possible during the 
observation period.  
At the end of the observation period, the participants will return the devices to the site. In case the 
participants are not able to visit the site, they will be provided with instructions on how to return 
the devices.  
9.1.2 
Outcomes  
A complete mapping of objectives, outcomes and variables is available in Section 14.1.2. 
9.1.2.1 
Primary Outcomes  
The primary objective is to 1) describe the distribution of sensor collected data with COPD 
exacerbations, as well as 2) to predict COPD exacerbations by building a statistical model.  
Severity of acute exacerbations of COPD (AECOPD) are defined using the GOLD definitions 
based on treatment consequences (event-based) (Vogelmeier 2017): AECOPDs are defined as “an 
acute worsening of respiratory symptoms that results in additional therapy”. Exacerbations are 
classified as 1) mild if they are treated with short-acting bronchodilators only; 2) moderate if they 
are treated with short-acting bronchodilators plus antibiotics and/or oral corticosteroids; or 3) 
severe if the patient visits the emergency room or requires hospitalization because of an 
exacerbation. 
The occurrence of exacerbations during the observation period will be defined as follows:   
• For moderate/severe exacerbation requiring a physician’s intervention, emergency room visit 
or hospitalization, the severity, date of the exacerbation, and the duration of the exacerbation 
will be recorded via an eCRF.  
• For mild exacerbations: self-reported; treated by the participant without intervention by a 
physician will be documented in the patient application labeling section (days with added 
treatment). 
The duration of exacerbations during the observation period will be defined as follows:   
The duration of a severe/ moderate exacerbation will be derived from the duration of added 
medication from the group of systemic corticosteroids and/or antibiotics which define moderate 
exacerbations by GOLD. Days in-hospital for severe exacerbations will also be captured.  
The duration of mild exacerbations will be derived from the event “additional relieve medication 
taken” noted in the labelling section of the patient facing applicaton (which defines mild 
exacerbations). Duration and start / stop will be derived from these patient entries.  

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9.1.2.2 
Secondary Outcomes  
The outcomes defined to meet secondary study objectives are described in Table 1. 
Table 1 
Outcomes to Achieve Secondary Objectives  
Secondary objective 
Outcome definition 
Number 
of 
objective 
To evaluate the correlation of sensor 
collected data with  
a) patients´ self-assessed health 
status and symptoms (CAT) at 
baseline and study end,  
b) lung function and lab values at 
baseline and study end,  
c) and with history of mild, moderate 
and severe exacerbations at study 
end.   
a) Patients' health status and symptoms at baseline (Day 0) 
and study end will be measured as the summary score 
across items of the CAT questionnaire that consists of 8-
items in which participants can choose a score from 0 to 5, 
for each visit   
b) Lung function will be assessed using plethysmography and 
lab values including complete blood count (CBC) with 
differential, blood gas analyses (BGA), procalcitonin and CRP 
will be assessed as per standard practice at baseline (Day 0) 
and at study end (for details see Section 9.3)   
c) number, date of onset and duration of mild, moderate, and 
severe exacerbations, respectively, during the observation 
period  
3 
Sensor derived data may be related 
to the CAT score, therefore, an 
additional objective is to investigate 
whether changes in physical activity, 
heart rate, heart rate variability, 
temperature, respiration rate, cough 
frequency, and sleep pattern in the 3-
month observation period, are 
associated with changes of the 
patient self-assessed symptoms 
(CAT). 
Please see above (3a) 
During the observation period the CAT score will be obtained 
on a daily basis. Daily summary score across items of the 
CAT questionnaire will be computed. 
4 
To build a model for predicting 
patient self-assessed symptoms 
(CAT) score on daily basis and 
change in the CAT score (and 
change of CAT score by 2 points or 
more considered as MCID) 
employing sensor collected data on 
physical activity, heart rate, heart rate 
variability, temperature, respiration 
pattern, cough frequency, and/or 
sleep pattern. 
Patients' health status and symptoms at baseline (Day 0) will 
be measured as the summary score across items of the CAT 
questionnaire that consists of 8-items in which participants 
can choose a score from 0 to 5. During the observation 
period the CAT score will be obtained via a digital application 
on a daily basis.   
5 

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For participants in the calibration cohort: 
1. Participants capable of giving signed informed consent, as described in Section 10.1, which 
includes compliance with the requirements and restrictions listed in the ICF and this 
protocol 
2. Participants ≥40 and ≤80 years at baseline 
Participants are not eligible for this study if they fulfill any of the following exclusion criteria: 
For participants with COPD: 
1. Participants who, at the discretion of the Investigator, are unlikely to complete the study or 
will not be able to provide reliable information for the study  
2. Clinically relevant and/or serious concurrent medical conditions including, but not limited 
to visual problems, severe mental illness or cognitive impairment, musculoskeletal or 
movement disorders, cardiac disease (e.g., heart failure, arrythmia [esp. atrial fibrillation 
and conduction blocks]), lung cancer (currently treated) that in the opinion of the 
Investigator, would interfere with participant’s ability to participate in the study or draw 
meaningful conclusions from the study  
3. Participants with a cardiac pacemaker, defibrillators, or other implanted electronic devices 
4. Participants with known allergies or sensitivity to silicon or hydrogel 
5. Less than 6 weeks since previous moderate/severe exacerbation  
For participants in the calibration cohort:  
1. Participants who, at the discretion of the Investigator, are unlikely to complete the study or 
will not be able to provide reliable information for the study  
2. Clinically relevant and/or serious concurrent medical conditions including, but not limited 
to visual problems, severe mental illness or cognitive impairment, musculo-skeletal or 
movement disorders, cardiac disease (e.g., heart failure, arrythmia [esp. atrial fibrillation 
and conduction blocks]), lung cancer (currently treated) that in the opinion of the 
Investigator, would interfere with participant’s ability to participate in the study or draw 
meaningful conclusions from the study  
3. Participants with a cardiac pacemaker, defibrillators, or other implanted electronic devices 
4. Participants with known allergies or sensitivity to silicon or hydrogel 
5. Diagnosis of pulmonary disease including, but not limited to COPD, asthma, pulmonary 
fibrosis, with impact on the lung function and exercise capacity  
9.2.2 
Definition of Study Cohorts and Description of Devices  
Cohorts 
A cohort of participants with COPD will be established. This cohort will consist of all eligible 
patients (based on all inclusion criteria and none of the exclusion criteria, see section 9.2.1) at Day 
0 visit. Participants will be enrolled consecutively, based on the scheduled visits occurring in 11 
health centers in Germany. 
In addition, for device calibration purposes a cohort of non-COPD participants will be established. 
These participants will be recruited at 1 internal medicine center in Germany. 

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At the Baseline visit (Day 0), the eligible participants (all inclusion and none of the exclusion 
criteria) of both cohorts will receive a set of devices (adhesive patch device with sensors and 
phone).  
Devices  
The Vivalink wearable device will be used to collect data on physical activity, heart rate, heart rate 
variability, temperature, respiration pattern, cough frequency and sleep pattern. The model of the 
Vivalink wearable device that will be used in the study is the same as the CE marked model VV-
330 with the addition of temperature monitoring. The new model inclusive of temperature 
monitoring has not yet received the CE mark. Details of the device are presented in Table 3.   
Table 3 
Vivalink Wearable Device.  
Text in blue italics comes direct from the manufacturer or manufacturer’s literature. 
Device photo including accessories 
 
Brand Name 
Medical Wearable Platform SDK-01 
Manufacturer 
VivaLNK, Inc. 
Name or number of the 
model(s)/type(s) 
Model: VV-330 + temperature monitor 
Software version 
Planned special release for Merck KGaA,  
Accessories 
Charging Case, Adhesives (hold the ECG recorder in place during 
recording), USB Charging Cable + USB electrical outlet adapter 
Intended purpose 
Below in italics is the intended purpose of the CE marked Model VV-
330 as supplied by VivaLNK. The device to be used in the study, 
includes a temperature monitoring algorithm not covered by the CE 
marked device described below. 
“Medical Wearable Platform SDK-01 is intended to record, store and 
transfer electrocardiogram (ECG) and accelerometer data. The 
platform has the capability to provide Heart Rate, Respiratory Rate 
and R-R Interval using the ECG rhythm. The ECG recorder patch is 
an ambulatory, continuous recording patch, intended for at-home or 
hospital, by clinicians or health professionals who intend to monitor 
their patient's physiological and health conditions for an extended 
period of time. The device is not intended for patients under 18 
years old. This Instructions for Use is only limited to the use of the 
hardware and the Software Development Kit (SDK). It does not 
include any information about the mobile application or user 
interfacing device as that is outside the scope of the system.“ 
The period of validity of CE certificate 
for model VV-330. 
Issue date: 2019-11-08 
Expiry Date: 2024-05-26 

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NOTE: the model to be used in the 
study has been modified from the CE 
marked device to add an temperature 
monitoring algorithm (a software only 
change). 
Statement of deviation from the CE 
marked device 
The device used in the study will be the same as the CE marked 
model VV-330 with the addition of temperature monitoring 
capabilities. A temperature sensor already present in the model VV-
330 has been “activated” by the addition of an algorithm. The 
temperature sensor was already physically present in the wearable 
patch at the time of the CE mark, but was not turned on, tested or 
evaluated by the Notified Body for the current CE mark status. 
Description of device materials in 
contact with body tissues 
Body-contacting materials are on the Adhesive, which includes 
proprietary textile and medical-grade adhesive layers with hydrogel 
conductive contacts.  
Statement that this device does not 
include any medicinal substances, 
human or animal tissues or their 
derivatives, or other biological active 
substances 
“Our device does not include any medicinal substances, human or 
animal tissues or their derivatives, or other biological active 
substances.” 
Reference to the compliance of 
applicable national regulations 
VV-330 complies with the EU Medical Device Regulation (MDR) 
2017/745 and meets the requirements in Annex1 General Safety 
and Performance Requirements. The addition of the temperature 
monitoring algorithm has not yet been evaluated by the Notified 
Body for conformance. 
Describe the necessary training and 
experience required for the use of the 
MD. 
VV-330 + temperature monitor is intended to be used by adult 
patients (18 or older) and their health care providers. No special 
training outside of familiarization of the general instructions from the 
approved labelling is needed. 
LTE Phone (EDGE Device)  
An EDGE device serves as a data transmission route from the Vivalink adhesive patch to the 
clinical database. The EDGE device is a Long-Term Evolution (LTE) phone which functionality 
is limited to data transfer and to the study software application that includes a questionnaire and 
the possibility to label events (see above). On this EDGE device a daily CAT questionnaire will 
be presented to the participant (see Section 9.1.1). 
9.2.3 
Observation Period  
Participants will be followed-up for 3 months (until End of Study visit) or until premature 
discontinuation from study, whichever occurs first.  
Participants in the calibration cohort will be followed-up for 2 weeks. 
9.2.4 
Frequency of Assessments  
An overview of the planned assessments is provided in Table 4 and Table 5. 

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COPD cohort 
The participants will visit the sites as per routine practice and the timing of the visits and 
assessments performed will be as per the treating physician judgment. Results of the assessments 
will be collected upon availability.  

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Table 4 
Planned Assessments: COPD Cohort  
Assessments 
Baseline Visit 
Day 0 
Exacerbation Visits 
(moderate and severe) 
End of Study 
3 Months ± 14 days 
Comments 
Participant Informed consent 
X 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Physical examination 
X 
X 
X 
 
COPD history 
X 
 
 
  
Baseline Medication 
X 
 
 
 
Record changes in medication 
(COPD and other) 
 
X 
X 
Changes in medication means changes of 
medication at the time of the current visit 
(including newly prescribed medication) as 
compared to the baseline visit (Day 0) 
Comorbidities 
X 
 
 
 
Smoking status  
X 
 
 
 
Exacerbation history 
X 
 
 
 
Moderate and severe 
exacerbations during observation 
period 
 
X 
X 
Moderate and severe exacerbations should be 
recorded that occurred between Day 0 and the 
current visit (including exacerbations at the time 
of the visit) 
Lung function (Plethysmography) 
X 
X 
X 
For the Baseline visit (Day 0), data from the past 
2 weeks are acceptable.  
End of study satisfaction 
questionnaire 
 
 
X 
 
(S)AE recording 
 
Continuous recording 
Serious Adverse Device Effects 
(SADE) and Device Deficiency 
(DD) reporting 
 
Continuous reporting 
CAT collection via App 
Daily at home 
 
Data collection via App (labeling 
events and activities) 
Daily at home 
Includes medication data used to identify mild 
exacerbations 

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Laboratory values (if available from clinical practice) 
For the Baseline visit (Day 0), data from the past 
2 weeks are acceptable. 
C-reactive protein (CRP) 
X 
X 
 
X 
 
 
 
Procalcitonin  
X 
X 
X 
 
Blood count (including 
eosinophiles, neutrophiles, Hb) 
X 
X 
X 
 
Capillary blood gas analysis: pO2 
and pCO2; SpO2 
X 
X 
X 
 
Table 5 
Planned Assessments Calibration Cohort  
Assessments 
Day 0 
End of Study 2 Weeks 
Comments 
Participant informed consent 
X 
 
 
Inclusion/Exclusion criteria 
X 
 
Assessed by Investigator by review of medical history and/or 
participant reported medical history 
Demographics 
X 
 
 
Medical history 
X 
 
 
Comorbidities 
X 
 
 
Medication 
X 
X 
 
End of Study satisfaction 
questionnaire 
 
X 
 
 
(S)AE recording 
 
Continuous recording 
SADE and DD reporting 
 
Continuous reporting 
Data collection via App (labeling 
events and activities) 
Daily at home 
 

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9.2.5 
Withdrawal from the Study  
Participants are free to discontinue the study at any time without giving their reasons. Participants 
will be withdrawn from study participation for any of the following reasons: 
• Informed consent withdrawal 
• Participant is unable to handle the devices and has proven to not provide reliable data 
• The study is prematurely stopped by the sponsor 
9.3 
Variables  
The following variables will be collected for this study (pending availability): 
Several biometric parameters will be measured in a time-dependent manner using the Vivalink 
wearable device. Values measured from day 8 to 14 will be used as baseline data (e.g. for 
determining parameter changes during the observation period or as co-factor in model building) 
unless this time period is within a 2-week distance of an exacerbation. In this case the next 7-day 
period with a distance of 4 weeks from an exacerbation will be considered the baseline in this 
context. 
Variables measured with the Vivalink wearable device (including, but not limited to):  
• Physical activity including stair climbing, (calculated based on continuous accelerometer 
measurement) [daily average] (derived parameter) 
• Heart rate as beats per minute [daily average] (derived parameter) 
• Resting heart rate (resting state as determined by accelerometer, beats per minute) [daily 
average] (derived parameter) 
• Heart rate variability reflecting differences in time intervals between 2 R-waves in the ECG 
(milliseconds) [daily average (where applicable) of the following parameters: SDRR (standard 
deviation of RR intervals), SDNN (standard deviation of NN intervals), SDNNI (Mean of the 
standard deviations of all the NN intervals for each 5 min segment of a 24 h HRV recording), 
RMSSD (Root Mean Sum of Squared Distance), ln(RMSSD) (natural logarithm of RMSSD),  
pNN50 (percentage of successive RR intervals that differ by more than 50 ms) SI (stress index), 
LF power (low frequency fraction of HRV, 0.04 – 0.15 Hz), HF power (high frequency portion 
of HRV, 0.15 – 0.40 Hz), LF/HF (ratio of LF-to-HF power); for details of calculation check see 
Shaffer 2017] (derived parameters). 
• Temperature [daily average, minimum -maximum values]   
• Respiration rate (breath per minute) [daily average, minimum -maximum values] (derived 
parameter) 
• Ratio of inspiration vs expiration time [daily average min-max] (derived parameter) 
• Cough frequency (derived parameter) 
• Sleep pattern (derived parameter) 

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Self-measured Variables:  
• Self-reported COPD symptoms via the CAT questionnaire 
• Self-reported activities (coughing, coughing with sputum production, spray use, non scheduled 
spray use, eating, going to bed, waking up, walking, climbing stairs, and physical exercise) as 
collected by the participant app 
• Self-reported satisfaction with the study, collected via end of study questionnaire 
Covariates (status at the time of Day 0, closest record prior to): 
• Demographics data at baseline: (sex, age, height, and weight, race and ethnicity) 
• Body mass index will be calculated based on height and weight 
• Smoking status (current, ex-, non-smoker) 
• Medical history at baseline  
o Date of diagnosis of COPD  
o Number of moderate or severe exacerbations prior to baseline visit (preceding 36 
months, in case available) 
• Comorbidities at baseline 
• Current medication including COPD treatment at baseline 
• COPD severity (GOLD stage) 
Lung Function and Laboratory variables 
(at Day 0, moderate/severe exacerbation visit and End of study visit) 
• Body plethysmography parameters: FEV1 [L], FVC [L], FEV1/FVC, TLC [L] (total lung 
capacity), RV [L] (residual volume), FRCpleth [L] (functional reserve capacity), IC [L] 
(inspiratory capacity), Raw [kPa s L-1] (=ratio of sRaw to FRCpleth; airway resistance), sRaw [kPa 
s] (specific airway resistance), VT [L] (mean tidal volume), ERV [L] (expiratory reserve 
volume), IRV [L] (inspiratory reserve volume). For definitions see Criée 2011. 
• Blood gas analysis:(capillary) pO2 [mmHg], O2 saturation [%] and pCO2 [mmHg], 
• Serum CRP [mg/l] and serum procalcitonin levels [ng/ml] 
• Blood count (CBC with differential); only values that are available with routine blood counts: 
Hb [g/dL], Hct [%], Erythrocyte count [106/µL], MCV [fL], MCH [pg], MCHC [g/dL], 
Reticulocytes [x10³/µL] [‰ (of erythrocytes)], RDW [], platelet count [10³/µL], WBC count 
[x10³/µL], Lymphocytes [x10³/µL] [%], Monocytes [x10³/µL] [%], Neutrophils [x10³/µL] [%], 
Eosinophils [x10³/µL] [%], Basophils [x10³/µL] [%] 
Derived and transformed data needed for the analysis are described in Section 9.7.1.1.  
A complete mapping of objectives, outcomes and variables is available in Section 14.1.2. 

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9.4 
Data Source  
The data source used for this study will consist of patient charts from 11 centers (e.g. academic, 
referral, community) in Germany as well as from a device, which will get handed out to the 
participant. 
The data informing this study will be extracted from patient medical records by the site personnel 
by means of an electronic Case Report Form (eCRF) directly in an electronic data capture system. 
In addition, a PRO questionnaire (CAT, filled in by the participant home electronically), and 
wearable devices (adhesive patch device with sensors) will be used for data collection. The data 
recorded in the eCRF should be consistent with the relevant source documents. Further details are 
provided in Section 9.6. 
9.5 
Study Size  
Sample size calculation is based on the second part of the primary objective, especially on 
predicting exacerbations of a severe or moderate type as outcome.  
Assuming a desirable sensitivity and specificity of 0.85 for our algorithm and requiring that the 
lower 95% confidence limit should be at least 0.50 (with a probability of 0.95) for this exploratory 
approach, the number of observed exacerbation events needed is 18 (Flahault 2005). 
Assuming that patients with COPD within our eligibility criteria (GOLD stage II-IV with a history 
of at least 2 moderate and/or severe exacerbations within any 12 month period within the last 3 
years and at least 1 moderate or severe exacerbation within the last 12 months) show a frequency 
of 2 moderate or severe exacerbations per year, participants with COPD will have 0.5 events in 3 
months (the in-study time). Further assuming that event occurrence over 3 months for every 
individual participant follows a Poisson distribution with parameter λ =0.5, the number of events 
in the overall study population is also Poisson distributed and the corresponding parameter is the 
sum of individual parameters λ. Calculations show that a λ of 30 is needed to reach an upper 
cumulative distribution probability of 0.99 for observing at least 18 exacerbations. Therefore, 60 
participants are needed to observe at least 18 exacerbation events within the 3-month observation 
period. 
The events of interest in the context of the present study are COPD exacerbations (severe or 
moderate), exactly the onset of an exacerbation. For building the binary classifier predictive 
models we also require “no exacerbation” events. We will sample such events randomly from 
periods with no exacerbations, avoiding 2 weeks before and after an exacerbation.  
Considering a drop-out rate of 10%, the estimated number is 67 participants with COPD that need 
to be included in this study.  
This recruitment number is also in good agreement with published studies with regards to the 
ability to build predictive models for exacerbations. Studies with similar recruitment numbers 
(Yañez 2012) have been able to predict exacerbations based on single parameters studied. Strong 
features can compensate for low numbers in COPD machine learning model building as shown in 

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Al Rajeh 2020, and using several features improves the accuracy of predictive models as seen in 
Jensen 2012. 
The study will also observe 10 participants in a calibration cohort for a limited time (2 weeks). 
This calibration cohort is intended to obtain sensor parameter ranges for individuals who are not 
suffering from COPD or other pulmonary diseases. These parameter ranges will be used to 
calculate distance measures of parameters (e.g. physical activity) for participants with COPD, and 
obtain additional sensitivity measures for the sensors used with regards to distinguish COPD 
symptoms from a calibration population. The number of participants for these secondary objectives 
is chosen on an exploratory basis, no sample size calculation has been conducted here. As we 
expect no major perturbations (e.g. exacerbations) within the calibration population, we deem a 
time period of 2 weeks sufficient for generating a representative sample of the participants sensor 
data.  
9.6 
Data Management  
9.6.1 
Data Collection  
The data collection in this study consists of different components, which are outlined in Figure 2 
below. Those components encompass different methods and tools:  
• Clinical Data: A cloud-based Electronic Data Capture (EDC) System. The purpose of the 
EDC system is the setup, collection, and review of study data entered by the site personnel. The 
data is entered through electronical case report forms (eCRF) by qualified and trained site staff.  
• Patient Reported Data: Electronic Questionnaire through an EDGE device provided to the 
participants as part of the study. 
• Medical Device Data: A wearable device (ECG, accelerometer, temperature) for the 
participants. The device is linked with the study EDGE device. 
Figure 2 
Schema of the Data Collection  
 

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Data from all described sources will be processed, evaluated, and stored in pseudonymized form 
in accordance with applicable data protection regulations. The Investigator must ensure that the 
eCRFs and any other associated documents forwarded to the Sponsor or its designated organization 
contain no mention of any participant names. The data from all sources will be transferred into a 
validated Clinical Database (CDB). The CRO or its designee will be responsible for data 
processing, in accordance with the CRO’s data management procedures. Database lock will occur 
once quality control and quality assurance procedures (including Serious Adverse Events 
[SAE]/SADE reconciliation) and coding activities have been completed. PDF files of the (e)CRFs 
will be provided to the Investigators at the completion of the study. 
9.6.2 
Data Collection Systems  
The main purpose of the CDB is to process and aggregate data from several sources for further 
central processes, like data validation, analysis, and data submissions. The CDB serves as data 
repository and is used to run quality control measures throughout the study. 
Clinical Data 
The Vault EDC system of Veeva Inc. is used for documentation of all relevant study data collected 
by the Investigator via eCRF. The main purpose of the eCRF is to obtain data required by the study 
protocol in a complete, accurate, legible, and timely manner. The data in the eCRF should be 
consistent with the relevant source documents. The Investigator or designee is responsible for 
ensuring that the data collected during the course of this study is accurate and documented 
appropriately on all applicable forms. eCRF data collection is following the study design. The 
software is accessed through a login with password secured web-interface.  
Patient Reported Data 
For the patient reported data collection, a Smartphone (a so-called EDGE device) with study 
specific functionality will be provided to the study participants. The main purpose of the device is 
to transmit data from the study participant to the CDB. It will contain the following software to 
collect data from participants: 
• A daily PRO questionnaire (CAT questionnaire)  
• Further information from the label section of the patient application with the following items: 
coughing, coughing with sputum production, spray use, nonscheduled spray use, eating, going 
to bed, waking up, walking, climbing stairs, and physical exercise 
• In addition, but outside of the app, the participants will be asked to fill in an end of study 
questionnaire on user satisfaction with the study, device and application. 
Medical Device Data 
All device data will be collected via the Vivalink wearable patch and an associated LTE 
smartphone. Participants and site physicians do not receive feedback or diagnostic data based on 
collected device data to not intervene with the regular treatment.  

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The Vivalink device contains 3 physical sensors for temperature, ECG, and a 3-axis accelerometer. 
The following parameters are therefore the primary (raw) outputs of the device: 
• ECG in an approximate Einthoven I configuration 
• Temperature 
• Movement data in the 3 axes of the accelerometer 
Vivalink will provide the following derived data: 
• Heart Rate 
• Physical activity 
• Respiratory Rate 
Using the raw data and participant labelling information, a number of further derived data will be 
generated by Merck as listed under variables. 
Participants in the COPD and calibration cohorts will receive their devices at study inclusion, be 
instructed on use and return the devices at study end. Data will be collected continuously during 
the study. 
Security of data transmission and storage 
Data transmission and storage will comply to EU-General Data Protection Regulation (EU-GDPR) 
and to the German “Bundesdatenschutzgesetz” BDSG. Data from the medical device will be 
transmitted in encrypted and pseudonymized way. Servers for data storage will be located in 
Europe, and data stored in a secure encrypted format.  
9.6.3 
Query Management  
If entries in the eCRF are incorrect or incomplete, queries will be created. Queries are inquiries 
about the entries in the eCRF. Queries may be automated or manually entered. Manual queries 
may only be submitted by the CRO. In case entries in the eCRF must be changed, those changes 
are documented within an audit trail. The time of the data change, the person making the change, 
the clear attribution of participants and variables, the old and the new value and, if necessary, the 
reason for the change are stored. 
9.7 
Data Analysis  
Further details will be provided in an integrated Analysis Plan (IAP) that will be finalized prior to 
study start (inclusion of first participant). 

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9.7.1 
Analysis Sets  
Two Analysis Sets will be defined: 
1. Participants with COPD including all patients with COPD included in the study, 
i.e, all patients with COPD fulfilling all of the inclusion criteria and none of the 
exclusion criteria (see Section 9.2.2). 
2. Participants in the calibration cohort included in the study (see Section 9.2.2). 
9.7.1.1 
Derived and Transformed Data  
 
Variable 
Original data 
Description of derived data 
Body mass index (BMI 
[kg/m2]) 
Measured height and 
weight. 
(Demographics data at 
baseline) 
Weight (kg) / (Height [cm]/100)2 
Physical activity, including 
stair climbing 
Continuous accelerometer 
measurement, self-
reported activities 
Classification algorithm, similar to the one 
described in Fadel 2019 
Heart rate 
ECG 
Beats per minute. 
Resting heart rate 
Accelerometer, ECG 
Resting state as determined by accelerometer, 
Beats per minute extracted from ECG 
Heart rate variability reflecting 
differences in time intervals 
between 2 R-waves in the ECG 
(milliseconds) 
SDRR , SDNN, SDNNI, 
RMSSD, ln(RMSSD),  pNN50, 
SI, LF power, HF power, LF/HF 
ECG 
For details of calculation check see Shaffer 2017 
Respiration rate 
ECG 
Measure of R-R peaks, and application of 
algorithms as the ones described in Varon 2020 
Ratio of in- vs. expiration time 
ECG 
Measure of R-R peaks, and application of 
algorithms as the ones described in Varon 2020 
Cough frequency 
Accelerometer, ECG, self-
reported activities 
Predictive algorithm similar to the one described 
in Georgescu 2019 
Sleep pattern 
Accelerometer, self-
reported activities 
Self reported going to bed and waking up, 
combined with accelerometer data to improve 
accuracy of sleeping time, plus accelerometer 
analysis to infer sleep quality. 
9.7.1.2 
Missing Data  
For variables obtained only at the baseline visit, missing values will not be replaced.  
For the self-reported satisfaction questionnaire items, collected at the end of study visit, missing 
values will not be replaced. For variables measured daily during the observation period such as 
sensor-generated data, CAT score, and labelling information, missing data will not be imputed for 
all descriptive statistical analyses performed. The CAT score and derived sensor variables may be 
imputed for the purpose of building machine learning models if needed to avoid loss of instances 

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using a suitable imputation method (e.g. LOCF, forward filling, multiple imputation [MI]). 
Sensitivity analyses will be conducted to assess the impact of imputation. 
For variables with values collected at baseline, at the exacerbation visit and at end of study visit, 
missing values will not be imputed for all descriptive statistical analyses. Lung function parameters 
and laboratory values may be imputed for the purpose of building machine learning models if 
needed to avoid loss of instances by LOCF method if the last (previous) available value is recorded 
within 2 weeks before the date of the visit of interest. In cases where no value for a variable is 
available for a participant, imputation strategies across instances may be used (e.g. median 
imputation or iterative imputation methods). Sensitivity analyses will be conducted to assess the 
impact of imputation.   
9.7.2 
Statistical Methods  
Descriptive statistics will include: 
• For continuous variables: mean, SD, median, first and third quartiles, minimum and maximum 
values, and number of missing values. 
• For categorical variables: counts and percentages. Percentage will be calculated with the 
denominator being the total number of participants with non-missing values for the variable of 
interest in the cohort at the corresponding time point. 
9.7.2.1 
Primary Objectives  
Primary objective 1): To describe the distribution of sensor collected data on physical activity, 
heart rate, heart rate variability, temperature, respiration rate, cough frequency, and sleep pattern, 
by severity of COPD exacerbations. 
This analysis will be performed on the COPD participants set. 
• Sensor collected data on physical activity, heart rate, heart rate variability, temperature, 
respiration rate, cough frequency, sleep pattern, at baseline (Day 0), in the period Day 8 to Day 
14, and shortly prior (14 days prior to, 7 days prior) to, during an exacerbation and after an 
exacerbation (8 to 14 days after, 2 weeks after, 3 weeks after, up to 4 weeks after an 
exacerbation) will be reported as mean (SD) and/or median (Interquartile Range) for continuous 
variables and counts and frequency (%) for categorical variables. The analysis will be done on 
the group of severe or moderate exacerbations and on exacerbations by type. 
Primary objective 2): To predict moderate or severe COPD exacerbations by building a statistical 
model employing sensor-derived data and demographic and medical covariates. 
This objective aims at predicting the occurrence of a severe or moderate exacerbation, in other 
words, predicting an event out of the combined group of severe and moderate exacerbations. It is 
desirable to predict an AECOPD as early as possible, therefore dependency of model metrics on 
the time period before exacerbation will be explored. 

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As input to the model a number of algorithms (e.g. self-learning algorithms) for obtaining derived 
parameters such as cough frequency, physical activities and sleep pattern, heart rate variability, 
temperature, respiration pattern, cough frequency, or sleep pattern will be developed first using 
the labeling of activities dataset obtained via the app. Said derived features will help to understand 
the importance of different raw data patterns, so that explanatory models can be built on top of the 
machine learning algorithms (Molnar 2022), as a way to support rationalization for physicians and 
regulatory organizations. 
Different machine learning algorithms (e.g. gradient boosting, SVMs, K-nn) will be evaluated, and 
their performance will be assessed by estimating their accuracy, specificity, sensitivity, and area 
under ROC metrics. 
This analysis will be performed on the COPD participants set.  
Based on previous analysis of clinical data, both in literature and internally, methods that are 
known to be useful on data where some features are strongly correlated with the desired outcome 
will be used, in order to create unbiased models. The following methods will be used: 
• Logistic regression 
• Random Forest 
• K-nearest neighbors 
• Boosting methods (e.g. Gradient boosting machine, GBM) 
• Support vector machines (SVM) 
Other methods may be tested. 
9.7.2.2 
Secondary Objectives  
Secondary Objective 3):  
To evaluate the correlation of sensor collected data with  
a) patients´ self-assessed health status and symptoms (CAT) at baseline and study end,  
b) lung function and lab values at baseline and study end,  
c) and with history of moderate and severe exacerbations at study end 
This analysis will be performed on the COPD participants set. 
Coefficients of correlation with 95% CI of sensor collected data on physical activity, heart rate, 
heart rate variability, temperature, respiration rate, cough frequency, sleep pattern with patients’ 
health status (CAT) at baseline (Day 0) and study end, lung function (e.g. FEV1) at baseline 

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The study protocol, each step of the data capture procedure, and the handling of the data, as well 
as the eventual study report, may be subject to independent Clinical Quality Assurance. Audits 
may be conducted at any time during or after the study to ensure the validity and integrity of the 
study data. 
For key statistical results, the validation of statistical programming will use a risk-based approach 
according to Good Automation Manufacturing Practices (GAMP)-5 principles.  
A self-validation approach will be used for other results, where the quality control process involves 
a code review where critical errors will be identified, using the following checks: 
• Adherence to requirements and specifications as per the protocol have been respected 
• Adherence to standards, e.g. program header, comments, Good Programming Practice 
Guideline 
• Review of the statistical outputs: 
- 
for consistency of populations sizes 
- 
minimum and maximum values 
- 
overall relevance of results 
- 
consistency with the tables and figures templates 
All programs and analysis datasets will be stored in a centralized electronic data warehouse on 
secure, password-protected and validated, GxP compliant servers. These secure servers are 
accessible only from the Merck and CRO intranet where access is restricted to relevant employees 
and computers which access these servers must have approved usage rights and training 
certifications to use the system. 
The results reported in the result section of the final report will be reviewed by the scientist to 
ensure an accurate transcription of results. 
9.9 
Limitations of the Research Methods  
• The data is collected from a very limited number of study sites in Germany. Hence the study 
population may not be representative of the population of patients with COPD. In addition, the 
fact that participation in the study requires cognitive capabilities to use applications and devices 
used for data collection in the study may cause selection bias towards a younger age group.    
• Daily averages will be calculated to represent continuous measurements each day. There may 
be additional information encoded in smaller time periods (hour by hour or minute by minute) 
data or through defining bouts of activity.  
• Some of the outcomes are based on subjective self-assessment e.g. COPD symptoms and health 
status will be assessed by the CAT score. In validation studies, the CAT score has been shown 
to be a valid and reliable tool to assess perceived health status (Jones 2013), though validity of 
the online version remains to be proven.   
• The number of observed exacerbations will be low, and predictive models will need to be 
refined and validated in a larger population. 

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• Severe and moderate AECOPDs will likely be encountered in only ~40% of the participants 
with COPD. This may impact the generalizability of predictive models for AECOPDs. 
• This study is a national study in Germany and will only recruit patients with sufficient 
proficiency in the German language. It is therefore impossible to assess potential bias in the 
gathered data and conclusions with regards to language, ethnicity, cultural background, country 
of origin, and social factors not encountered in the study population. This refers both to PROs 
and the interpretation of sensor data. Future studies will need to study these potential biases in 
a multinational setting. 
• Mild exacerbations are captured via the labelling section in the patient facing application as 
“additional medication used” (self-reporting). Therefore, the capture of mild exacerbations 
depends on patients’ adherence to the intended application use and daily reporting. Mild 
exacerbations may therefore be under-reported (but also over-reported in case of erroneous 
entries). 
• Participants may not adhere to the intended constant wearing or charging regimens of the device 
and therefore available data may have too many gaps to allow meaningful interpretation. 
• Participants may wear the device not at the intended location or in the intended orientation. This 
may introduce errors into the interpretation of sensor derived data. Participants may enter wrong 
data into both the CAT questionnaire and the labelling section leading to difficulties in model 
building and conclusions from the study.  
• The device may have undetected technical errors that introduce errors into the sensor data 
leading to difficulties in model building and conclusions from the study. 
9.10 
Other Aspects  
9.10.1 
Ethical Conduct of the Study  
This study will be conducted in accordance with the clinical trial protocol, the current version of 
the Declaration of Helsinki , ISO14155, ICH-GCP (as applicable), and all national legal and 
regulatory requirements. 
9.10.2 
Independent Ethics Committee or Institutional Review Board  
This multicenter, prospective cohort study with a medical device is classified as “Sonstige 
Klinische Prüfung” (other clinical study) as per Article 82 Regulation (EU) 2017/745 /§3 No. 4 
MPDG. The medical device used in this study for physiological monitoring will be used modified 
to its CE marking with the addition of temperature monitoring capabilities. Prior to 
commencement of the study at a given site, the protocol will be submitted together with its 
associated documents to the responsible Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB) for its opinion. 
The study must not start at a site before the Sponsor has obtained written confirmation of a 
favorable opinion from the concerned IEC/IRB in accordance to §47 (2) No. 1 and §52 Section 1 
MPDG.  

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The written evidence of the favorable opinion from the concerned IEC/IRB will be filed in the trial 
master file and a copy will be sent to the Investigator. The written evidence should clearly identify 
the study, the protocol version, and the Informed Consent Form version reviewed. In addition, the 
IEC/IRB will be asked to provide documentation of the date of the meeting at which the study was 
discussed, and of the members and voting members present at the meeting.  
In accordance with § 54 MPDG, all changes to the protocol and any applicable documentation will 
be notified to the responsible IEC/IRB immediately. In case of substantial changes, the responsible 
IEC/IRB will be asked for favorable opinion in accordance with § 55 MPDG. Substantial changes 
will only be implemented, if the responsible IEC/IRB issues a favorable opinion or if the 
responsible IEC/IRB issues no rejection notice within 38 days after confirmation of a formally 
complete application.  
In case of temporary suspension or premature termination of the study, the responsible IRB/IEC 
will be notified within 15 days with indications of the reasons. If the temporary suspension or 
premature termination are performed out of security reasons, the responsible IRB/IEC will be 
notified within 24 hours in accordance with §64 MPDG. 
9.10.3 
Monitoring  
A CRO will perform monitoring according to the study’s Monitoring Plan. Investigators need to 
ensure that the Monitor has access to relevant documents during monitoring visits and that they 
and/or relevant site staff members are available to discuss any issues that may arise. 
Recruitment rates and exacerbation frequency in the COPD study population will be reviewed in 
2-week intervals to compare against assumptions and allow for timely adjustments of the study 
protocol and conducting sites to reach the projected minimum number of moderate or severe 
exacerbations (n=18). Participants will be instructed to inform any physician outside of this study 
of their participation in this study and the need to inform the respective PI on relevant medical 
events and exacerbations.  
The study monitor will send monitoring reports to the Sponsor. 
9.10.4 
Health Authorities  
The study must not start at a site before the protocol and any applicable documentation has been 
notified to the German Federal Institute for Drugs and Medical Devices (BfArM) in accordance 
with the § 47 (2) No. 2 and § 53 Section 1 MPDG. 
In accordance with § 54 MPDG, all changes to the protocol and any applicable documentation will 
be notified to BfArM immediately. 
In case of temporary suspension or premature termination of the study BfArM will be notified 
within 15 days with indications of the reasons. If the temporary suspension or premature 
termination are performed out of security reasons, the BfArM will be notified within 24 hours in 
accordance with §64 MPDG. 

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9.10.5 
Quality Assurance  
In compliance with regulatory requirements, the Sponsor, a third party on behalf of the Sponsor, 
competent authorities, or IRB/IECs may conduct quality assurance audits/inspections at any time 
during or following a study. The Investigator must agree to allow auditors/inspectors direct access 
to all study-related documents, including source documents, and must agree to allocate his or her 
time and the time of his or her study staff to the auditors/inspectors in order to discuss findings 
and issues. 
The protocol, each step of the data capture procedure, and the handling of the data, as well as the 
study report, may be subject to independent Clinical Quality Assurance. Audits may be conducted 
at any time during or after the study to ensure the validity and integrity of the study data. 
9.10.6 
Medical Device Supply, Accountability and Handling  
The Medical Device will be shipped by the manufacturer to the CRO and subjected to a receiving 
inspection. After successful receiving inspection the Medical Devices will be equipped with an 
ID, tracked and stored at the CRO in a restricted area. Only designated personnel involved in the 
supply chain of the Medical Devices will have access. The Medical Devices will be prepared for 
shipment to the sites by the CRO and tracked after handover to the logistic company.   
The site will confirm the intact receipt of the Medical Device shipment in writing to the CRO. All 
Medical Devices must be stored in accordance with the manufacturer instructions. The investigator 
is responsible for assurance of adequate storage. The Device must be stored in a lockable room or 
locker, so that only investigator and specifically designated study personnel can have access. Only 
participants enrolled in the study may receive the devices and only authorized site staff may supply 
the device.  
At the end of the study, all Medical Devices will be returned by the participants and checked for 
completeness at the site. Those devices and unused devices are returned to the CRO. The CRO 
will check, store and return the Medical Devices to the manufacturer. 
Storage, dispensing and return of Medical Devices must be documented by the site and the CRO. 
In case of reported device deficiencies, including malfunction, usability issues, or inadequacy in 
the information supplied by the manufacturer including labelling, the devices will be returned to 
the CRO, if already supplied, and the sponsor will be informed. Poorly performing devices will be 
replaced during the study and returned to the CRO by the site. 
The study team at the CRO and site staff involved in the supply chain will be trained on the process. 
9.10.7 
Archiving  
The archive should be maintained for the period specified by local regulations (10 years in 
Germany) (MPDG/appendix XV EU-MDR). All original participant files (medical records) must 
be stored at the site (hospital, research institute, or practice) for the longest possible time permitted 

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by the applicable regulations. In any case, the Investigator should ensure that no destruction of 
medical records is performed without the written approval of the Sponsor. 
10 
Protection of Human Participants  
The sponsor will use safeguards to comply with national and European Union requirements for 
protecting the well-being and rights of human participants. To ensure the protection of privacy of 
participants, the sponsor is using data which have been pre anonymized and have had all protected 
health information removed. The sponsor will have no access to these data and will be unable to 
link these data to or identify the participants of the study. The sponsor will also restrict the access 
to the data to ensure that only those study personnel who have been appropriately trained and are 
in compliance with all of Merck’s Codes of Ethics can examine the data. 
10.1 
Participant Information and Informed Consent  
An unconditional prerequisite for a participation in the study is a written informed consent. The 
participants written informed consent must be given before any study-related activities are carried 
out. 
Adequate information must therefore be given to the participant by the Investigator before 
informed consent is obtained. A participant information sheet in the local language (German) will 
be provided by the Sponsor for the purpose of obtaining informed consent. In addition to providing 
this written information to a potential participant, the Investigator will inform the participant 
verbally of all pertinent aspects of the study (the language used in doing so must be chosen so that 
the information can be fully and readily understood by laypersons).   
The Informed Consent Form must be signed and personally dated by the participant and the 
Investigator. The signed and dated declaration of informed consent will remain at the Investigator’s 
site and must be safely archived by the Investigator. A copy of the signed and dated information 
and consent form should be provided to the participant prior to participation. 
Whenever important new information becomes available that may be relevant to the participant’s 
consent, the written participant information sheet and any other written information provided to 
participants will be revised by the Sponsor and be submitted again to the IEC/IRB for review and 
favorable opinion. The agreed, revised information will be forwarded to each participant in the 
study. The Investigator will explain the changes to the previous version. 
10.2 
Participant Identification and Privacy  
A unique participant number will be assigned to each participant at inclusion. This number will 
serve as the participant identifier in the study as well in the study database. 
The Investigator must ensure that the participants’ anonymity is maintained. On the eCRFs or other 
documents submitted to the Sponsor, participants should not be identified by their names, but by 
their assigned identification numbers. If participant names are included on copies of documents 
submitted to the Sponsor, the names (except for initials) must be obliterated and the assigned 
participant numbers added to the documents. 

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The Investigator should keep a separate log of participants’ identification numbers, names, 
addresses, telephone numbers and hospital numbers (if applicable). Documents not for submission 
to the Sponsor, such as signed Informed Consent Forms, should be maintained in strict confidence 
by the Investigator. 
Only authorized persons will have access to identifiable personal details, if required for data 
verification. The participant’s original medical data that are reviewed at the site during source data 
verification by the Monitor, audits, and Health Authority inspections will be kept strictly 
confidential. The Investigator agrees to provide direct access to these documents to the Sponsor 
and to Health Authority representatives. The Investigator is responsible for retrieving information 
from personal medical records. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing participant data. Participants will be informed accordingly and will be requested to give 
their consent on data handling procedures in accordance with national regulations. 
11 
Management and Reporting of Adverse Events and Device 
Deficiencies  
11.1 
Definition of (Serious) Adverse Events and other safety related 
events  
Adverse Event (AE) (Art. 2 [57] MDR) 
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs 
(including an abnormal laboratory finding) in participants, users, or other persons whether or not 
related to the medical device. 
Note: medical conditions presented and documented at study start, that do not worsen in severity 
or frequency during the study are defined as Baseline Medical Conditions and elective procedures, 
and NOT to be considered adverse events. 
Serious Adverse Event (SAE) (Art. 2 [58] MDR) 
Any adverse event that led to any of the following: 
(a) 
death, 
(b) 
serious deterioration in the health of the participant that resulted in any of the following: 
(i)  
life-threatening illness or injury, 
(ii) 
permanent impairment of a body structure or a body function, 
(iii)  hospitalization or prolongation of patient hospitalization, 

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(iv)  medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
(v)  chronic disease, 
(c) 
fetal distress, fetal death or a congenital physical or mental impairment or birth defect. 
Note: planned hospitalization for pre-existing condition, or a procedure required by the study 
protocol, without a serious deterioration of the health status of the participant, is not considered an 
SAE. 
Device deficiency (Art. 2 [59] MDR) 
Inadequacy of the medical device with respect to its identity, quality, durability, reliability, safety, 
or performance, including malfunction, user errors and inadequate information supplied by the 
manufacturer. 
Malfunction (ISO14155) 
Failure of a medical device to perform in accordance with its intended purpose when used in 
accordance with the instructions for use or the study protocol. 
Device deficiency with Serious Adverse Device Effect (SADE) potential (Art. 80 [1c] MDR) 
Any device deficiency that might have led to a serious adverse event if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less fortunate. 
Adverse Device Effect (ADE) (ISO14155) 
Adverse events possibly, probably, or causally related to the use of a medical device or procedures.  
This includes any adverse event resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, operation, or any malfunction of the medical device used 
in the study. This includes any event that is a result of a use error or intentional misuse.  
Serious Adverse Device Effect (SADE) (ISO14155) 
Adverse device effect (ADE) that has resulted in any of the consequences characteristic of a serious 
adverse event. 
Unanticipated Serious Adverse Device Effect (USADE) (ISO14155) 
SADE which by its nature, incidence, severity, or outcome has not been identified in the current 
risk assessment. 
Adverse events categorization 
The adverse events are categorized by the PI and the Sponsor or authorized designee using the 
following algorithm:   

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Does the AE meet the seriousness criteria? 
• No, it is not serious 
• Is the relationship to the device or the procedure possible, probable, or causal? 
• 
No: non-related AE 
• 
Yes: ADE 
• Yes, it is serious: SAE 
• Is the relationship to the device or the procedure possible, probable, or causal? 
• 
No: non-related SAE 
• 
Yes: SADE 
▪ Is it anticipated (within expected type, severity, and frequency of the 
complications)? 
o No: unanticipated SADE (USADE) 
o Yes: anticipated SADE (ASADE) 
Events Not to be considered as AEs 
Medical conditions presented and documented at study start that do not worsen in severity or 
frequency during the study are defined as Baseline Medical Conditions and elective procedures 
and are NOT to be considered adverse events. 
11.2 
Severity of Adverse Events  
Investigators should assess the severity/intensity of any AE as follows: 
Mild: 
The participant is aware of the event or symptom, but the event or symptom is 
easily tolerated. 
Moderate: 
The participant experiences sufficient discomfort to interfere with or reduce his 
or her usual level of activity. 
Severe: 
Significant impairment of functioning: the participant is unable to carry out usual 
activities. 
11.3 
Causality Assessment  
A causal relationship towards the device(s) used in the study or the procedure of the investigation 
should be rated by the Investigator as follows (MDCG 2020-10/1): 
• Not related: The relationship to the device or procedures can be excluded. 
• Possible: The relationship with the use of the device is weak but cannot be ruled out completely. 
Alternative causes are also possible. 
• Probable: The relationship with the use of the device seems relevant and/or the event cannot 
reasonably be explained by another cause. 

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• Causal relationship: The serious event is associated with the device or with procedures beyond 
reasonable doubt. 
The Investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to the device used or study procedures will be 
considered and investigated. 
The Investigator will also consult the Vivalink device instructions for use and/or the Vivalink 
device current risk assessment, when applicable, in his/her assessment. 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SADE has occurred, and the Investigator has minimal 
information to include in the initial report to the CRO. However, it is very important that the 
Investigator always makes an assessment of causality for every event before the initial 
transmission of the SADE data to the CRO. 
The Investigator may change his/her opinion of causality in light of follow-up information and 
create a SADE follow-up report with the updated causality assessment. 
11.4 
Recording of Adverse Events  
The recording period for (S)AEs/DDs begins when the participant is initially included in the study 
(date of signature of first informed consent) and continues until the last study protocol-specific 
procedure. 
During the conduct of the study, the Investigator must fully record all the following: 
• any AE; 
• any SAE; 
• any DD that might have led to a serious adverse event if appropriate action had not been taken, 
intervention had not occurred, or circumstances had been less fortunate; 
• any new findings in relation to any event referred to in the previous points. 
AEs/DDs must be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative) to the Investigator during visits defined in the 
SoA of the study protocol. The Investigator must record all directly observed events and all 
spontaneously reported events by the study participant. In addition, each study participant will be 
questioned about AEs/DDs. 
All safety data AEs/SAEs, as specified above, occurring during the study, must be documented 
and recorded in the Case Report Form (CRF) by the Investigator, including its description, 
seriousness, severity (grading), duration (onset and resolution dates), causal relationship, any other 
potential causal factors, actions taken with the device, required treatment and outcome of the AE. 

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Reporting of any new information on a previously reported event (follow-up) will follow the 
procedures and timelines of the original report. 
The CRO must forward the follow-up information within 72 hours to Global Patient Safety and to 
the manufacturer of the medical device, as noted above for initial reports. 
11.6 
Safety Reporting to the Competent Authorities and IEC/IRBs.  
The Sponsor or authorized designee reports to the Competent Authorities (CA) any reportable 
event defined in Section 11.5.  
The period for reporting must take account of the severity of the event: 
• For all reportable events which indicate an imminent risk of death, serious injury, or serious 
illness and that requires prompt remedial action for other patients, users or other persons or a 
new finding to it: Immediately, but not later than 2 calendar days after awareness by the Sponsor 
or authorized designee of a new reportable event or of new information in relation with an 
already reported event. 
• This includes events that are of significant and unexpected nature such that they become 
alarming as a potential public health hazard. It also includes the possibility of multiple deaths 
occurring at short intervals. 
• Any other reportable events or a new finding/update to it: Immediately, but not later than 7 
calendar days following the date of awareness by the Sponsor or authorized designee of the new 
reportable event or of new information in relation with an already reported event. 
Where necessary to ensure timely reporting, the sponsor or authorized designee may submit an 
initial report that is incomplete followed up by a complete report. 
The reporting to the IECs/IRBs follows the requirements of the local ethics committees in 
Germany. 
The Sponsor or authorized designee provides the CA and the IEC/IRB with the documentation 
defined in Section 11.4 at their request. 
Periodic safety reporting 
The Sponsor or authorized designee sends to the CA a quarterly summary evaluation with the 
information of all reportable SADEs and DDs occurred during the conduct of the study. 
12 
Plans for Disseminating and Communicating Study Results  
12.1 
Study Report  
The study will be summarized in a final report that accurately and completely presents the study 
objectives, methods, results, limitations of the study, and interpretation of the findings in 
accordance with Annex XV Chapter I Section 2.8 and Chapter II Section 7 of Regulation (EU) 
2017/745. In accordance with §64 MPDG, 12 months after completion of the study, the final report 

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will be submitted to BfArM; in case of premature termination or temporary suspension of the 
study, the study report will be submitted within 3 months.  
12.2 
Publication  
Findings from this study will be shared in scientific meetings/congresses and described in one or 
more manuscripts submitted to relevant peer-reviewed medical journal(s), after the approval of the 
final study report. Authorship will follow the guidelines proposed by the International Committee 
of Medical Journal Editors (ICMJE). Authors will adhere to the ICMJE guidelines, specifically, 
all authors will have (1) made substantial contributions to conception and design, acquisition of 
data, or analysis and interpretation of data; (2) participated in drafting the article or revising it 
critically for important intellectual content; (3) approved the version to be published, and (4) 
agreed to be accountable for all aspects of the work in ensuring that questions related to the 
accuracy or integrity of any part of the work are appropriately investigated and resolved. In 
addition, any potential conflicts of interest will be disclosed. 
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the study, and a publication plan will be agreed in advance between the Investigator and the 
Sponsor. Any publications and presentations of the results (abstracts in journals or newspapers, 
oral presentations, etc.), either in whole or in part, by the Investigator or representatives will 
require pre-submission review by the Sponsor. The Sponsor will ensure that the internal pre-
submission review will take place within a reasonable timing (i.e. a month) and will not suppress 
or veto publications but maintains the right to delay publication in order to protect intellectual 
property rights. 
13 
References  
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Landis SH, Muellerova H, Mannino DM, et al. Continuing to Confront COPD International Patient 
Survey: methods, COPD prevalence, and disease burden in 2012–2013. Int J Chron Obstruct 
Pulmon Dis. 2014; 9: 597–611.  
McLean S, Nurmatov U, Liu JL et al. Telehealthcare for chronic obstructive pulmonary disease. 
Cochrane Database Syst Rev. 2011; 7: CD007718.  
Molnar C. Interpretable Machine Learning: A Guide For Making Black Box Models Explainable. 
2nd Ed. 2022. Independently Published, Munich, Germany.  
Müllerová H, Dransfield MT, Thomashow B, et al. on behalf the COPD Biomarker Qualification 
Consortium and the CAT Governance Board. Clinical development and research applications of 
the COPD Assessment Test (CAT). Am J Respir ét Care Med. 2020; 201:1058-1067.  
Pedone C, Chiurco D, Scarlata S. Incalzi RA. Efficacy of multiparametric telemonitoring on 
respiratory outcomes in elderly people with COPD: a randomized controlled trial. BMC Health 
Serv Res. 2013 13:82..  
Quaderi SA and Hurst JR. The unmet global burden of COPD. Glob Health Epidemiol Genom. 
2018. 3:e4.  
Rhodes K, Jenkins M, de Nigris E, et al. Relationship between risk, cumulative burden of 
exacerbations and mortality in patients with COPD: modelling analysis using data from the 
ETHOS study. BMC Med Res Methodol. 2022; 22:150  
Shaffer F, Ginsberg JP. An Overview of Heart Rate Variability Metrics and Norms. Front Public 
Health. 2017; 5:258.  
Sullivan SD, Ramsey SD, Lee TA. The Economic Burden of COPD. Chest 2000; 117:5S-9S.  
Varon C, Morales J, Lázaro J. et al. A Comparative Study of ECG-derived Respiration in 
Ambulatory Monitoring using the Single-lead ECG. Sci Rep. 2020; 10:5704.  

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Vogelmeier CF, Criner GJ, Martinez FJ et al. Global strategy for the diagnosis, management, and 
prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. Am J 
Respir Crit Care Med. 2017; 195:557-582.  
WHO. 
Chronic 
obstructive 
pulmonary 
disease 
(COPD). 
https://www.who.int/respiratory/copd/burden/en/ (20 May 2022)  
Yañez AM, Guerrero D, Perez de Alejo R, et.al. Monitoring breathing rate at home allows early 
identification of COPD exacerbations. Chest 2012; 142:1524-1529.  
Zimmermann SC, Huvanandra J, Nguyen CD, et al. Day-to-day variability of forced oscillatory 
mechanics for early detection of acute exacerbations in COPD. Eur Respir J. 2020. 456:1901739.  

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14 
Appendices  
14.1 
Additional Information  
14.1.1 
End of the Study Questionnaire  
English Wording: 
1) The study app was easy to use 
1. Fully agree 2. Agree 
3. Disagree 4. Fully disagree 
 
2) The written instruction I received at the beginning of the study was easy to understand 
1. Fully agree 2. Agree 
3. Disagree 4. Fully disagree 
 
3) The verbal instruction I received at the beginning of the study was easy to understand 
1. Fully agree 2. Agree 
3. Disagree 4. Fully disagree 
 
4) Answering the questionnaire daily was acceptable for me 
1. Fully agree 2. Agree 
3. Disagree 4. Fully disagree 
 
5) Regularly labeling events was acceptable for me 
1. Fully agree 2. Agree 
3. Disagree 4. Fully disagree 
 
6) Regularly recharging the devices was acceptable for me 
1. Fully agree 2. Agree 
3. Disagree 4. Fully disagree 
 
7) I am satisfied with the support received during the study from the site 
1. Fully agree 2. Agree 
3. Disagree 4. Fully disagree 
 
8) I am satisfied with the support received during the study from the help center 
1. Fully agree 2. Agree 
3. Disagree 4. Fully disagree 5. I did not need support 
from the help center 
 
9) I am interested to have access to health-related data (e.g., activity level)  
1. Fully agree 2. Agree 
3. Disagree 4. Fully disagree 
 
10) I would give my physician  access to real-time health related data (e.g., heart rate, 
respiratory rate, temperature) for the benefit of my treatment 
1. very likely 2. Maybe 3. very unlikely 
 
11) I am using my own smartphone (not the one in the study) daily 
1. agree 2. Disagree 3. I don’t have a smartphone 

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German Wording: 
1) Die App für die Studie war einfach zu bedienen  
1: stimme voll zu  2: stimme eher zu  
3: stimme eher nicht zu 
4: stimme überhaupt nicht zu  
 
2) Die schriftliche Einweisung, die ich vor der Studie erhalten habe, war leicht verständlich 
1: stimme voll zu  2: stimme eher zu 
3: stimme eher nicht zu 
4: stimme überhaupt nicht zu  
 
3) Die mündliche Einweisung, die ich vor der Studie erhalten habe, war leicht verständlich 
1: stimme voll zu 
2: stimme eher zu 
3: stimme eher nicht zu  
4: stimme überhaupt nicht zu  
 
4) Es war für mich akzeptabel, den Fragebogen täglich auszufüllen  
1: stimme voll zu  2: stimme eher zu  
3: stimme eher nicht zu 
4: stimme überhaupt nicht zu  
 
5) Es war für mich akzeptabel, regelmäßig Aktivitäten (z.B. Treppensteigen) zu 
kennzeichnen  
1: stimme voll zu  2: stimme eher zu  
3: stimme eher nicht zu  
4: stimme überhaupt nicht zu  
 
6) Es war für mich akzeptabel, die Geräte regelmäßig aufzuladen  
1: stimme voll zu  2: stimme eher zu  
3: stimme eher nicht zu 
4: stimme überhaupt nicht zu  
 
7) Ich bin mit der Unterstützung zufrieden, die ich während der Studie von meinem 
Studienarzt erhalten habe 
1: stimme voll zu  2: stimme eher zu  
3: stimme eher nicht zu  
4: stimme überhaupt nicht zu  
 
8) Ich bin mit der Unterstützung zufrieden, die ich während der Studie vom Service-Center 
erhalten habe 
1: stimme voll zu  2: stimme eher zu  
3: stimme eher nicht zu  
4: stimme überhaupt nicht zu  5: Ich habe keine Unterstützung benötigt 
 
9) Es ist für mich interessant, Zugang zu Daten über meinen Gesundheitszustand (z.B. mein 
Aktivitätsniveau) zu haben 
1: stimme voll zu  2: stimme eher zu  
3: stimme eher nicht zu  
4: stimme überhaupt nicht zu  
 
10) Um eine verbesserte Behandlung zu erhalten, würde ich meinem Arzt Zugang zu 
gesundheitsbezogenen Daten in Echtzeit (z.B. Atemfrequenz, Herzfrequenz, Temperatur, 
…)  gewähren 
1: ziemlich wahrscheinlich 
2: vielleicht 
3: wahrscheinlich nicht 

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11) Ich benutze mein eigenes Smartphone (nicht das Smartphone in der Studie) täglich 
1: stimme zu  2: stimme nicht zu  
3: Ich besitze kein Smartphone 

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14.1.2 
Mapping of Objectives, Outcomes and Variables  
 
Number 
of 
objective 
Objective 
Outcome definition 
Variables and Sources 
1 
To describe the distribution of sensor 
collected data on physical activity, 
heart rate, heart rate variability, 
temperature, respiration rate, cough 
frequency, and sleep pattern, by 
severity of COPD exacerbations 
 
Severe/moderate COPD 
exacerbations (requiring a physician’s 
intervention, emergency room visit or 
hospitalization) during the observation 
period. 
 
COP exacerbation from the physician charts (for the 
severe/moderate exacerbation): 
- 
Occurrence (Yes/No) of COPD exacerbation 
- 
Severity of COPD exacerbation (moderate, severe) 
Sensor data (Vivalink wearable device) collected daily: 
- 
Physical activity including stair climbing (derived 
parameter) 
- 
Heart rate as beats per minute [daily average] (derived 
parameter)  
- 
Resting heart rate [daily average] (derived parameter)  
- 
Heart rate variability [daily average] (derived parameter)  
- 
Temperature [daily average, minimum -maximum values]  
- 
Respiration rate (breath per minute) [daily 
average] (derived parameter)  
- 
Ratio of in- vs expiration time [daily average min-max] 
(derived parameter)  
- 
Cough frequency (derived parameter)  
- 
Sleep pattern (derived parameter)  
Self-reported activities as collected daily by the participant 
app:  
- 
Coughing 
- 
coughing with sputum production 
- 
spray use, non-scheduled spray use 
- 
eating, going to bed, waking up 
- 
walking, climbing stairs 
- 
physical exercise 

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Number 
of 
objective 
Objective 
Outcome definition 
Variables and Sources 
2 
To predict moderate or severe COPD 
exacerbations by building a statistical 
model employing sensor-derived data 
and demographic and medical 
covariates. 
Severe/moderate COPD 
exacerbations (requiring a physician’s 
intervention, emergency room visit or 
hospitalization) during the observation 
period. 
 
COPD exacerbation from the physician charts (for the 
severe/moderate exacerbation): 
- 
Occurrence (Yes/No) of COPD exacerbation 
- 
Severity of COPD exacerbation (moderate, severe) 
Sensor data (Vivalink wearable device) collected daily: 
- 
Physical activity including stair climbing (derived 
parameter) 
- 
Heart rate as beats per minute [daily average] (derived 
parameter)  
- 
Resting heart rate [daily average] (derived parameter)  
- 
Heart rate variability [daily average] (derived parameter)  
- 
Temperature [daily average, minimum -maximum values]  
- 
Respiration rate (breath per minute) [daily 
average] (derived parameter)  
- 
Ratio of in- vs expiration time [daily average min-max] 
(derived parameter)  
- 
Cough frequency (derived parameter)  
- 
Sleep pattern (derived parameter)  
Self-reported activities (e.g., coughing, sports, sleeping) as 
collected by the participant app:  
- 
Coughing 
- 
coughing with sputum production 
- 
spray use, non-scheduled spray use 
- 
eating, going to bed, waking up 
- 
walking, climbing stairs 
- 
physical exercise 
Other covariates (at Day 0) from the physician chart: 
- 
Demographics data at baseline: (sex, age, height, and 
weight, race and ethnicity)  
- 
Body mass index will be calculated based on height and 
weight  
- 
Smoking status (current, ex-, non-smoker)  
- 
Medical history at baseline   
- 
Date of diagnosis of COPD   

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Number 
of 
objective 
Objective 
Outcome definition 
Variables and Sources 
- 
Number of moderate or severe exacerbations prior to 
baseline visit (preceding 36 months, in case available)  
- 
Comorbidities at baseline  
- 
Current medication including COPD treatment at baseline  
- 
COPD severity (GOLD stage) 
Other covariates (Lung Function and Laboratory variables at 
Day 0, moderate/severe exacerbation visit and End of study 
visit) from the physician chart: 
- 
Body plethysmography parameters: FEV1 [L], FVC [L], 
FEV1/FVC, TLC [L] (total lung capacity), RV [L] (residual 
volume), FRCpleth [L] (functional reserve capacity), IC [L] 
(inspiratory capacity), Raw [kPa s L-1] (=ratio of sRaw to 
FRCpleth; airway resistance), sRaw [kPa s] (specific 
airway resistance), VT [L] (mean tidal volume), ERV [L] 
(expiratory reserve volume), IRV [L] (inspiratory reserve 
volume).  
- 
Blood gas analysis:(capillary) pO2 [mmHg], O2 [%] 
saturation and pCO2 [mmHg]    
- 
Serum CRP [mg/l] and serum procalcitonin levels [ng/ml] - 
- 
Blood count (CBC with differential); only values that are 
available with routine blood counts: Hb [g/dL], Hct [%], 
Erythrocyte count [106/µL], MCV [fL], MCH [pg], MCHC 
[g/dL], Reticulocytes [x10³/µL] [‰ (of erythrocytes)], RDW 
[], platelet count [10³/µL], WBC count [x10³/µL], 
Lymphocytes [x10³/µL] [%], Monocytes [x10³/µL] [%], 
Neutrophils [x10³/µL] [%], Eosinophils [x10³/µL] [%], 
Basophils [x10³/µL] [%]  
3 
To evaluate the correlation of sensor 
collected data with  
a) patients´ self-assessed health 
status and symptoms (CAT) at 
baseline and study end,  
b) lung function and lab values at 
baseline and study end,  
c) and with history of mild, moderate 
and severe exacerbations at study 
end.  
a) Patients' health status and 
symptoms at baseline (Day 0) and 
study end will be measured as the 
summary score across items of the 
CAT questionnaire that consists of 8-
items in which participants can 
choose a score from 0 to 5, for each 
visit    
b) Lung function will be assessed 
using plethysmography and lab 
values including Complete Blood 
Count with differential, Blood Gas 
Patients' health status and symptoms at baseline visit and at 
study end visit from patients app/questionnaire: 
Summary CAT score 
Lung function and Laboratory values at baseline visit and study 
end visit from physician charts 

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Number 
of 
objective 
Objective 
Outcome definition 
Variables and Sources 
Analysis, procalcitonin and CRP will 
be assessed as per standard practice 
at baseline (Day 0) and at study end 
(for details see Section 9.3)    
c) number, date of onset and duration 
of mild, moderate, and severe 
exacerbations, respectively, during 
the observation period  
- 
Body plethysmography parameters: FEV1 [L], FVC [L], 
FEV1/FVC, TLC [L] (total lung capacity), RV [L] (residual 
volume), FRCpleth [L] (functional reserve capacity), IC [L] 
(inspiratory capacity), Raw [kPa s L-1] (=ratio of sRaw to 
FRCpleth; airway resistance), sRaw [kPa s] (specific 
airway resistance), VT [L] (mean tidal volume), ERV [L] 
(expiratory reserve volume), IRV [L] (inspiratory reserve 
volume).  
- 
Blood gas analysis:(capillary) pO2 [mmHg], O2 saturation 
[%] and pCO2 [mmHg]  
- 
Serum CRP [mg/l] and serum procalcitonin levels [ng/ml]  
- 
Blood count (CBC with differential); only values that are 
available with routine blood counts: Hb [g/dL], Hct [%], 
Erythrocyte count [106/µlL, MCV [fL], MCH [pg], MCHC 
[pg/L], Reticulocytes [x10³/µL] [‰ (of erythrocytes)], RDW 
[], platelet count [10³/µL], WBC count [x10³/µL], 
Lymphocytes [x10³/µL] [%], Monocytes [x10³/µL] [%], 
Neutrophils [x10³/µL] [%], Eosinophils [x10³/µL] [%], 
Basophils [x10³/µL] [%] 
COPD exacerbations during the observation period from the 
physician charts (for the severe/moderate exacerbation) 
and from the patients app (for the mild exacerbations):  
Number, date of onset, duration of COPD exacerbations 
4 
Sensor derived data may be related to 
the CAT score, therefore, an 
additional objective is to investigate 
whether changes in physical activity, 
heart rate, heart rate variability, 
temperature, respiration rate, cough 
frequency, and sleep pattern in the 3-
month observation period, are 
associated with changes of the patient 
self-assessed symptoms (CAT). 
 
Please see above (3a)  
During the observation period the 
CAT score will be obtained on a daily 
basis. Daily summary score across 
items of the CAT questionnaire will be 
computed.  
 
Self-reported COPD symptoms via the CAT questionnaire daily 
obtained from the patients app: 
- 
Daily summary score (The total CAT score will have a 
maximum = 40). 
- 
Change of the CAT score of 2 points or more 
Sensor data (Vivalink wearable device) collected daily: 
- 
Physical activity including stair climbing (derived 
parameter) 
- 
Heart rate as beats per minute [daily average] (derived 
parameter)  
- 
Resting heart rate [daily average] (derived parameter)  
- 
Heart rate variability [daily average] (derived parameter)  
- 
Temperature [daily average, minimum -maximum values]  

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Number 
of 
objective 
Objective 
Outcome definition 
Variables and Sources 
- 
Respiration rate (breath per minute) [daily 
average] (derived parameter)  
- 
Ratio of in- vs expiration time [daily average min-max] 
(derived parameter)  
- 
Cough frequency (derived parameter)  
- 
Sleep pattern (derived parameter)  
Self-reported activities as collected by the patients app: 
- 
Coughing 
- 
coughing with sputum production 
- 
spray use, non-scheduled spray use 
- 
eating, going to bed, waking up 
- 
walking, climbing stairs 
- 
physical exercise 
5 
To predict the CAT score and 
changes thereof by building a 
statistical model employing sensor-
derived data and demographic and 
medical covariates. 
 
Patients' health status and symptoms 
at baseline (Day 0) will be measured 
as the summary score across items of 
the CAT questionnaire that consists of 
8-items in which participants can 
choose a score from 0 to 5. During 
the observation period the CAT score 
will be obtained via a digital 
application on a daily basis.    
Self-reported COPD symptoms via the CAT questionnaire daily 
obtained from the patients app: 
- 
Daily summary score (The total CAT score will have a 
maximum = 40). 
- 
Change of the CAT score of 2 points or more 
Sensor data (Vivalink wearable device) collected daily: 
- 
Physical activity including stair climbing (derived 
parameter) 
- 
Heart rate as beats per minute [daily average] (derived 
parameter)  
- 
Resting heart rate [daily average] (derived parameter)  
- 
Heart rate variability [daily average] (derived parameter)  
- 
Temperature [daily average, minimum -maximum values]  
- 
Respiration rate (breath per minute) [daily 
average] (derived parameter)  
- 
Ratio of in- vs expiration time [daily average min-max] 
(derived parameter)  
- 
Cough frequency (derived parameter)  
- 
Sleep pattern (derived parameter)  
Self-reported activities as collected by the patient app:  
- 
Coughing 
- 
coughing with sputum production 

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Number 
of 
objective 
Objective 
Outcome definition 
Variables and Sources 
- 
spray use, non-scheduled spray use 
- 
eating, going to bed, waking up 
- 
walking, climbing stairs 
- 
physical exercise 
Other covariates (at Day 0) from the physician chart: 
- 
Demographics data at baseline: (sex, age, height, and 
weight, race and ethnicity)  
- 
Body mass index will be calculated based on height and 
weight  
- 
Smoking status (current, ex-, non-smoker)  
- 
Medical history at baseline   
- 
Date of diagnosis of COPD   
- 
Number of moderate or severe exacerbations prior to 
baseline visit (preceding 36 months, in case available)  
- 
Comorbidities at baseline  
- 
Current medication including COPD treatment at baseline  
- 
COPD severity (GOLD stage) 
Other covariates (Lung Function and Laboratory variables at 
Day 0, moderate/severe exacerbation visit and End of study 
visit) from the physician chart: 
- 
Body plethysmography parameters: FEV1 [L], FVC [L], 
FEV1/FVC, TLC [L] (total lung capacity), RV [L] (residual 
volume), FRCpleth [L] (functional reserve capacity), IC [L] 
(inspiratory capacity), Raw [kPa s L-1] (=ratio of sRaw to 
FRCpleth; airway resistance), sRaw [kPa s] (specific 
airway resistance), VT [L] (mean tidal volume), ERV [L] 
(expiratory reserve volume), IRV [L] (inspiratory reserve 
volume).  
- 
Blood gas analysis:(capillary) pO2 [mmHg], O2 saturation 
[%] and pCO2 [mmHg]   
- 
Serum CRP [mg/l] and serum procalcitonin levels [ng/ml] - 

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