The Stroke Box: a Patient-centered eHealth Approach for Improving Post-stroke Care.
Conditions: Stroke
Sponsor: Leiden University Medical Center

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THE STROKE BOX 
(February 2022) 

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PROTOCOL TITLE ‘The Stroke Box: a patient-centered eHealth approach for improving 
post-stroke care.’ 
Protocol ID 
P21.113 
Short title 
The Stroke Box 
EudraCT number 
Not applicable 
Version 
3 
Date 
18-02-2022
Coordinating investigator/project 
leader 
Prof. Marieke J. H. Wermer (m.j.h.wermer@lumc.nl) 
Principal investigator(s) (in Dutch: 
hoofdonderzoeker/uitvoerder) 
Drs. Hendrikus J. A. van Os (h.j.a.van_os@lumc.nl) 
Drs. Hermes A. J. Spaink (h.a.j.spaink@lumc.nl)  
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Department of Neurology, Leiden University 
Medical Center 
Subsidising party 
NA 
Independent expert (s) 
Dr. Erik H. Niks (e.h.niks@lumc.nl) 
Laboratory sites <if applicable> 
NA 
Pharmacy <if applicable> 
NA 
PROTOCOL SIGNATURE SHEET 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
5 
SUMMARY 
7 
1. 
INTRODUCTION AND RATIONALE 
9 
2. 
OBJECTIVES 
11 
3. 
STUDY DESIGN 
12 
4. 
STUDY POPULATION 
13 
4.1 
Population (base) 
13 
4.2 
Inclusion criteria 
13 
4.3 
Exclusion criteria 
13 
4.4 
Sample size calculation 
13 
5. 
TREATMENT OF SUBJECTS 
15 
5.1 
Investigational product/treatment 
15 
5.2 
Use of co-intervention (if applicable) 
15 
5.3 
Escape medication (if applicable) 
15 
6. 
INVESTIGATIONAL PRODUCT 
16 
6.1 
Name and description of investigational  product(s) 
16 
6.2 
Summary of findings from non-clinical studies 
18 
6.3 
Summary of findings from clinical studies 
18 
6.4 
Summary of known and potential risks and benefits 
18 
6.5 
Description and justification of route of administration and dosage 
19 
6.6 
Dosages, dosage modifications and method of administration 
19 
6.7 
Preparation and labelling of Investigational Medicinal Product 
20 
6.8 
Drug accountability 
20 
7. 
NON-INVESTIGATIONAL PRODUCT 
21 
8. 
METHODS 
22 
8.1 
Study parameters/endpoints 
22 
8.1.1 
Main study parameter/endpoint 
22 
8.1.2 
Secondary study parameters/endpoints 
22 
8.1.3 
Other study parameters 
23 
8.2 
Randomisation, blinding and treatment allocation 
23 
8.3 
Study procedures 
23 
8.4 
Withdrawal of individual subjects 
26 
8.5 
Replacement of individual subjects after withdrawal 
26 
8.6 
Follow-up of subjects withdrawn from treatment 
26 
8.7 
Premature termination of the study 
26 
9. 
SAFETY REPORTING 
27 
9.1 
Temporary halt for reasons of subject safety 
27 
9.2 
AEs, SAEs and SUSARs 
27 
9.2.1 
Adverse events (AEs) 
27 
9.2.2 
Serious adverse events (SAEs) 
27 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
28 
9.3 
Annual safety report 
28 

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9.4 
Follow-up of adverse events 
28 
9.5 
[Data Safety Monitoring Board (DSMB) / Safety Committee] 
28 
10. 
STATISTICAL ANALYSIS 
29 
10.1 
Primary study parameter(s) 
29 
10.2 
Secondary study parameter(s) 
29 
10.3 
Other study parameters 
29 
10.4 
Interim analysis (if applicable) 
29 
11. 
ETHICAL CONSIDERATIONS 
30 
11.1 
Regulation statement 
30 
11.2 
Recruitment and consent 
30 
11.3 
Objection by minors or incapacitated subjects (if applicable) 
30 
11.4 
Benefits and risks assessment, group relatedness 
30 
11.5 
Compensation for injury 
31 
11.6 
Incentives (if applicable) 
31 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
32 
12.1 
Handling and storage of data and documents 
32 
12.2 
Monitoring and Quality Assurance 
32 
12.3 
Amendments 
32 
12.4 
Annual progress report 
32 
12.5 
Temporary halt and (prematurely) end of study report 
33 
12.6 
Public disclosure and publication policy 
33 
13. 
STRUCTURED RISK ANALYSIS 
34 
13.1 
Potential issues of concern 
34 
13.2 
Synthesis 
34 
14. 
REFERENCES 
35 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the application 
form that is required for submission to the accredited Ethics Committee; in 
Dutch: Algemeen Beoordelings- en Registratieformulier (ABR-formulier) 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
CVRM 
Cardio Vascular Risk Management 
DSMB 
Data Safety Monitoring Board 
EMR 
Electronic Medical Record 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
GP 
General Practitioner 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
IMD 
IMDD 
Investigational Medicinal Product Dossier  
Investigation with Medical Device 
Investigational Medical Device Dossier 
LUMC 
Leiden University Medical Centre 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
mRS 
Modified Rankin Scale 
PIF 
Patient Information Form 
(S)AE 
(Serious) Adverse Event  

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SPC 
Summary of Product Characteristics; in Dutch: officiële productinformatie 
IB1-tekst 
Sponsor 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; in 
Dutch: Uitvoeringswet AVG 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 
 

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SUMMARY 
 
Rationale: Although there have been major advances in (personalized) stroke treatment in 
the last decade, the need for prevention of stroke remains critical. Prevention of recurrent 
stroke is currently primarily organized through management of cardiovascular risk factors 
including lifestyle, hypertension and atrial fibrillation (AF). To improve the cardiovascular risk 
management of stroke patients, more frequent measurements of blood pressure and heart 
rhythm are essential. In addition, actively engaging the patient with their own recovery could 
lead to an improved lifestyle. Recent studies have shown telemonitoring of patients can 
improve care, help with prevention of disease, and reduce healthcare costs, whilst keeping 
the patient more engaged with their disease.  
The LUMC “Box” has shown to effectively monitor blood pressure of patients after myocardial 
infarction with equal results and patient satisfaction rates compared to standard care with 
less physical contact moments. We plan to use this framework for improving post-stroke care 
by introducing more frequent blood pressure and heart rhythm measurements. Additionally, 
we will provide more information around lifestyle improvement and have the patient actively 
engage with their weight and physical activity. 
In this study we will be evaluating the technical feasibility and clinical implementation of the 
home-based self-measurements using the Box in a post-stroke pilot setting: the Stroke Box. 
The results will be used as a basis for the power calculation for a future randomized clinical 
trial on the effect of the Box on hypertension treatment and AF detection. 
Objective: The overall aim of this pilot is to evaluate the technical feasibility and clinical 
implementation of the Stroke Box by evaluating user experience and hypertension 
management. The primary objective is gathering data on blood pressure management for 
power calculation for a future randomized clinical trial where the effect of the Stroke Box on 
hypertension management and AF detection will be studied. The secondary objectives will be 
gathering and evaluating data on heart rhythm, weight and activity of patients using the 
Stroke Box, evaluating the technical- and workflow implementation for healthcare 
professionals, evaluating the self-management and user-experience of patients, assessing 
the patient adherence to the self-measurements and pharmacotherapeutic prophylactic 
therapy, and evaluating the correct functioning of the IT infrastructure, hardware and LUMC 
Care app, and to assess the correct use of all stakeholders involved in the eHealth support 
and telemonitoring with the Stroke Box. 
Study design: This study is a prospective cohort study to evaluate the implementation of the 
Stroke Box and gather data. For the first 5 patients we will mainly evaluate the technical 
procedures of the study in addition to the other objectives. For the remainder, we will be 
gathering data on blood pressure management, patient engagement and have a user-based 

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evaluation of the eHealth infrastructure during a six-month follow-up period. We will do 
evaluations of the collected data based on a before-after comparison of blood pressure and 
questionnaire results. 
Study population: Patients admitted for a TIA, ischemic or haemorrhagic stroke in the 
LUMC. We will include 55 patients in total of which in the first 5 patients we specifically focus 
on testing and evaluating the technical feasibility. 
Intervention (if applicable): The Stroke Box will contain a blood pressure monitor, weighting 
scale, single-lead ECG wristwatch with activity tracking and associated apps. Patients are 
asked to measure the associated factors on a weekly basis. In addition, all patients will be 
asked to fill in a questionnaire at the start and the end of the study. Patients will participate 
for 6 months in the pilot. 
Main study parameters/endpoints: The primary objective of this study is the gathering of 
data on blood pressure management as a basis for power analysis in future trials. The 
secondary objectives will be gathering and evaluating data on heart rhythm, weight and 
activity of patients, evaluating the technical- and workflow implementation for healthcare 
professionals, evaluating the self-management and user-experience of patients, assessing 
the patient adherence to the self-measurements and pharmacotherapeutic prophylactic 
therapy, and finally evaluating the technical feasibility for all stakeholders. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: Patients are asked to measure weight, blood pressure and heart rhythm 
on a weekly basis, which takes approximately 5-10 minutes. All devices used by patients for 
personal management in this study are non-invasive, easy-to-use, CE marked and 
electrically safe within their intended use. Using the devices comes with very limited risks. 
This study has several potential benefits for patients. First, patients can measure their own 
blood pressure, heart rhythm and weight, which can give them more insight in their own 
health and may spark a healthier lifestyle (the so-called ‘patient empowerment’). 
Furthermore, these data give the GP or GP nurse more insight in the health status of 
patients, potentially leading to better cardiovascular risk management and hypertension 
control. Finally, the regular ECG measurements might help in detecting occult AF in patients 
at risk for AF. 
 
 

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1. INTRODUCTION AND RATIONALE 
Although there have been major advances in (personalized) stroke treatment in the last 
decade, the need for prevention of stroke remains critical.1 Currently in the Netherlands, 
prevention of stroke is primarily performed by the general practitioner (GP) in their 
cardiovascular risk management (CVRM). Lifestyle management, blood pressure 
regulation and cholesterol lowering interventions are the cornerstones in prevention of 
neuro- and cardiovascular disease. Resources - primarily time – are, however, limited in 
healthcare which leaves room for improvements to the CVRM. Post-stroke CVRM 
consists of regular visits to the GP or GP nurse where blood pressure, lifestyle and 
medication adherence is monitored. Although these visits are regular, a recurring problem 
is that these measurements are not always accurate. A patient may have taken his or her 
medication just before the measurement, is in a different and potentially stressful 
environment or might be fatigued from travel all of which can affect blood pressure. In 
addition to hypertension, atrial fibrillation (AF) is also an important risk factor.2 However, 
studies show AF is missed during a hospital admission in a substantial number of stroke 
patients.3 
 
Recent studies have shown telemonitoring of patients can improve healthcare. A study in 
patients with hypertension showed that increased monitoring and subsequent treatment 
led to a better controlled blood pressure in patients who were treated for hypertension.4 
Moreover, the application of telehealth reduces healthcare costs by a combination of 
preventing unnecessary hospitalisation, clinic visits and use of medical resources and by 
offering a solution for the demand of an effective chronic disease management with focus 
on patient-centered care.5-9 
 
Over the past five years, smartphone compatible detectors of neuro- and cardiovascular 
disease parameters have been released on the consumer market. Examples of these 
wearable eHealth tools include ECG monitors, blood pressure monitors, activity trackers 
and fat percentages monitors. These monitors have often been validated and are CE-
marked for use in the European Union within their intended use. Therefore, wearable 
eHealth technology is a promising tool to improve patient monitoring and patient safety. 
 
Studies also show that home monitoring of blood pressure leads to more accurate 
measurements, reflecting actual blood pressure better than GP practice measurements.10 
Even for patients with poorly controlled blood pressure in primary care, home monitoring 
can significantly reduce the blood pressure.11 Using a wearable ECG monitor, blood 
pressure sensor, activity tracker and weight scale at-home monitoring of stroke-risk is 
made well accessible. The thereby improved CVRM could hence improve chances for 
prevention of a recurrent stroke and also reduce the costs of unnecessary GP visits.  
 
At the Leiden University Medical Center (LUMC) “The Box” initiative is getting widely 
adopted, providing a solid foundation for expanding to other areas of the clinic.12 It is one 
of the three pillars of the LUMC2.0 digital strategy as it can effectively support patients by 

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giving them more insight into their own health status. Moreover, results from earlier “Box” 
studies, such as the “Cardio Box” for care after myocardial infarction, showed that 
patients were very satisfied with the care they received and that the blood pressure 
regulation in patients with the Box was as good as in regular care. This “Box” has many 
similarities to the project described here giving us confidence that the implementation of 
the Stroke Box can improve care. Additionally, "The Box" was cost effective with 
increased efficiency of care.13 We therefore selected this well tested workflow as a basis 
for our patient-centered eHealth approach for improving post-stroke care. 
 
Before performing a randomized controlled clinical trial investigating the effects of the 
self-measurements on blood pressure and heart rhythm with the Stroke Box, we will run a 
pilot on a small group of patients.  
 
For the first 5 patients in this pilot we mainly test the technical feasibility of the eHealth 
infrastructure and evaluate the stakeholder experience. This is essential because this 
study differs from previous Box projects in several ways. First, our patient population is 
expected to be generally older compared to previous studies and will likely have 
substantial physical or cognitive disabilities as a result of the stroke which may  lead to a 
reduced adaptation to the self-monitoring and use of eHealth devices. Second, this is the 
first Box-related project in which the Box is used to facilitate the transfer between hospital 
and home care. Therefore the transfer to and communication with GPs, i.e. feasibility of 
setting up a collaboration with multiple practices, will have to be evaluated. 
 
In the remaining 50 patients, we evaluate the clinical implementation where we will collect 
data as a basis for the power calculation in the future trial. In this protocol we will describe 
the setup of this pilot study. 
 
 

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2. OBJECTIVES 
Primary Objective:  
● Gathering data on self-measured blood pressure and AF detection of patients using the 
Stroke Box as a basis for power analysis of a future randomized controlled clinical trial 
and performing a quality assessment of the collected data. 
 
Secondary Objectives: 
● Gathering data on self-measured heart rhythm, weight and activity of patients using the 
Stroke Box, and performing a quality assessment of the collected data. 
● Evaluation of the potential change in self-management, patient engagement and user 
experience of the patients using the Stroke Box, using questionnaires. 
● Assessment of patient adherence to the self-measurements and pharmacotherapeutic 
prophylactic therapy, using questionnaires. 
● To evaluate our implementation of the IT infrastructure, hardware and LUMC Care app, 
and to assess the correct use of all stakeholders involved in the eHealth support and 
telemonitoring with the Stroke Box. The devices themselves and their functioning are 
not a subject of research. 
● User based evaluation of the technical – and workflow implementation for healthcare 
professionals using the Stroke Box, using questionnaires. 
 
 
 

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3. STUDY DESIGN 
In this pilot study we will evaluate the technical feasibility and clinical implementation of the 
Stroke Box in a small prospective cohort. After providing the Stroke Box to the patients, 
detailed information will be provided on the use of the Stroke Box and the patient will be 
helped with their first use. 
 
The patient will use the Stroke Box to take at-home measurements for six months. Here we 
will be gathering data on blood pressure management, cardiac rhythm, patient engagement 
and have a user-based evaluation of the eHealth infrastructure. Patients will perform regular 
home measurements which the GP can use at the regular visits, and a nurse specialist in the 
LUMC will assess ECG measurements. We will keep close contact with both patient and GP 
to help in case of any questions. The patients will have access to the LUMC Box Support 
helpdesk who are an established customer service desk to help with any Box-related issues. 
We will ask the patients and GPs to contact us in case of any questions they might have. At 
the end of the pilot the user evaluation will be done through a questionnaire. 
 
During the regular GP visits after the stroke related hospital admission, the GP and the nurse 
specialist will have insight in the collected data. We will evaluate the GP’s experience of the 
data insight and technical usability using a questionnaire. 
 
The study is estimated to take 12 months where we will have 6 months of inclusions and 6 
months of follow-up. 
 
 

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4. STUDY POPULATION 
4.1 Population (base)  
We will recruit patients visiting for a TIA or admitted for an ischemic or haemorrhagic 
stroke in the LUMC.  
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the 
following criteria: 
- 
The patient is admitted with a clinical diagnosis of a TIA, ischemic or 
haemorrhagic stroke in the LUMC 
- 
The patient is able to communicate in Dutch (patients with severe aphasia - 
defined as not being able to respond to the questionnaires or perform the self-
measurements – are excluded) 
- 
The patient is at least 18 years of age 
- 
The patient will be discharged from the hospital directly to home 
- 
The patient has hypertension during hospital admission as defined by systolic 
blood pressure >140mmHg during two separate blood pressure 
measurements 
- 
The patient has a suitable smartphone and is able to use it in a reasonable 
sense 
- 
The GP of the patient is willing to collaborate in the study 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
- 
The patient does not have internet access at home 
- 
Patient is unwilling to sign the informed consent form 
- 
Patient is considered an incapacitated adult 
- 
The patient is a pregnant or breastfeeding woman 
- 
The GP of the patient is not willing to partake in the study 
 
4.4 Sample size calculation 
In the LUMC there are 450 stroke patients per year, 50-60% of which are 
immediately discharged home. Of these patients we expect 85% willing to sign the 
informed consent form and have the GP willing to cooperate in the pilot. We will be 
including patients for a maximum of 6 months, in this time there will be about 105 
potential patients for our study according to our calculations. We will be including 55 
patients. We will use this patient population to estimate incidence of blood pressure 
out of the therapeutic window (>140mmHg) for the power analysis of a future clinical 
trial. 

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In 37.5% of patients, we expect to see a change in blood pressure in 6 months,14 
this would amount to 20 patients in our population of 55 patients. This would be 
sufficient to power a future trial focusing on blood pressure measurements using the 
Stroke Box infrastructure. Earlier studies focussing on long term recording of heart 
rhythm in patients with cryptogenic stroke found occult atrial fibrillation in 9% to 16% 
of patients.3,15 As 87% of stroke patients have ischemic strokes16 and about a third 
of those have cryptogenic strokes, we expect to find cryptogenic strokes in about 
29% of the LUMC stroke population.17 Therefore, we expect around two to three 
patients in which we would detect atrial fibrillation after hospital discharge. This 
would be the minimum to power a future trial focussing on atrial fibrillation detection 
using the ECG smartwatch. In conclusion, 55 patients amounts to the minimum size 
we would need to obtain sufficient results. 
 
 

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5. TREATMENT OF SUBJECTS 
5.1 Investigational product/treatment 
Patients receive the Stroke Box containing several monitoring devices. The Stroke Box 
uses a dedicated app, the LUMCcare app. A list of devices is presented below and 
described in more detail in section 6 of this protocol. All devices and products are CE-
marked and used within the scope of their intended use in this certification. 
 
The devices within The LUMC Box are connected to the LUMCcare app. All 
measurements performed by the patient with the connected devices will be automatically 
uploaded into the LUMCcare app, and safely transferred to the hospital for evaluation. 
Furthermore, illness specific questionnaires are presented within the app at the 
appropriate time points. 
 
The Stroke Box contains the following devices and products: 
● Withings BPM connect 
● Withings Body Weight Scale 
● Withings Move ECG Watch 
● LUMCcare app 
● Withings Health Mate app 
● IkOefenZelf access (for 10 patients only) 
● StopAdvisor app access 
 
5.2 Use of co-intervention (if applicable) 
Not applicable. 
 
5.3 Escape medication (if applicable) 
Not applicable. 
 
 

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6. INVESTIGATIONAL PRODUCT  
6.1 Name and description of investigational  product(s) 
Withings Body Weight Scale 
The Withings body weight scale is a CE-marked Bluetooth enabled weight scale which 
measures weight, body fat mass, heart rate and the CO2 ppm in the air. It sends the 
results to the LUMCcare app. The Withings Weight Scale is battery powered, CE-marked 
and electrically safe. In order to measure weight, patients have to stand on the weight 
scale. Data are automatically sent to the smartphone via Bluetooth.  
 
Withings BPM Connect 
The Withings BPM Connect Blood Pressure Monitor is a CE-marked, Bluetooth enabled 
blood pressure cuff which can be placed around the upper arm of the patients. The 
inflation and deflation of the cuff will lead to a systolic and diastolic blood pressure, as well 
as a heart rate, which are shown on the device itself and in the LUMCcare app on the 
smartphone. The Withings BPM Connect Blood Pressure Monitor is battery powered and 
electrically safe. It is CE-marked for blood pressure measurement. A previously published 
study that showed that median values are within the 5 mmHg range.18 
 
Withings Move ECG Watch 
The Withings Move ECG Watch is a wearable, CE-marked, Bluetooth enabled smart 
watch. The wristwatch combines single lead ECG measurements with activity tracking 
such as walking, running, swimming and many other activities and workouts. It measures 
steps, distance and calories consumed and sends all its results to the LUMCcare app via 
Bluetooth. The Withings Move ECG Watch is battery powered and electrically safe.  
 
LUMCcare app 
Data are presented on the LUMCcare app. The data resides within the Withings Health 
Mate connection app on the smartphone in encrypted form. The Withings Health Mate 
connection app initial logon will require several privacy-related patient data: full name and 
date of birth. This procedure complies with the LUMC requirements and has been 
approved by the LUMC security officer. For the Withings connection app, an integration 
(API) in the Electronic Medical Record (EMR, EPD-Vision) has been built. This API has 
been functional for 6 years already. Physicians and specialized nurses can thus evaluate 
the e-Health measurements of the patients in the EMR. 
The LUMCcare app presents the data to the patient in an intuitive interface. The app is co-
created with Pharos, the advocate group for people with low literacy, in order to ascertain 
the measurements are understandable for a large group of patients. The app reminds 

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patients to take measurements based on the protocol prescribed by the health care 
provider. It allows patients to fill in questionnaires at appropriate time points. The app 
communicates with the LUMC infrastructure according to LUMC guidelines and is 
approved by the LUMC security officer. As for how to use the app, patients will receive 
oral and written instructions. If they run into problems, a helpdesk is available, which is run 
by an LUMC employed technician. 
 
Withings Health Mate app 
The Withings3 Health Mate connection app requires a user specific account, that is 
accessed using a hospital-provided, coded username and a password. The account 
cannot be linked to an individual patient. This procedure complies with the LUMC 
requirements and has been approved by the LUMC security officer. For retrieving the data 
from the Withings Health Mate app, the LUMC uses an API connection, which unlocks the 
patient measurement data. This API has been functional for 6 years already. Authorized 
users can thus evaluate the e-Health measurements of the patients in the electronic 
patient file. 
 
Data is securely shared with the GP office via Medical Dashboard, an dedicated 
information portal that allows GPs to assess specific data from the LUMC. The Medical 
Dashboard is operational at the LUMC for already 8 years and complies with the LUMC 
requirements and has been approved by the LUMC security officer. Over the course of the 
next years, the underlying technology will be updated to new technology, in line with the 
established roadmap of the It&DI department of the LUMC. This effort is currently 
underway and may result in selection of a novel target architecture for regional 
connectivity in the coming period. All efforts will be taken to ensure this study protocol can 
continue also during implementation of novel architectures. 
 
In addition to this, the Health Mate app also gives the patient insight into his/her 
measurements. Moreover, when the Move ECG detects signs of AF during a 
measurement the patient is notified via the watch and the app. The patient is instructed to 
then take up contact with our specialist nurse. 
 
IkOefenZelf 
Rehabilitation centre Basalt developed the portal “ikoefenzelf.nl” for online stroke 
rehabilitation. The goal of “ikoefenzelf.nl” is to implement the use of eRehabilitation and to 
give stroke patients the opportunity to practice where, when, and how often they want. 
More practice contributes to more participation and a better quality of life. The portal is 

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already used by at least 50% of all stroke patients in Basalt and offers stroke patients 
blended care applications for both physical and cognitive/mental training. After logging in 
to the portal using a hospital-provided, coded username and a password, patients can 
start their personal training, prepared for them by the rehabilitation professionals. The 
platform consists of education about stroke and the applications “Physitrack” 
(physiotherapy and occupational therapy), “MindDistrict” (psychology and social work), 
“Topwoordvinding” (speech therapy) and a time writing module (occupational therapy).19 
 
StopAdvisor 
The StopAdvisor app for support of smoking cessation has been developed by the 
Trimbos Institute, Pharos and NeLL, and is based on a scientifically proven intervention 
developed by the University College London. The StopAdvisor app is currently being used 
in collaboration with SineFuma, and will be made available to those patients participating 
in the pilot who smoke and are interested. 
 
Coding the data 
In general, the Withings connection-app requires an e-mail address, first name, last name, 
birth date and password for the patient in order to register himself. Without those details, 
the app cannot be used. Therefore, for privacy reasons, all patients receive a personal 
account. The key between the anonymous e-mail address of this account and the patient 
identity resides in the Electronic Medical Record (EPD-Vision). This procedure complies 
with LUMC requirements and has been approved by the LUMC security officer. 
 
6.2 Summary of findings from non-clinical studies 
 Not applicable, as this research cannot have been carried out in non-clinical settings. 
 
6.3 Summary of findings from clinical studies 
 Not applicable.  
 
6.4 Summary of known and potential risks and benefits 
Patients will have to measure their weight, temperature, blood pressure and heart rhythm 
on a regular basis. Regularly, they also will be asked questions about their general 
health. These activities may take some of their time. 
A potential risk is that patients may be incorrectly assured that their data is monitored all 
the time by a trained physician. This might give them a false sense of security and hold 
them back from seeking medical assistance when this is required. To prevent this, we will 

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very clearly state in the patient information form (PIF) that this is not the case, and will 
make this integral part of the explanation when a patient starts with The Box. 
A second potential risk is that patients may become alarmed by an incorrect detection of 
atrial fibrillation by the Withings Move ECG. Since it is not CE marked for AF detection, 
and given the results from a current validation study, we cannot exclude the occurrence 
of false positives or negatives. The smart watch and associated app give a warning when 
the measurement shows irregularities. It then either results in an “inconclusive” 
measurement or detects “atrial fibrillation”. It has been shown that this occurs when there 
are small irregularities in the hearth rhythm, such as atrial or ventricular extrasystoles or 
short pauses . The device then usually results in “inconclusive” but can also show “atrial 
fibrillation”. This can hence (incorrectly) distress the patient and cause him/her to seek 
unnecessary medical help. We will remedy this by clearly instructing the patient with what 
to do and who to contact in case of suspected AF. 
After a measurement the Withings Move ECG performs a standard analysis resulting in 
either “normal”, “inconclusive” or “atrial fibrillation”. If their ECG smartwatch shows “atrial 
fibrillation” they are instructed to contact a dedicated nurse specialist who will check the 
measurements and refer them to the cardiology outpatient clinic if necessary. If the result 
is “inconclusive”, the patient is asked to repeat the measurement the next day. When the 
repeated measurement shows “inconclusive” again or when the measurement shows a 
warning for potential AF, they are instructed to also contact the dedicated nurse specialist 
who will contact the patient for further follow-up if necessary. 
All devices used by patients for personal management in this study are CE marked, non-
invasive, easy-to-use and electrically safe within their intended use. Using the devices is 
with very limited risks. 
This study has multiple potential benefits for the patients: First, patients can measure 
their own blood pressure, weight, activity, and heart rhythm, which can reassure patients 
and give them more insight in their own health (the so-called ‘patient empowerment’). 
Furthermore, this data gives the doctor more insight in the health status of patients, 
potentially leading to better hypertension management and earlier detection of atrial 
fibrillation. 
 
6.5 Description and justification of route of administration and dosage 
Not applicable. 
 
6.6 Dosages, dosage modifications and method of administration 
Not applicable. 

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6.7 Preparation and labelling of Investigational Medicinal Product 
Not applicable. 
 
 
6.8 Drug accountability 
Not applicable. 
 
 

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7. NON-INVESTIGATIONAL PRODUCT 
Not applicable. 
 

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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 
Main study parameter/endpoint 
The primary objective of this study is the gathering of data on blood pressure 
management as a basis for power analysis in future trials. This will be evaluated by 
a before-after-comparison of systolic and diastolic blood pressure in mmHg as 
measured by the self-measurements with the Stroke Box. 
8.1.2 Secondary study parameters/endpoints  
The secondary objectives of this study are:  
● Gathering data on self-measured heart rhythm from the Withings Move ECG 
as an indicator of atrial fibrillation, weight and activity of patients using the 
Stroke Box, and performing a quality assessment of the collected data as 
assessed by regularity of assessments and frequency of occurrence of 
measurement error. 
● The potential change in self-management of the patients due to the Stroke 
Box as measured through changes in lifestyle. This will be measured using 
changes in results from questionnaires on physical activity and healthy 
lifestyle intentions taken at the start and at the end of the study and the 
development of weight of the patient.  
For the evaluation of physical activity we will adapt the Short Questionnaire to 
Assess Health enhancing physical activity questionnaire (SQUASH)20, for the 
evaluation of healthy lifestyle intentions we will use the Healthy Lifestyle 
Intentions (HLI) questionnaire. 
The evaluation of the self-management of the patient will be assessed by the 
Reach Efficacy Adoption Implementation Maintenance (RE-AIM) model with a 
mixed model evaluation based on the normalization process theory.21-23  
● Assessment of the patient adherence to the self-measurements and 
pharmacotherapeutic prophylactic therapy, using the Partners In Healthcare 
(PIH) questionnaire which measures how the patient manages his/her own 
disease. At the end of the study a comparison will be made between the group 
of patients who used the IkOefenZelf platform and those who did not. 
● The technical implementation and patient adherence to the self-
measurements by analysing how often they performed the measurements, if 
they experienced any problems as measured through the questions they 
asked during the study, and how they experienced the overall implementation 
as measured through the mHealth App Usability Questionnaire (MAUQ)24 at 
the end of the study. 
● User based evaluation of the technical – and workflow implementation for the 
GPs using the Stroke Box as evaluated with the Acceptability of Intervention 
Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility 
of Intervention Measure (FIM)25 questionnaires for healthcare professionals. 

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8.1.3 
Other study parameters  
● Age 
● Sex 
● Body Mass Index 
● Cardiovascular risk factors including medication (hypertension, diabetes 
mellitus, hypercholesterolemia, smoking, alcohol) 
● Cardiovascular medical history (atrial fibrillation, stroke including all subtypes, 
heart failure, myocardial infarction) 
● Stroke specific (stroke related disabilities as assessed by the National 
Institutes of Health Scale Score at discharge, modified Rankin Scale at 
discharge) 
● The GP practice where the patient is registered and how the self-
measurements are shared with the GP (i.e. via Medical Dashboard or 
manually) 
 
 
8.2 Randomisation, blinding and treatment allocation 
This is a non-randomized, non-blinded study.  
 
8.3 Study procedures 
For the small prospective cohort for the pilot, patients who are admitted for an 
ischemic or hemorrhagic stroke in the LUMC will be included in the day or days 
before dehospitalization and after post-stroke stabilization. After inclusion we will 
personally contact the GP of the patient to also ask their willingness to collaborate in 
the pilot. After agreement of their GP, the included patients will receive the Stroke 
Box with all devices listed under section 6 of this protocol. Patients will be instructed 
on usage of the devices by a neurology PhD student. Furthermore, for each device 
a detailed user guide is available on https://hartlongcentrum.nl/informatie-voor-
patienten/the-box/handleidingen/.  
If extra help is necessary, patients will have an e-consult in which a patient does not 
have to go to the hospital. Instead, he or she will talk with a specialist from the Box-
helpdesk who will be able to guide the patient through the self-measurements and 
provide technical assistance where necessary. 
Patients will be asked to measure their weight and blood pressure once a week 
where they are recommended to do this on the same day and time every week. 
Additionally, they will be asked to keep track of their activity data (i.e. steps) on a 
regular basis, which can be monitored continuously by wearing the smartwatch. All 

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data will be automatically transferred to the LUMC. In order to code the data, 
patients will receive an anonymous email address, as described earlier in this 
protocol. Data will be stored on LUMC-owned servers. 
The patient’s blood pressure measurements and lifestyle data (measured weight 
and activity) is accessible for the GP through Medical Dashboard. For GPs who do 
not yet work with Medical Dashboard, the patient will be asked to show his 
measurements to the GP in the following way during the regular visits. The patient 
can either show his measurements in the app or make a printout of the data to be 
shown to the GP or GP nurse.  
When the patient records abnormal measurements indicating a high or rapid 
increase in blood pressure, they are instructed to not immediately contact a 
physician. This, in order to reduce the amount of (unnecessary) additional consults 
with the GP. Specifically, the patient is instructed to only contact their GP if they 
record a systolic blood pressure >140 mmHg for three days in a row or take up 
immediate contact if they record a systolic blood pressure >180 mmHg which is 
cause for immediate adjustment of the hypertension medication according to the 
NHG guidelines. 
In addition to the standard care where patients receive a 48-hour Holter, patients 
who are suspected to have atrial fibrillation because of e.g. a cryptogenic stroke will 
be asked to also perform home measurements of their heart rhythm on a daily basis. 
They are recommended to do this on the same day and time every day. They will be 
very clearly instructed that their ECG measurements are not monitored regularly and 
that they should contact 112 in case of emergency.  
After a measurement the Withings Move ECG performs a standard analysis 
resulting in either “normal”, “inconclusive” or “atrial fibrillation”. If their ECG 
smartwatch shows “atrial fibrillation” they are instructed to contact a dedicated nurse 
specialist who will check the measurements and refer them to the cardiology 
outpatient clinic if necessary. If the result is “inconclusive”, the patient is asked to 
repeat the measurement the next day. When the repeated measurement shows 
“inconclusive” again or when the measurement shows a warning for potential AF, 
they are instructed to also contact the dedicated nurse specialist who will contact the 
patient for further follow-up if necessary. It should be noted that a clinical diagnosis 
will never be based on the self-measurements. Instead they serve as an early 
screening tool leading to patients with potential AF to be invited to the cardiology 
outpatient clinic to receive a diagnosis via the standard Holter measurement. 
All ECG data are collected after the study and re-inspected by a PhD researcher of 
the LUMC for AF and in case of doubt checked again by an experienced 
cardiologist. In case of suspected AF, the patient is invited to the cardiology 
outpatient clinic. As 87% of stroke patients have ischemic strokes16 and about a 

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third of those have cryptogenic strokes, we expect to find cryptogenic strokes in 
about 29% of the LUMC stroke population.17 
Finally, the first ten patients with a modified Rankin Scale (mRS) ≥ 2 will receive 
access to the IkOefenZelf platform and will be asked to perform the practice 
modules on a regular basis. 
Patients who smoke will also be asked to install the StopAdvisor app. This app will 
help them to quit smoking. The app is freely available from the IOS App Store and 
the Google Play Store. 
Questionnaires 
At the start and end of the study the patient will receive several questionnaires to 
evaluate their experiences with self-management, physical activity, healthy lifestyle 
intentions, their user experience, and their experience with eHealth. To evaluate the 
change in physical activity and lifestyle of the patient, they will be asked to fill out the 
SQUASH and HLI questionnaires at the start and end of the study. These 
questionnaires investigate respectively the amount of physical activity (e.g. sports) a 
patient has and what their intentions to a healthy lifestyle are (which includes 
questions on e.g. diet, smoking and alcohol use). In order to evaluate the 
experience of the patient with the self-management, they will be asked to fill out the 
PIH questionnaire at the start and the end of the pilot which measures how the 
patient manages his/her own disease. Finally, to evaluate the patient experience 
with the overall implementation of the Stroke Box, we will ask them to fill out the 
MAUQ questionnaire at the end of the study which includes questions on the 
technical ease-of-use, the general appearance and usefulness of the Stroke Box. 
Moreover, we will evaluate the GP experience with the Stroke Box via the AIM, IAM 
and FIM25 questionnaires for healthcare professionals which are four-item measures 
of implementation outcomes that are often considered “leading indicators” of 
implementation success.26 An overview of the questionnaires used is given in the 
Table below. 
Implementation will be assessed by the Reach Efficacy Adoption Implementation 
Maintenance (RE-AIM) model with a mixed model evaluation based on the 
normalization process theory.21-23 The implementation will be evaluated from the 
perspective of the neurologists, GPs, practice assistant GP and patients.  
 
Subject 
Questionnaire 
Estimated time 
Physical activity 
Short Questionnaire to Assess Health 
enhancing physical activity questionnaire 
(SQUASH)20 
5 min 
Healthy lifestyle intentions 
Healthy lifestyle intentions questionnaire 
4 min 

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Self-management 
Partners In Health (PIH) questionnaire18 
4 min 
Patient experience 
mHealth App Usability Questionnaire 
(MAUQ)24 
4 min 
GP experience 
Acceptability of Intervention Measure 
(AIM), Intervention Appropriateness 
Measure (IAM), and Feasibility of 
Intervention Measure (FIM)25 
3 min 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences. The investigator can decide to withdraw a subject from the study 
for urgent medical reasons. 
 
8.5 Replacement of individual subjects after withdrawal 
If a subject decides to withdraw from the study, they will not be replaced. 
 
8.6 Follow-up of subjects withdrawn from treatment 
Subjects who withdraw from treatment will be followed according to regular medical 
care. 
 
8.7 Premature termination of the study 
Not applicable. 
 
 

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety.  The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 
Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the investigational product. All 
adverse events reported spontaneously by the subject or observed by the 
investigator or his staff will be recorded. 
9.2.2 
Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ 
hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes 
listed above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse 
event. 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 
8 days to complete the initial preliminary report.  
 

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Because this study is without any risks for the patient, we will report all SAEs once 
per year. 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
Not applicable. 
 
9.3 Annual safety report 
Not applicable. 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical 
specialist. SAEs need to be reported until end of study within the Netherlands, as 
defined in the protocol  
 
9.5 [Data Safety Monitoring Board (DSMB) / Safety Committee] 
Not applicable. 
 
 

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10. STATISTICAL ANALYSIS 
10.1 Primary study parameter(s) 
We will use descriptive statistics to assess blood pressure management, patient 
engagement and user-based evaluation of the eHealth infrastructure. We will analyze 
their self-measurement frequency of blood pressure, heart rhythm, weight, and activity 
using the mean measurements per week. The dropout rate will be described and the 
change in blood pressure in mmHg. This will be used as a basis for sample size 
calculation for future trials. 
Moreover, we will use descriptive statistics to assess the clinical characteristics of our 
sample population. 
 
10.2 Secondary study parameter(s)  
We will evaluate the change in lifestyle and user experience using qualitative 
questionnaires. Here we will make a quantitative comparison between questionnaires 
taken at the start and at the end of the study where we take into account the baseline 
characteristics of the patient, the type of stroke at hospital admission and whether the 
patient followed the IkOefenZelf modules as potential confounders. 
 
10.3 Other study parameters 
We will perform a qualitative comparison between GP practices that are used to box vs 
practices that are new with box based on the responses we get from the respective GPs. 
 
10.4 Interim analysis (if applicable) 
Not applicable. 
 
 

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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki 
(version 10, October 2013) and in accordance with the Medical Research Involving 
Human Subjects Act (WMO). 
 
11.2 Recruitment and consent 
Recruitment of patients will be done by the resident physician on duty at that moment. 
He/She will check for potential interest in the study with patients and, in case of consent, 
introduce the researcher. Patients will be asked to participate by a dedicated PhD-
Student during the day or days prior to dehospitalization, after the patient has been 
stabilized after stroke. In case of a TIA visit in the LUMC, patients are asked to participate 
in between clinical procedures during this day. Patients will be given written information 
about the study. Patients are allowed a reflection period of 24 hours if they wish to have 
so. If patients agree to participate, written informed consent will be obtained by a 
dedicated PhD-Student. Of course, patients can refuse participation at any time without a 
reason.  
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
Not applicable. 
 
11.4 Benefits and risks assessment, group relatedness 
Additional to their usual care patients will be asked to fill in several questionnaires at the 
start and end of the study and will measure their blood pressure, activity, weight and 
potentially their heart rhythm regularly. The devices used in the pilots are non-invasive 
and easy to use. 
Potential benefits of participating in this study are both short and long term. In the short 
term, patients may develop an increased awareness with regards to their health, leading 
to an improved lifestyle. This, on the long term may reduce the risk of cardiovascular 
disease by a possible positive change in lifestyle. 
 
A major potential risk is the false sense of safety created by the self-measurements. 
Patients may, incorrectly, assume that a physician constantly monitors their wellbeing and 
therefore not directly seek treatment when this is required. We will therefore explicitly 
make sure this is avoided by indicating this at inclusion, in the patient information form. In 

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the Withings Healthmate app, a notification is also included by default indicating that the 
patient’s data is not monitored by a physician. 
 
11.5 Compensation for injury 
The sponsor requested the accredited METC for dispensation from the statutory 
obligation to provide insurance, because participating in this study is without risks. 
 
11.6 Incentives (if applicable) 
All devices will be provided by the LUMC. Patients do not have to pay for the devices. 
Patients are allowed to keep their devices after the study is finished. This is the same for 
patients who withdraw from the study. 
 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Routine health care data will be accessible through the electronic patient system of the 
GP where the patient is registered. After approval, all necessary patient study data will be 
collected in a coded database. The key to which is available at the research coordinator 
H.J.A. van Os. Only investigators are authorized to look into the data. A key file will be 
made, to be able to trace back each individual patient. Both files will be password 
protected and the password for both files will be changed every three months. No mobile 
data carriers (i.e. USB-drive, DVD) will be used for that purpose.  
Data Collection Forms, Case Report Forms, Informed Consent Forms and all other study 
documentation containing subject information will be stored under locked conditions when 
not in use. Computers and all storage devices containing study data will be password-
protected. Data stored on the computer will use an alphanumeric code to identify the 
subject. Access to data is restricted to study personnel and when required the REC or 
other regulatory bodies as required by law. Essential trial documents and data, as well as 
a data back-up, will be retained for at least fifteen years. The data back-up will be stored 
on the network drive of the principal investigator, within the LUMC. To access this 
network drive, it is required to know the investigator’s password, which is changed every 
three months. Also, it is required to know the passwords to the anonymized database as 
well as the key file, which are also changed every three months. 
 
12.2 Monitoring and Quality Assurance  
This study has been classified as of negligible risk (according to the LUMC risk score form 
V07-F01). We propose to let nurses from LUMC who are independent function as a 
monitor for this research project. 
 
12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 

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the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC at the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason for such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC 
within 15 days, including the reasons for the premature termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC.  
 
12.6 Public disclosure and publication policy 
We expect this project to give information of home monitoring in patients with a high risk 
of neuro- and cardiovascular disease. We will gain information on knowledge 
implementation of "The Box" in primary care. This is of importance to health managers, 
medical professionals and patients. It is our intention to publish the results in a peer 
reviewed medical journal. 
 
 

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13. STRUCTURED RISK ANALYSIS  
13.1 Potential issues of concern 
Not applicable 
 
13.2 Synthesis 
Participating in this study is without any risks. Therefore, chapter 13.1 has been skipped. 
"The Box" is an effective program for home monitoring patients. The extra burden due to 
the research aspect of this study is minimal and is outweighed by the benefits of 
participation. 
 
 
 
 

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