Introduction of EndoSign ® in Management of Barrett's Oesophagus - a Swedish Feasibility Study
Phase: NA
Conditions: Barrett Esophagus
Sponsor: Vastra Gotaland Region

 
 
ISOCLINICAL INVESTIGATION PLAN 
 
 
Introduction of EndoSign ® in management of Barrett’s oesophagus - a 
Swedish feasibility study 
 
 
 
 
 
Version number:  
1.1 
Date:  
2023-11-29 
 
 
Sponsor:  
Västra Götalandsregionen (VGR) 
 
Coordinating 
Investigator  
 
Svein Olav Bratlie, MD, PhD 
Institute of Clinical Sciences - Department of Surgery, 
Gothenburg University, Sweden  
svein.olav.bratlie@vgregion.se 
+46313428218 
 
 
 
 
 
Revision history 
Document version 
Date of Issue 
Summary of Change 
1.0 
2023-07-01 
 
1.1 
2023-11-29 
Minor changes inclusion and 
exclusion criteria 
More details about 
endoscopy procedure 
 
 
 

 
Clinical Investigation Plan 
Study Code: ES-100 
 
 
CIV-ID: CIV-23-06-043373 
 
Version No: 
 
1.1 
Date: 
 
2023-11-29 
 
 
 
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Table Of Contents 
Signatures ............................................................................................................................... 5 
Contact information ................................................................................................................. 8 
Funding and research agreement ................................................................................................ 9 
List of used acronyms and abbreviations ..................................................................................... 9 
1. 
Synopsis .........................................................................................................................11 
2. 
Identification and description of the investigational device....................................................12 
2.1. 
Description of the investigational device......................................................................12 
2.2. 
Intended purpose ......................................................................................................13 
2.3. 
Manufacturer of the investigational device ...................................................................13 
2.4. 
Model/type ..............................................................................................................13 
2.5. 
Target population ......................................................................................................13 
2.6. 
Detailed description of the investigational device and materials coming into contact with the 
human body ........................................................................................................................14 
2.7. 
Medical or surgical procedures ...................................................................................14 
2.8. 
Summary of required training/experience needed ..........................................................14 
2.9. 
Background .............................................................................................................14 
2.10. Rationale of study .....................................................................................................15 
3. 
Risks and clinical benefits of the investigational device and clinical investigation ....................16 
3.1. 
Expected clinical benefits ..........................................................................................16 
3.2. 
Anticipated adverse device effects ..............................................................................17 
3.3. 
Risks associated with participation in the clinical investigation ......................................17 
3.4. 
Steps to be taken to control or mitigate risks ................................................................17 
3.5. 
Rationale for benefit-risk ratio ....................................................................................17 
4. 
Objectives and hypotheses of the clinical investigation .........................................................17 
4.1. 
The purpose of the clinical investigation ......................................................................17 
4.2. 
Objectives and endpoints ...........................................................................................18 
Objective ............................................................................................................................18 
Endpoint ............................................................................................................................18 
5. 
Design of the clinical investigation ....................................................................................20 
5.1. 
General information ..................................................................................................20 

 
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5.2. 
Settings and locations ................................................................................................20 
5.3. 
Study timetable ........................................................................................................20 
5.4. 
Subjects ...................................................................................................................20 
 
Inclusion criteria ................................................................................................20 
 
Exclusion criteria (any of the following) ...............................................................20 
 
Investigation population .....................................................................................21 
 
Criteria and procedures for subject withdrawal or discontinuation. ...........................21 
 
Subject enrolment ..............................................................................................21 
5.5. 
Description of the clinical procedures and diagnostic methods relating to the clinical 
investigation .......................................................................................................................21 
 
EndoSign® test procedure ..................................................................................21 
 
Endoscopy ........................................................................................................22 
 
Follow-up .........................................................................................................23 
 
Adverse events ..................................................................................................23 
 
Flow chart ........................................................................................................23 
Table 1 ...........................................................................................................................23 
6.9 
End of the clinical investigation ..................................................................................24 
6.10 
Biological sampling procedure ...................................................................................24 
6.10.1 
Handling, storage, and destruction of biological samples ........................................24 
6.10.2 
Biobank ............................................................................................................24 
6.11 
Monitoring plan ........................................................................................................24 
7 
Statistical considerations ...................................................................................................25 
7.1 
Sample size justification ............................................................................................25 
8 
Data management and protection .......................................................................................25 
8.1 
Case Report Form .....................................................................................................25 
8.2 
Archiving ................................................................................................................25 
8.3 
Data protection .........................................................................................................26 
9 
Amendments to the CIP ....................................................................................................26 
10 Deviations from the CIP ...................................................................................................26 
11 Device traceability and accountability ................................................................................27 
12 Statements of compliance .................................................................................................27 
12.1 
Compliance to the investigational plan, good clinical practice, and regulations .................27 

 
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12.2 
Ethical review of the clinical investigation ...................................................................27 
12.3 
Insurance .................................................................................................................27 
13 Informed consent process ..................................................................................................28 
13.1 
General process for informed consent ..........................................................................28 
14 Adverse events, adverse device effects and device deficiencies .............................................28 
14.1 
Definitions ...............................................................................................................28 
14.1.1 
Adverse Event ...................................................................................................28 
14.1.2 
Adverse Device Effect ........................................................................................28 
14.1.3 
Serious Adverse Event .......................................................................................29 
14.1.4 
Serious Adverse Device Effect ............................................................................29 
14.1.5 
Unanticipated Serious Adverse Device Effect .......................................................29 
14.1.6 
Device Deficiency .............................................................................................29 
14.2 
Recording and Reporting ...........................................................................................29 
14.2.1 
Recording .........................................................................................................29 
14.2.2 
Reporting ..........................................................................................................30 
14.2.3 
Assessment of Causality .....................................................................................30 
14.3 
List of foreseeable Adverse events ..............................................................................31 
15 Premature termination of the clinical investigation ...............................................................32 
16 Publication policy ............................................................................................................33 
17 Bibliography ...................................................................................................................33 
18 Appendix ........................................................................................................................33 
 
 
 

 
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Signatures 
Sponsor 
I am responsible for ensuring that this CIP includes all essential information to be able to 
conduct this clinical investigation. I will submit the CIP and all other important clinical 
investigation-related information to the responsible investigator(s) so that they can conduct 
the clinical investigation correctly. I am aware that it is my responsibility to hold the staff 
members who work with this clinical investigation informed and trained. 
 
 
 
Sponsor’s signature                                                                  Date 
Printed name 
 
 
 

 
Clinical Investigation Plan 
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Coordinating Investigator  
I have read this CIP and agree that it includes all essential information to be able to conduct 
the clinical investigation. By signing my name below, I agree to conduct the clinical 
investigation in compliance with this Clinical investigation plan, the Declaration of Helsinki, 
SS-EN ISO14155:2020 (Good Clinical Practice), and the current national and international 
regulations governing the conduct of this clinical investigation. 
I will submit this CIP and all other important clinical investigation-related information to the 
staff members and investigators who participate in this clinical investigation, so that they can 
conduct the clinical investigation correctly. I am aware of my responsibility to continuously 
keep the staff members and investigators who work with this clinical investigation informed 
and trained.  
I am aware that quality control of this clinical investigation will be performed in the form of 
monitoring, audit, and possibly inspection. 
 
 
Coordinating Investigator’s signature                                          Date 
Printed name 
 
 
 

 
Clinical Investigation Plan 
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Principal Investigator 
I have read this CIP and agree that it includes all essential information to be able to conduct 
the clinical investigation. By signing my name below, I agree to conduct the clinical 
investigation in compliance with this Clinical investigation plan, the Declaration of Helsinki, 
SS-EN ISO14155:2020 (Good Clinical Practice), and the current national and international 
regulations governing the conduct of this clinical investigation. 
I will submit this CIP and all other important clinical investigation-related information to the 
staff members who participate in this clinical investigation, so that they can conduct the 
clinical investigation correctly. I am aware of my responsibility to continuously keep the staff 
members who work with this clinical investigation informed and trained.  
I am aware that quality control of this clinical investigation will be performed in the form of 
monitoring, audit, and possibly inspection. 
 
 
 
 
Site 
 
 
Principal Investigator’s signature                                                    Date 
 
 
Printed name 
 
 

 
Clinical Investigation Plan 
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Contact information 
 
Role 
 
Sponsor  
Västra Götalandsregionen (VGR) 
 
Coordinating Investigator 
 
Sahlgrenska University Hospital 
Svein Olav Bratlie, MD, PhD 
Institute of Clinical Sciences - Department 
of Surgery, Gothenburg University, Sweden  
+46313428218  
svein.olav.bratlie@vgregion.se 
Principal Investigator 
 
Sahlgrenska University Hospital 
Per Löfdahl, MD 
Institute of Clinical Sciences - Department 
of Surgery, Gothenburg University, Sweden 
+46313428562 
per.lofdahl@vgregion.se 
 
 
Principal Investigator  
 
Karolinska University Hospital 
Stephan Haas, Assistant Professor, Senior 
Consultat 
Center for Digestive Diseases; Karolinska 
University Hospital 
 
stephan.haas@regionstockholm.se 
Principal Investigator  
 
Ersta Hospital 
Anders Thorell, Professor, Consultant 
Surgeon 
Karolinska Institutet, Dep of Clinical 
Science, Danderyds Hospital & Dep of 
Surgery, Ersta Hospital, Stockholm, 
Sweden 
anders.thorell@erstadiakoni.se 
Principal Investigator 
 
Skåne University Hospital 
Martin Jeremiasen, MD, PhD 
Surgery, Department of Clinical Sciences 
Lund, Lund University, Skane University 
Hospital, Lund, Sweden 
 
+46 (0)46172992 
martin.jeremiasen@med.lu.se 
Principal Investigator  
 
Vrinnevi Hospital 
Thomas Franzén, MD, PhD, Associate 
Professor, Senior Consultant Surgeon 
Department of Surgery at Region 
Östergötland/Linköping University 

 
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Role 
 
 
thomas.franzen@regionostergotland.se 
Investigators 
Peter Elbe, MD         
peter.elbe@regionstockholm.se 
Bengt Håkanson, MD, Consultant Surgeon 
bengt.hakanson@erstadiakoni.se 
Staffan Törnudd, MD, Consultant Surgeon 
staffan.tornudd@regionostergotland.se 
 
Advisor 
Rebecca Fitzgerald, Professor             
rcf29@cam.ac.uk 
Study coordinator 
Christina Biörserud, RN, PhD 
Institute of Clinical Sciences - Department 
of Surgery, Gothenburg University, Sweden  
+46313428404 
christina.biorserud@vgregion.se 
Laboratory 
Cyted Head Office, 22 Station Road, 
Cambridge, CB1 2J, UK 
hello@cyted.ai 
 
Funding and research agreement  
This clinical investigation is initiated by academic researchers. The sponsor pays for overall 
costs of the study, e.g. application costs, costs for data management and some material costs. 
Each site pays for its material, laboratory analysis, premises and personnel costs. Some 
material and laboratory costs are funded by Cyted Laboratorium.  
List of used acronyms and abbreviations 
Abbreviation 
Term/Explanation 
ADE 
Adverse Device Effect  
AE 
Adverse Event 
BE 
Barrett's oesophagus 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form  
DD 
Device Deficiency 
DMC 
Data Monitoring Committee 
EMR 
Endoscopic Mucosal Resection 
ESCC 
Esophageal squamous cell carcinoma 
ESD 
Endoscopic Submucosal Dissection  

 
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GCP 
Good Clinical Practice 
GERD 
Gastroesophageal reflux disease 
IB 
Investigator’s Brochure 
IFU 
Instructions for Use 
IM 
Intestinal metaplasia 
SS-EN ISO 
Swedish Standard - European standard International Organization for 
Standardization  
ITT 
Intention-to-treat = including all data from all subjects who have 
participated in the  clinical investigation 
MDCG  
Medical Device Coordination Group 
PMCF 
Post-Market Clinical Follow Up  
PP 
Per Protocol analysis = including only data from subjects who have 
completed the clinical investigation completely in accordance with the 
CIP, with no deviations from the CIP 
RFA 
Radiofrequency ablation  
SADE 
Serious Adverse Device Effect  
SAE  
Serious Adverse Event 
USADE 
Unanticipated Serious Adverse Device Effect 
VAS 
Visual analog scale 
 
 
 

 
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1. Synopsis 
Background and rationale: 
  
Investigational device: 
EndoSign® Cell collection device 
Number of subjects: 
75 (15 per site) 
Inclusion criteria: 
● Patients with histopathologically confirmed 
diagnosis (intestinal metaplasia) of Barrett's 
oesophagus (BE) and at least C0M1 
● Active monitoring with planned surveillance 
endoscopy within 3 to 12 months 
● Age: 18 – 84 years 
Exclusion criteria: 
● Scheduled for other endoscopic treatment (e.g. 
ablation) at the next surveillance endoscopy 
● Alarm symptoms 
○ Dysphagia and/or food sticking 
○ Dyspepsia and weight loss 
○ Dyspepsia and anaemia 
● Patient with a diagnosis of an oropharyngeal, 
oesophageal or gastro-oesophageal tumour 
● Patient who has had treatment to the oesophagus 
e.g. endoscopic mucosal resection, endoscopic 
submucosal dissection, radio frequency ablation, 
surgery within the previous two months 
● Patient known to have gastric or oesophageal 
varices or cirrhosis of the liver 
● Patient with a known anomaly of the oesophagus 
e.g. webbing, pouch, stricture etc 
● Patients unable to give consent 
● Patients who have had a stroke or any other 
neurological disorder where their swallowing has 
been affected  
● Patients who have had a myocardial infarction in 
the last 3 months 
● Patients who have had fundoplication or other 
surgery to oesophagus and proximal stomach 
● Patients using anti-trombotic drugs which cannot 
be temporarily discontinued 

 
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Study objectives: 
● To determine whether it is feasible to use EndoSign 
® Cell collection device in patients with Barrett's 
oesophagus under surveillance 
● Acquire data and experience to assess whether it is 
possible to perform a full scale study in the future 
and identify what design modifications are needed  
● Determine steps necessary for implementation in 
secondary care. 
Study endpoints: 
● Acceptability 
● Safety 
● Assess the feasibility of recruitment 
● Implementation in secondary care 
● Data collection method and outcome measures 
● Preliminary evaluation of histopathological results 
Planned duration of the 
clinical investigation: 
Q4 2023 – Q3 2024 
 
2. Identification and description of the investigational device 
2.1. Description of the investigational device 
EndoSign® Cell collection device is a CE-marked non-endoscopic cell collection device 
used to detect Barrett's oesophagus, early cancer and other oesophageal conditions. It 
consists of a tethered sponge in a gelatine capsule attached to a string that is swallowed 
and when removed from the stomach, it collects cells along its way. The sample is then 
put into a preservative which is stable at room temperature. It is processed in a central 
laboratory and can be assessed for Barrett's biomarker Trefoil Factor 3 (TFF3), atypia and 
will be stained for p53 as an indicator for dysplasia or cancer. 
 

 
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2.2. Intended purpose  
The EndoSign® cell collection device is to be used for the collection of cells from the surface 
of the oesophagus for molecular, cytological, and histological analyses. 
 
The investigational device is CE marked and will be used according to its intended purpose in 
this clinical investigation. 
2.3. Manufacturer of the investigational device 
Name: Cyted Ltd 
Address: 22 Station Road, Cambridge, CB1 2JD United Kingdom 
Contact: +1 508-261-8000 
2.4. Model/type 
Generic denomination: Cell Collection Device 
Device name: EndoSign® Cell collection device 
Device trade name: ES-CYT-102 
Model: Not applicable 
Medical device classification: Class I 
European Medical Device nomenclature: A99 (Devices for administration, withdrawal 
and collection- other) 
2.5. Target population 
Target Population: Patient’s aged 18 and over 

 
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Intended User Group: The EndoSign® Cell collection device is to be administered by 
trained healthcare professionals such as medical doctors, registered nurses, and other 
qualified health professionals trained in use of the device 
2.6. Detailed description of the investigational device and materials coming into 
contact with the human body 
See Appendix A – EndoSign® Cell collection device instruction manual  
2.7. Medical or surgical procedures 
See Appendix A – EndoSign® Cell collection device instruction manual 
2.8. Summary of required training/experience needed 
Any personnel administering the EndoSign® will undergo a training webinar and in 
person training until they are signed off as competent (usually 8-10 procedures).  
2.9. Background 
The incidence of esophageal adenocarcinoma has increased dramatically in the Western 
world in recent decades [1]. Barrett's oesophagus is a premalignant condition with an 
approximately 0.3% annual risk of developing into adenocarcinoma[2]. Globally, 
Esophageal squamous cell carcinoma (ESCC) still accounts for 90% of new cases of 
esophageal cancer[3], but in Sweden, adenocarcinoma is more common. 
Symptomatic oesophageal cancer has a poor prognosis as the disease is often detected in 
late stages. However, the prognosis for early/superficial cancer is very good. 
According to epidemiological studies the prevalence of Barrett’s oesophagus is between 
0,5 - 2%. [4] Less than 10% of patients resected for adenocarcinoma have previously been 
diagnosed with Barrett's oesophagus[5] and therefore in most cases of esophageal 
adenocarcinoma there has been no way to prevent progress. 
There are now good endoscopic treatments for dysplasia and early cancer, such as 
endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD) and 
radiofrequency ablation (RFA).  
 
Patients diagnosed with Barrett's oesophagus are usually included in a surveillance 
program according to European guidelines [6]. Surveillance intervals are stratified 
according to BE lengths. Studies have shown that surveillance leads to earlier detection of 
cancer and improved survival[7, 8]. Endoscopic surveillance is an invasive method with 
high costs. Some patients have difficulty tolerating upper GI endoscopy, which can 
therefore lead to discomfort, stress and anxiety.[9]. There is a reason to believe that the 
number of surveillance endoscopies in patients at low-risk of developing cancer can be 
reduced. On the other hand, high-risk patients should undergo intensified follow-up and 
treatment in tertiary referral centers.  
 
There is currently no evidence that general screening for BE lowers mortality in EAC and 
endoscopic screening for Barrett's oesophagus is only considered in high risk groups. [6, 
10] 

 
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The EndoSign® is a CE-marked non-endoscopic cell collection primarily used for the 
detection of Barrett's oesophagus, early cancer, and other oesophageal conditions such as 
eosinophilic esophagitis. The device is composed of a tethered sponge housed within a 
HPMC capsule, which is connected to a string for easy retrieval. 
 
When swallowed and subsequently pulled out of the stomach, it gathers cell samples 
along its path. These samples are then preserved in a room temperature stable medium. 
They are subsequently sent to a central laboratory for processing and can be analysed for 
Barrett's biomarker Trefoil Factor 3 (TFF3), atypia, and stained for p53, which serves as 
an indicator for dysplasia or cancer. 
 
The EndoSign®'s cell collection, sample processing, and analysis capabilities parallel 
those of the previously used Cytosponge. Cytosponge-TFF3 test has been shown to detect 
Barrett’s oesophagus effectively. A review of 5 studies underscored the safety and high 
patient acceptability of this procedure [11]. Remarkably, over 90% of patients succeed in 
swallowing the Cytosponge on the first try with no serious adverse events reported to date. 
The risk of detachment is minimal, being less than 1:5,000, and the most common side 
effect is a sore throat 
 
 
Iqbal et al showed in a systematic review that Cytosponge-TFF3 detects Barrett's 
oesophagus with a sensitivity and specificity of 81% and 91%, respectively. [12] 
 
EndoSign® is a new cell collection device was recently introduced and is currently being 
evaluated in the Cytoprime 2 project. Based on the equivalency claims to the 
Cytosponge™ (see Appendix B), the device has been adopted for routine use by National 
Health Services, England. The EndoSign capsule sponge is: 
● Simple for practitioners to use, streamlining training and clinic delivery 
● Quick to administer, reducing the time taken for the procedure 
● Designed to be easy to swallow, improving patient experience 
● Affordable with a cost reduction per unit compared to Cytosponge™ 
● Safe during withdrawal due to tvalidated and improved mechanical properties of the 
thread attachment. 
 
2.10. Rationale of study 
When it comes to surveillance of Barrett's oesophagus, there is a need to enhance the 
clinical pathway and streamline the use of resources. There is also a reason to evaluate 
and introduce alternative surveillance methods that are better tolerated by patients. Cell 
collection device with sponge can be one such method, EndoSign® has not yet been used 
in Swedish healthcare and the method therefore needs to be evaluated in our setting. The 
similar cell collection device Cytosponge have been used as a triage tool, patients under 
surveillance could be divided into various risk groups. This might direct medical 
interventions toward people who are most at risk of developing cancer. In the future, Cell 

 
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collection device with sponge might be used to screen patients with gastroesophageal 
reflux disease (GERD) for Barrett's oesophagus. 
 
In order to be able to conduct high-quality research on Barrett's oesophagus, a sufficiently 
large patient base is needed. Both regional and county hospitals conduct surveillance, so it 
would be advantageous if they all collaborated in future research on Barrett's oesophagus 
in Sweden. 
 
With this feasibility study, it is possible to introduce and assess EndoSign® within the 
Swedish Barrett network at a number of hospitals in a controlled manner, which can serve 
as a crucial foundation for carrying out larger multi-center studies in the future. 
3. Risks and clinical benefits of the investigational device and clinical 
investigation 
3.1. Expected clinical benefits 
Early detection of oesophageal cancer is the single most important factor in improving the 
outcome of treatment. This is made possible by identifying patients at risk of developing 
oesophageal cancer and following these in a surveillance protocol.  
 
Today, no screening is being conducted for Barrett's oesophagus but this is debated. ESGE 
guidelines recommend screening of high-risk patients. Cell collection device on a sponge, 
such as Cytosponge-TFF3, has shown promising results in targeted screening of Barrett's 
oesophagus in patients with GERD. 
 
Surveillance of Barrett's is conducted with repeated endoscopies where the quality 
depends on the experience and skill of the endoscopist. There are studies that have shown 
that endoscopists to varying extent fail to adhere to recommended guidelines regarding 
e.g. how biopsies should be taken. 
 
The availability of endoscopy differs between hospitals and has been generally limited 
during the COVID-19 pandemic. Surveillance is costly and with the implementation of 
cell collection device with sponge it could be possible to re-design clinical pathways and 
reduce the number of endoscopies needed, which would also increase availability. Most 
patients will not develop cancer and it would be desirable to prioritize endoscopy 
resources to the patients who benefit the most.  
 
Cytosponge-TFF3 has been used as a triage to prioritize patients to endoscopy.[13] There 
is a need to study and validate whether the use of sponge devices coupled with TFF3-
analysis in surveillance can improve surveillance, reduce resource utilization and improve 
outcomes in patients. This feasibility study is an important first step in order to be able to 
conduct larger studies in the future. 
 

 
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TFF3- analyses of the cell materials from the sponge is performed by Cyted laboratory in 
the UK and there is reason to evaluate how the logistics of this work. 
3.2. Anticipated adverse device effects 
Potential complications include: Mucosal laceration or perforation requiring secondary 
intervention, Bleeding, Aspiration, Intestinal obstruction, Tissue damage, Dysphagia, 
Pain, Sore throat., Dyspepsia indigestion reflux, Oesophageal or gastric pain, Nausea or 
vomiting, Voice disturbance, Diarrhoea or an upset stomach, Chest pain or discomfort, 
Vasovagal attack. Headache, Hernia, Detachment of the sponge.  
3.3. Risks associated with participation in the clinical investigation 
Participation in the clinical investigations means that the subject will undergo at least one 
EndoSign® test and a gastroscopy, which entails (albeit a small) risk of complications. 
3.4. Steps to be taken to control or mitigate risks 
The clinical investigation is conducted in hospitals, which are well-equipped to handle any 
complications or unexpected results. Healthcare professionals leading the study sessions 
are knowledgeable about the research project and the treatments being used. 
3.5. Rationale for benefit-risk ratio 
The advantages for the individual subject are an in-depth investigation (in addition to 
surveillance) of Barrett's esophagus where the EndoSign® coupled with TFF3-analysis 
can detect atypia, dysplasia and early cancer. 
 
In the long term, this and future studies can potentially improve the quality of surveillance 
and treatment of Barrett's esophagus. 
4. Objectives and hypotheses of the clinical investigation 
4.1. The purpose of the clinical investigation 
• To determine whether it is feasible to use EndoSign® with TFF3 analysis coupled 
with p53 and atypia in patients with Barrett's oesophagus under surveillance 
• Acquire data and experience to assess whether it is possible to perform a full scale 
study in the future and identify what design modifications are needed  
• Determine steps necessary for implementation in secondary care.  
 

 
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4.2. Objectives and endpoints 
Objective 
Endpoint 
 
To assess patient 
acceptability for 
EndoSign® 
i. 
EndoSign® test 
experience compared 
to upper GI endoscopy 
ii. 
EndoSign® swallowing 
failures 
iii. 
Willingness to 
undergo EndoSign® 
again 
i. 
Adapted ENDOPREM 
and a visual analog 
scale to rate experience 
ii. 
Number of patients that 
are unable to swallow 
and attempts made 
iii. 
Questionnaire 
 
To assess safety of 
EndoSign®  in secondary 
care 
i. 
Rates of adverse 
events up to 7 days 
after EndoSign®  test 
i. 
All adverse events 
reported during 
procedure, ER-visits 
and 7-day follow up.  
To assess the feasibility 
of recruitment 
 
i. 
Proportion of eligible 
patients who 
participate 
ii. 
Quantify the number 
of patients that 
potentially can be 
recruited 
 
i. 
Patients accepting 
invite and consent 
divided by total of 
patients invited 
ii. 
Number of patients in 
surveillance per site  
To assess the 
implementation of 
EndoSign® 
i. 
Costs and resources 
required to introduce 
EndoSign® in 
secondary care 
ii. 
Determine technology 
and equipment needs 
and training 
iii. 
Clinical staff 
experience and 
acceptability of 
EndoSign®  in regards 
of training, skills, 
reliability, side effects 
and user information 
i. 
Interviews with staff 
and healthcare 
professionals  
ii. 
Equipment needed per 
session  
iii. 
Number of sessions 
needed until fully 
trained.  
iii. 
Interview with clinical 
staff 
iv. 
Number of days from 
samples are sent to 
laboratory in UK until 
test results arrive 

 
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iv. 
Logistics of TFF3-
analysis of EndoSign®  
and response times 
To evaluate data 
collection method and 
outcome measures 
 
i. 
Feasibility of 
questionnaires 
ii. 
Response rate for 
questionnaires 
iii. 
Withdrawal and drop-
out rates 
iv. 
Follow-up rates 
i. 
Validate adapted 
ENDOPREM 
ii. 
The proportion of 
patients who completes 
each questionnaire 
iii. 
The proportion of 
patients who, for 
various reasons, do not 
complete the study 
iv. 
The proportion of 
patients who complete 
the follow-up 
Preliminary evaluation of 
results and patient 
outcomes 
 
i. 
Demographics of the 
patient group 
ii. 
Patient reported 
outcome, 
questionnaire 
iii. 
EndoSign® -TFF3 test 
results (atypia, p53 
status, TFF3 status) 
iv. 
Number of inadequate 
samples 
v. 
Classification of 
patients into different 
risk groups and show 
preliminary results 
when used as triage 
method 
vi. 
Results from 
endoscopy and 
biopsies and compare 
to EndoSign®  test 
results 
 
i. 
Data collected and 
reported in the CRF 
collected at first visit 
ii. 
VAS, adapted 
ENDOPREM, EQ-5D 
iii. 
Proportion of patients 
with adequate sampling 
with positive test 
iv. 
Reason for not 
generating result  
v. 
Number of patients 
categorizes into low, 
moderate and high risk 
according to p53 and 
atypia, combined with 
clinical factors age, sex, 
length of segment.  
vi. 
Length of BE-segment, 
visible lesion, intestinal 
metaplasia, low-grade 
dysplasia, high grade 
dysplasia 

 
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5. Design of the clinical investigation 
5.1. General information 
This clinical investigation is designed as a single-armed multi-center feasibility study and 
is expected to be conducted 2023/2024. The aim is to include 15 consecutive patients per 
site (75 patients in total) attending routine endoscopy in Barrett’s esophagus surveillance. 
 
5.2. Settings and locations 
The study will be conducted at the following hospitals: 
● Sahlgrenska University Hospital, Gothenburg 
● Karolinska University Hospital, Stockholm 
● Skåne University Hospital, Lund 
● Ersta Hospital, Stockholm 
● Vrinnevi Hospital, Norrköping 
 
5.3. Study timetable 
 
Estimated subject enrollment start Dec 1st 2023 
Estimated last enrollment: April 1st 2024 
Last follow up: Oct 31st 2024 
5.4. Subjects 
 
Inclusion criteria 
• Patients with histopathologically confirmed diagnosis (intestinal metaplasia) of 
Barrett's oesophagus (BE) and at least C0M1 
• Active monitoring with planned surveillance endoscopy within 3 to 12 months 
• Age 18 – 84 years 
 
Exclusion criteria (any of the following) 
• Scheduled for other endoscopic treatment (e.g. ablation) at the next surveillance 
endoscopy 
• Alarm symptoms 
o Dysphagia and/or food sticking 
o Dyspepsia and weight loss 
o Dyspepsia and anaemia 
• Patient with a diagnosis of an oropharyngeal, oesophageal, or gastro-oesophageal 
tumour 

 
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• Patient who has had treatment to the oesophagus e.g. endoscopic mucosal 
resection, endoscopic submucosal dissection, radio frequency ablation, surgery 
within the previous two months 
• Patient known to have oesophageal varices or cirrhosis of the liver 
• Patient with a known anomaly of the oesophagus e.g. webbing, pouch, stricture 
etc.  
• Patients unable to give consent 
• Patients who have had a stroke or any other neurological disorder where their 
swallowing has been affected  
• Patients who have had a myocardial infarction in the last 3 months 
• Patients who have had fundoplication or other surgery to oesophagus and 
proximal stomach 
• Patients using anti-trombotic drugs which cannot be temporarily discontinued 
 
 
Investigation population 
75 (15 patients per site) 
 
 
Criteria and procedures for subject withdrawal or discontinuation. 
All study participants may discontinue their participation in the study at any time 
without this affecting their continued surveillance and future treatments. Collected 
data for the patient will be retained or destroyed depending on the patient's desire 
 
 
Subject enrolment 
A nurse or physician identifies eligible patients to undergo a gastroscopy as part of 
Barrett's oesophagus surveillance. These patients are asked for participation in the 
study via an invitation letter or telephone call. Interested patients will be provided 
with written information about the study and EndoSign® information leaflet. If the 
patient chooses to participate, written informed consent will be obtained and stored 
locally. Each secondary care clinic will maintain an anonymized screening log that 
lists all screened patients. Recruitment continues until 75 patients are included.  
5.5. Description of the clinical procedures and diagnostic methods relating to the 
clinical investigation 
 
EndoSign® test procedure 
Study patients are referred to a separate visit to undergo the EndoSign® test. They 
will be required to refrain from food and liquids for 3–4 hours before the visit and 
they will respond to a socio-demographic- and clinical form and assessment of 
symptoms and EQ-5D.  
 

 
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The EndoSign® is administered by a nurse or healthcare professional that has 
undergone adequate procedure training. The procedure time is 7 minutes with an 
overall clinic session taking about 20- 30minutes in total. 
 
The patient is asked to swallow the EndoSign® capsule together with some water. 
The end of the suture is attached to an applicator which the nurse hands to the patient 
to hold. The capsule will be in the patient’s stomach for around 7minutes until it 
dissolves completely, allowing the sponge to expand to its full size. The sponge is 
withdrawn by the nurse using the suture. The patient can choose to get local 
anaesthetic spray into their throat before the sponge is removed. The sponge is then 
placed in a sample collection kit provided by Cyted and secured with a patient 
number identification label. 
 
The patient will be instructed to try again if they are unable to swallow the capsule 
the first time. Before being labelled as “EndoSign® swallowing failure," patients will 
have a maximum of two failed attempts.  
 
After 30 minutes, patients are asked to answer forms about anxiety level and 
procedure-specific questions to evaluate acceptability. The visual analog scale (VAS) 
and a quick questionnaire using the adapted ENDOPREM measure will be used.  
 
 
Endoscopy 
The subject is called to a surveillance endoscopy according to previous planning and 
undergo a standard upper GI endoscopy in accordance with ESGE guidelines. It can 
be performed with or without sedation. 
 
Diagnostic endoscopic landmarks for BE will be recorded written and with photo 
documentation. 
 
Biopsies will be taken according to a strict protocol including biopsies from the 
cardia. Mapping biopsies will be taken every 2 cm for all endoscopies where BE is 
discovered (in all 4 quadrants) according to the Seattle surveillance protocol. In 
addition, endoscopically-suspicious areas will be targeted for biopsies.  
 
After 30 minutes, patients are asked to answer forms about anxiety level and 
procedure-specific questions to evaluate acceptability. The visual analog scale (VAS) 
and a quick questionnaire using the adapted ENDOPREM measure will be used.  
 
The pathologist will process and examine each biopsy sample in accordance with 
standard clinical practice. Cases with dysplasia will be reviewed and discussed with 
an additional pathologist. When reviewing the biopsy data, the pathologists will be 
blinded to the result of the EndoSign® test. 
 
Participants will receive a letter from the endoscopist informing them of the 
endoscopy results in the usual manner. 

 
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Follow-up 
At follow-up, 7 and 90 days after both EndoSign® test and endoscopy, 
questionnaires and forms (adapted ENDOPREM, VAS, EQ-5D) will be sent to the 
patient either by mail or as a survey via REDCap.   
When the EndoSign® -TFF3 results arrive, these are filled into the database and a 
standardized feedback letter is sent to the patient with the test result. Patients will be 
given the option to phone the nurse administering the test for more information. If 
the cytology test result indicates atypia or dysplasia (p53 positive), the patient is 
called for a gastroscopy within 2 weeks and otherwise the patient will continue to be 
followed according to the previous surveillance regimen. 
 
 
Adverse events 
The research nurse will notify the endoscopist immediately if there is a EndoSign® 
detachment or other adverse event. A qualified healthcare expert would immediately 
remove the EndoSign® in the never-reported but theoretically possible case of 
inhalation.  
 
Subjects receive emergency contact information to be able to quickly make contact 
in the case of adverse events. 
 
 
Flow chart 
Table 1 
 
Procedure 
Visit 1 - 
EndoSign® 
Follow-up, 
7 day and 
90 days 
Visit 2 – 
Gastroscopy  
Follow-up, 
7 and 90 
days 
Incl/exclusion 
criteria 
√ 
 
 
 
Informed consent  
√ 
 
 
 
Medical history/ 
concomitant 
medications 
√ 
 
 
 
Patient reported 
outcome (VAS, 
ENDOPREM) 
√ 
√ 
√ 
√ 
Questionnaire, 
EQ-5D 
√ 
√ 
√ 
√ 
Adverse Events  
√ 
√ 
√ 
√ 
Clinical 
investigation end 
 
 
 
√ 
 

 
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6.9 
End of the clinical investigation 
The clinical investigation ends when the last subject has completed the last follow-up. The 
sponsor will notify the Swedish Medical Products Agency within 15 days after the end of 
the clinical investigation and send the clinical investigation report within 1 year after the 
end of the clinical investigation including an easily understandable summary.  
6.10 Biological sampling procedure 
6.10.1 Handling, storage, and destruction of biological samples 
The TFF3-samples are handled and analysed in accordance with a specified SOP and 
transported directly from the hospital to the central laboratory (Cyted) in the UK. The 
samples will be pseudonymized according to the specific clinical performance study 
identification number. Each sample will be processed using H&E (hematoxylin and 
eosin) and TFF3 immunohistochemistry. In all cases where atypia is detected, a p53 
staining will be performed as an indicator of significant pathology. All samples will be 
analysed within six months and destroyed immediately after the analysis.  
 
A special material transfer agreement will be drawn up for each hospital so that the 
samples can be sent and analysed in the UK (outside the EU). This information will 
also appear in the consent documents. 
 
6.10.2 Biobank 
This study is covered by the exception rule in the Biobank Act, which means that the 
Biobank Act does not apply to samples intended for research and which are analyzed 
within six months of the time of sampling and destroyed immediately after the 
analysis. Therefore, no biobank agreement will be signed, and no samples will be 
registered and/or stored. 
 
6.11 Monitoring plan 
The clinical investigation will be monitored by an independent monitor before the clinical 
investigation begins, during the clinical investigation conduct, and after the clinical 
investigation has been completed, so as to ensure that the clinical investigation is carried 
out according to the CIP and that data is collected, documented, and reported according to 
SS-EN ISO 14155:2020 and applicable ethical and regulatory requirements. Monitoring is 
performed as per the investigation’s monitoring plan and is intended to ensure that the 
subject’s rights, safety, and well-being are met as well as data in the CRF are complete, 
correct, and consistent with the source data. 

 
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7 Statistical considerations 
7.1 
Sample size justification 
The sample size needs to be in the upper range of what is typical in feasibility studies 
because the studies are conducted at multiple hospitals. 75 patients in total, or 15 patients 
per hospital, are considered to be enough to determine the feasibility of EndoSign®.  
A formal power calculation or sample size calculation is not necessary for this study 
because accuracy and effectiveness of the technology will not be evaluated. 
8 Data management and protection 
Data for all subjects who participate in the clinical investigation are coded with a specific 
clinical investigation identification number. All subjects are registered in a subject 
identification list (subject enrolment and identification list) that connects the subject’s 
name and personal number with a clinical investigation identification number. 
All data will be registered, managed, and stored in a manner that enables correct reporting, 
interpretation, and verification.  
8.1 
Case Report Form 
All data will be anonymized and stored in an electronic study database (e-CRF) using 
REDCap. The following data will be collected and reported directly in the CRF: 
● Sex, age, BMI 
● Smoking / Alcohol consumption 
● Use of PPI or other acid suppressants 
● Year of diagnosis 
● Prague classification according to previous endoscopy 
● Previous dysplasia 
● Previous endoscopic treatments 
● Patient-reported experience measurement data (ENDOPREM, VAS) 
● Questionnaire results (including EQ-5D) 
● EndoSign® -TFF3 test results 
● Gastroscopy results (including biopsy results) 
● Adverse events 
 
Both written and electronic changes or corrections on CRF will be dated, initialed and 
explained (if necessary) 
8.2 
Archiving 
The PI and sponsor will maintain the essential clinical investigation documents in the 
investigation site files archive and sponsor files archive, respectively. The sponsor shall 
keep all documentation and data for at least years after the clinical investigation has 
ended. The PI will archive all local investigation documentation for at least 10 years in 
accordance with Swedish law (Chapter 10, LVFS 2011:19). All documentation and data 

 
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will be stored at the Department of Surgery at Sahlgrenska University hospital, 
Gothenburg. 
8.3 
Data protection 
If any part of the data is handled by any other organization, inside or outside the European 
Union, appropriate agreements and/or other documentation will be established, to ensure 
that the data processing is performed in accordance with the provisions of the General 
Data Protection Regulation (EU ordinance 2016/679, GDPR) and other relevant 
legislation, before any data transfer takes place. 
 
The content of the informed consent form shall comply with relevant integrity and data 
protection legislation. In the subject information and the informed consent form, the 
subject will be given complete information about how collection, use and publication of 
their clinical investigation data will take place. The subject information and the informed 
consent form will explain how clinical investigation data are stored to maintain 
confidentiality in accordance with national data legislation. All information processed by 
the sponsor will be pseudonymized and identified with Study-ID.  
 
The informed consent form will also explain that for verification of the data, authorized 
representatives of the sponsor, as well as relevant authority, may require access to parts of 
medical records or study records that are relevant to the clinical investigation, including 
the subject’s medical history. 
 
9 Amendments to the CIP 
Amendments to the CIP will be agreed upon between the coordinating investigator and the 
sponsor. Substantial modifications must be approved by the Swedish Ethical Review 
Authority and/or the Swedish Medical Products Agency (as applicable) before 
implementation. 
10 Deviations from the CIP 
Investigator(s) are not allowed to deviate from the CIP except if it is for the protection of 
the subject´s rights, safety, or well-being under emergency circumstances. All such 
deviations shall be documented and reported to the sponsor, the Swedish Medical 
Products Agency and/or the Swedish Ethical Review Authority (as applicable) as soon as 
possible. 
All deviations shall be documented with an explanation and reported to the sponsor.  
Deviations will be reviewed by the sponsor and reported to the appropriate regulatory 
bodies as required. 

 
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11 Device traceability and accountability 
The investigational device(s) will only be used in the clinical investigation and according 
to the clinical investigation plan. The sponsor provides the site with written instructions 
and technical support.    
The investigator will keep records to document the physical location of all investigational 
devices from shipment to return/disposal. This record should include: name(s) of clinical 
investigation personnel  who received, used, returned, or disposed the device, the date of 
receipt, identification and quantity of each investigational device (batch number/serial 
number or unique code), the expiry date, the date or dates of use, subject study-ID, date on 
which the investigational device was returned, the date of return of unused, expired or 
malfunctioning investigational devices, and the date and documentation of disposal of the 
investigational devices as per instructions of the sponsor.  
12 Statements of compliance 
12.1 Compliance to the investigational plan, good clinical practice, and 
regulations 
The clinical investigation will be conducted in accordance with GCP, the clinical 
investigation plan, the ethical principles of the Declaration of Helsinki, the principles of 
SS-EN ISO 14155:2020 and current national and international regulations governing this 
clinical investigation. This is to ensure the safety and integrity of the subjects as well as 
the quality of the data collected. 
12.2 Ethical review of the clinical investigation 
The clinical investigation will commence when written approval/favorable opinion from 
the Swedish Ethical Review Authority has been received and at least 30 days has passed 
since the notification was confirmed by the Swedish Medical Products Agency. 
The final version of the informed consent form and other information provided to 
subjects, must be approved or given a written positive opinion by the Swedish Ethical 
Review Authority and/or the Swedish Medical Products Agency. The Swedish Ethical 
Review Authority and the Swedish Medical Products Agency must be informed of any 
changes in the CIP in accordance with the current requirements. 
12.3 Insurance 
According to the Patient Injury Act, voluntary subjects are equated with patients. The 
Swedish healthcare regions have signed a patient insurance with Landstingens Ömsesidiga 
Försäkringsbolag, LÖF 

 
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13 Informed consent process 
13.1 General process for informed consent 
The principal investigator shall ensure that the subject is given full and adequate oral and 
written information about the clinical investigation, its purpose, any risks and benefits as 
well as inclusion and exclusion criteria. Subjects must also be informed that they are free 
to discontinue their participation in the clinical investigation at any time without having to 
provide a reason. Subjects shall be given the opportunity to ask questions and be allowed 
time to consider the provided information and participation in the clinical investigation. If 
the person chooses to participate, both the subject and the investigator shall sign the 
informed consent form. A copy of the subject information as well as a copy of the 
informed consent form shall be provided to the subject. The subject’s signed and dated 
informed consent must be obtained before performing any activity specific to the clinical 
investigation. The process shall be documented in the subject’s source documents and the 
signed informed consents shall be maintained with the essential documents. If new 
information becomes available that can significantly affect a subject's future health and 
medical care, that information shall be provided to the affected subject(s) in written form. 
If new information is added to the clinical investigation, the subject has the right to 
reconsider whether he/she will continue their participation. 
14 Adverse events, adverse device effects and device deficiencies 
14.1 Definitions 
14.1.1 Adverse Event 
An Adverse Event (AE) is untoward medical occurrence, unintended disease or injury 
or any untoward clinical signs, including an abnormal laboratory finding, in subjects, 
users or other persons, in the context of a clinical investigation, whether or not related 
to the investigational device. 
This definition includes events that are anticipated as well as unanticipated events 
This definition includes events occurring in the context of a clinical investigation 
related to the investigational device, the comparator or the procedures involved. 
14.1.2 Adverse Device Effect 
An Adverse Device Effect (ADE) is any AE related to the use of an investigational 
medical device. 
This definition includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any 
malfunction of the investigational medical device. 
This definition includes any event resulting from use error or from intentional misuse 
of the investigational medical device. 
This includes ‘comparator’ if the comparator is a medical device. 

 
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14.1.3 Serious Adverse Event 
A Serious Adverse Event (SAE) is any AE that led to any of the following: 
a) death, 
b) serious deterioration in the health of the subject, 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, 
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 
14.1.4 Serious Adverse Device Effect 
A Serious Adverse Device Effect (SADE) is an ADE that has resulted in any of the 
consequences characteristic of a serious adverse event. 
SAEs related to procedures imposed by the clinical investigation plan but not with the 
use of the device shall not be considered Serious Adverse Device Effects. 
14.1.5 Unanticipated Serious Adverse Device Effect 
An Unanticipated SADE is an effect which by its nature, incidence, severity or 
outcome has not been identified in the current risk assessment. Procedures associated 
with the use of a device shall be addressed in the risk assessment, which makes it 
possible to determine whether the procedure related SAEs are Unanticipated Serious 
Adverse Device Effect or not. SAEs related to procedures imposed by the clinical 
investigation plan but not with the use of the device shall not be considered Serious 
Adverse Device Effects. 
For the anticipated adverse device effects, se section 4.2 above. 
14.1.6 Device Deficiency 
A Device Deficiency (DD) is any inadequacy in the identity, quality, durability, 
reliability, safety or performance of an investigational device, including malfunction, 
use errors or inadequacy in information supplied by the manufacturer. 
14.2 Recording and Reporting 
14.2.1 Recording 
The principal investigator or an authorized designee will record: 
• 
all AEs 
• 
all SAEs;  
• 
all DDs; 
• 
any new finding in relation to any of the above-mentioned events.  

 
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14.2.2 Reporting 
The investigators will report all SAEs and DDs to the sponsor, immediately but not 
later than 3 calendar days after investigation site study personnel’s awareness of the 
event.  
The sponsor will report to the Swedish Medical Products Agency all of the following 
reportable events:  
• 
any SAE that has a causal relationship with the investigational device or the investigation 
procedure, or where such causal relationship is reasonably possible; 
• 
any DD that might have led to a SAE if appropriate action had not been taken, 
intervention had not occurred, or circumstances had been less fortunate; and 
• 
any new findings in relation to any event referred to above.  
Reporting by the sponsor will be done by filling out the “Summary Reporting Form” 
(MDCG 2020-10/2). The form will be filled in/updated for each reportable event or 
for new findings/updates to already reported events. The form will be transmitted to 
the Swedish Medical Products Agency. For events that indicate an imminent risk of 
death, serious injury, or serious illness and that requires prompt remedial action for 
other patients/subjects, users or other persons or a new finding to it will be reported 
immediately, but not later than 2 calendar days after awareness by sponsor of a new 
reportable event or of new information in relation with an already reported event. Any 
other reportable events or a new finding/update to it will be reported immediately, but 
not later than 7 calendar days following the date of awareness by the sponsor of the 
new reportable event or of new information in relation with an already reported event. 
 
14.2.3 Assessment of Causality 
The relationship between each adverse event and the investigational device, the 
comparator and the investigation procedure will be assessed and recorded by the 
investigator and sponsor. For assessment of causality, the IB and the risk analysis 
report will be consulted. The sponsor and investigator will distinguish between SAEs 
related to the investigational device and those related to the procedures, relatedness to 
both is possible.   
Each SAE will be classified according to four different levels of causality: 
1. Not related  
Relationship to the device, comparator or procedures can be excluded when: 
- the event has no temporal relationship with the use of the investigational device, or the 
procedures related to application of the investigational device; 
- the SAE does not follow a known response pattern to the medical device (if the response 
pattern is previously known) and is biologically implausible; 
- the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or increase of 
the level of activation/exposure), do not impact on the serious adverse event; 
- the event involves a body-site or an organ that cannot be affected by the device or 
procedure; 
- the SAE can be attributed to another cause (e.g. an underlying or concurrent illness/ 
clinical condition, an effect of another device, drug, treatment or other risk factors); 

 
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- the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable; 
 
In order to establish the non-relatedness, not all the criteria listed above might be met at 
the same time, depending on the type of device/procedures and the SAE. 
 
2. Possible 
The relationship with the use of the investigational device or comparator, or the 
relationship with procedures, is weak but cannot be ruled out completely. Alternative 
causes are also possible (e.g. an underlying or concurrent illness/ clinical condition or/and 
an effect of another device, drug or treatment). Cases where relatedness cannot be 
assessed, or no information has been obtained shall also be classified as possible. 
 
3. Probable 
The relationship with the use of the investigational device or comparator, or the 
relationship with procedures, seems relevant and/or the event cannot be reasonably 
explained by another cause. 
 
4. Causal relationship 
The SAE is associated with the investigational device, comparator or with procedures 
beyond reasonable doubt when: 
- the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
- the event has a temporal relationship with investigational device use/application or 
procedures; 
- the event involves a body-site or organ that 
o the investigational device or procedures are applied to; 
o the investigational device or procedures have an effect on; 
- the serious adverse event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
- the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the SAE (when clinically feasible); 
- other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and 
an effect of another device, drug or treatment) have been adequately ruled out; 
- harm to the subject is due to error in use; 
- the event depends on a false result given by the investigational device used for diagnosis, 
when applicable; 
 
In order to establish the relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the SAE. 
14.3 List of foreseeable Adverse events 
 
Foreseeable adverse events* 
Incidence 
(%) 
Mitigation and treatment 
Adverse events 
 
Sore throat 
44 
Conservative treatment, analgesics 
Dyspepsia indigestion reflux  
13 
Conservative treatment, acid suppressants 
Oesophageal or gastric pain  
11 
Conservative treatment, analgesics 

 
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Feeling non-specifically unwell 
6 
Conservative treatment 
Nausea or vomiting  
6  
Conservative treatment, antiemetics 
Voice disturbance  
3  
Conservative treatment 
Diarrhea or an upset stomach  
4 
 
Chest pain or discomfort  
1  
Conservative treatment, analgesics 
Allergic reaction  
1 
Conservative treatment, allergy treatment 
Anxiety  
1 
Conservative treatment 
Bad taste  
1 
Conservative treatment 
Paroxysmal positional vertigo  
1 
Conservative treatment 
Blood clot excretion  
1 
Conservative treatment 
Vasovagal attack 
1 
Conservative treatment 
Nosebleed  
1 
Conservative treatment 
Headache 
1 
Conservative treatment, analgesics 
Bloodshot eye 
1 
Conservative treatment 
Chest infection 
1 
Conservative treatment, antibiotics 
Abrasion 
1 
Conservative treatment 
Fall 
1 
Conservative treatment, orthopedic consultation 
Serious adverse event 
 
Detachment of the sponge on day of the procedure 
1 
Endoscopy 
Hernia 
1 
Surgery 
Myocardial infarction 
1 
Cardiological treatment 
Perforation 
N/A 
Endoscopic or surgical intervention, conservative treatment, antibiotics 
Serious bleeding 
N/A 
Endoscopic or surgical intervention, blood transfusions 
15 Premature termination of the clinical investigation  
The sponsor may suspend or prematurely terminate either the clinical investigation at an 
individual investigation site or the entire clinical investigation for significant and documented 
reasons. The Swedish Medical Products Agency may suspend or prematurely terminate the 
clinical investigation at the applicable investigation sites. 
If suspicion of an unacceptable risk to subjects arises during the clinical investigation, or 
when so instructed by the Medical Products Agency, the sponsor will suspend the clinical 
investigation while the risk is assessed. The sponsor will terminate the clinical investigation if 
an unacceptable risk is confirmed. The sponsor will inform all investigators.  
The sponsor shall consider terminating or suspending the participation of a particular 
investigation site or investigator in the clinical investigation if monitoring or auditing 
identifies serious or repeated deviations on the part of an investigator. If the suspension or 
premature termination was in the interest of safety, the sponsor shall inform all other principal 
investigators. 
If, in the opinion of the investigator, the clinical observations in the clinical investigation 
suggest that it may be unsafe to continue the investigation at the site, the investigator may 
terminate participation in the investigation after consultation with the sponsor. A written 
statement fully documenting the reasons for such termination will be provided to the sponsor. 
If the clinical investigation is prematurely terminated, the investigators shall promptly inform 
the subjects and take necessary steps to finalize their engagement in the clinical investigation. 
All relevant investigation material must be collected, and accountability completed. 
If the clinical investigation is interrupted or terminated prematurely the sponsor will report to 
the Medical Products Agency within 15 days together with a justification. If the sponsor has 
temporarily halted or prematurely terminated the clinical investigation on safety grounds, the 
Medical Products Agency will be informed within 24 hours. A clinical investigation report 
will be prepared within three months of the early termination or temporary halt, irrespective 
of the results. In the event that the clinical investigation is restarted within three months of the 
temporary halt, the sponsor does not have to submit a clinical investigation report until the 
clinical investigation has been completed.  

 
Clinical Investigation Plan 
Study Code: ES-100 
 
 
CIV-ID: CIV-23-06-043373 
 
Version No: 
 
1.1 
Date: 
 
2023-11-29 
 
 
 
33 (34) 
 
The final clinical investigation report shall include detail with respect to the temporary halt. 
16 Publication policy 
The clinical investigation will be registered in a publicly accessible database before the start of 
recruitment activities and the content will be updated throughout the conduct of the clinical 
investigation and the results entered at completion of the clinical investigation. The results will be 
presented at national and international scientific meetings and published in scientific journals. 
 
17 Bibliography 
1. 
Helen G. Coleman, S.-H.X.a.J.L., The Epidemiology of Esophageal Adenocarcinoma   
Gastroenterology, 2018. 154(2): p. 390-405. 
2. 
Desai, T.K., et al., The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett's 
oesophagus: a meta-analysis. Gut, 2012. 61(7): p. 970-6. 
3. 
Abnet, C.C., M. Arnold, and W.-Q. Wei, Epidemiology of Esophageal Squamous Cell 
Carcinoma. Gastroenterology, 2018. 154(2): p. 360-373. 
4. 
Runge, T.M., J.A. Abrams, and N.J. Shaheen, Epidemiology of Barrett’s Esophagus and 
Esophageal Adenocarcinoma. Gastroenterology Clinics of North America, 2015. 44(2): p. 
203-231. 
5. 
Dulai, G.S., et al., Preoperative prevalence of Barrett's esophagus in esophageal 
adenocarcinoma: a systematic review. Gastroenterology, 2002. 122(1): p. 26-33. 
6. 
Weusten, B., et al., Endoscopic management of Barrett’s esophagus: European Society of 
Gastrointestinal Endoscopy (ESGE) Position Statement. Endoscopy, 2017. 49(02): p. 191-
198. 
7. 
El-Serag, H.B., et al., Surveillance endoscopy is associated with improved outcomes of 
oesophageal adenocarcinoma detected in patients with Barrett's oesophagus. Gut, 2016. 
65(8): p. 1252-60. 
8. 
Kastelein, F., et al., Impact of surveillance for Barrett's oesophagus on tumour stage and 
survival of patients with neoplastic progression. Gut, 2016. 65(4): p. 548-554. 
9. 
Kruijshaar, M., et al., The burden of upper gastrointestinal endoscopy in patients with 
Barrett’s esophagus. Endoscopy, 2006. 38(9): p. 873-878. 
10. 
Shaheen, N.J., et al., ACG Clinical Guideline: Diagnosis and Management of Barrett’s 
Esophagus. American Journal of Gastroenterology, 2016. 111(1): p. 30-50. 
11. 
Januszewicz, W., et al., Safety and Acceptability of Esophageal Cytosponge Cell Collection 
Device in a Pooled Analysis of Data From Individual Patients. Clin Gastroenterol Hepatol, 
2019. 17(4): p. 647-656 e1. 
12. 
Iqbal, U., et al., Safety and efficacy of a minimally invasive cell sampling device 
(‘Cytosponge’) in the diagnosis of esophageal pathology: a systematic review. European 
Journal of Gastroenterology & Hepatology, 2018. 30(11): p. 1261-1269. 
13. 
Pilonis, N.D., et al., Use of a Cytosponge biomarker panel to prioritise endoscopic Barrett's 
oesophagus surveillance: a cross-sectional study followed by a real-world prospective pilot. 
The Lancet Oncology, 2022. 23(2): p. 270-278. 
18 Appendix  
Appendix A – EndoSign® Cell collection device -_Instructions for use 

 
Clinical Investigation Plan 
Study Code: ES-100 
 
 
CIV-ID: CIV-23-06-043373 
 
Version No: 
 
1.1 
Date: 
 
2023-11-29 
 
 
 
34 (34)