Camera Capsule Endoscopy in the Routine Diagnostic Pathway for Colorectal Diseases
Phase: NA
Conditions: Colorectal Cancer
Sponsor: Odense University Hospital

DanCap 
Camera Capsule Endoscopy in the 
Routine Diagnostic Pathway for 
Colorectal Diseases 
 
Administrative Information 
Host institution: Department of Surgery, Odense University Hospital (OUH), Odense, Denmark  
Collaborating institutions: Department of Clinical Microbiology, OUH, Odense, Denmark 
 
Trial registration 
 
Protocol Version 
Issue Date: July 30 2024 
Protocol Amendment number: 2.9 
NCT number: NCT06475560  
 

 
Page 2 of 20 
 
Table of content 
Administrative Information ............................................................................................................................... 1 
Trial registration ............................................................................................................................................ 1 
Protocol Version ............................................................................................................................................ 1 
Roles and Responsibilities ............................................................................................................................. 3 
Internal Organization ..................................................................................................................................... 3 
Short summary .................................................................................................................................................. 4 
Background ........................................................................................................................................................ 4 
Aim & hypothesis............................................................................................................................................... 5 
Methods ............................................................................................................................................................ 5 
Study Design .............................................................................................................................................. 5 
Study Population ....................................................................................................................................... 5 
Inclusion Criteria ........................................................................................................................................ 6 
Exclusion Criteria ....................................................................................................................................... 6 
Patient flow ............................................................................................................................................... 6 
Data Collection and Management ............................................................................................................. 8 
Outcomes ................................................................................................................................................ 10 
Pathway-cost analysis .................................................................................................................................. 11 
Sample Size Estimation ............................................................................................................................ 14 
Interim Analysis & Monitoring ................................................................................................................ 14 
Deviation from standard treatment and care ......................................................................................... 15 
Study group & feasibility ................................................................................................................................. 15 
Ethics ............................................................................................................................................................... 15 
Data Management ................................................................................................................................... 16 
Procedure-related risks and disadvantages ............................................................................................ 16 
Dissemination .................................................................................................................................................. 17 
Financial Considerations .................................................................................................................................. 17 
References ....................................................................................................................................................... 18 
Appendices ...................................................................................................................................................... 20 
Overview .................................................................................................................................................. 20 
 
 
 

 
Page 3 of 20 
 
Roles and Responsibilities 
Role(s) and Responsibilities 
Contact Person 
Lead, overall coordination, ethical committee, and data protection 
Anastasios Koulaouzidis 
Project management 
Charlotte Løfberg 
Medical and scientific advice 
Gunnar Baatrup, Benedicte Schelde-Olesen, Issam Al-
Najami, Alexandra Agache, Ulrik S. Justesen and Anasta-
sios Koulaouzidis 
Data handling, quality control, and red flag meetings 
Ulrik Deding, Benedicte Schelde-Olesen,  and Lasse 
Kaalby Møller 
Data analysis and statistics 
Lasse Kaalby Møller, Camilla Stryhn, Ulrik Deding, and Al-
exandra Agache 
Study nurse 
Trine Nielsen  
Clinical contact and daily management 
Trine Nielsen, Lene Graversen, Anne-Mette Frisch An-
dersen, Sebastian Radic Eskemose and Anastasios Kou-
laouzidis 
Integration, Implementation, Clinical routines, and DRG-codes 
Ola Selnes, Charlotte Løfberg, Issam Al-Najami, Per 
Vadgaard Andersen and Niels Buch 
Economy and Contact to partners 
Anastasios Koulaouzidis and Kim Brixen 
 
Internal Organization 
Affiliation 
Individual(s) 
Odense University Hospital (OUH) 
Kim Brixen 
Department of Surgery A, OUH 
Claus Christian Vinther and Per V. Andersen 
SATC-C Research Unit, Svendborg 
Ola Selnes, Ulrik Deding, Lasse Kaalby Møller, Sebastian 
Radic Eskemose, Charlotte Løfberg, Alexandra Agache, 
Issam Al-Najami, Gunnar Baatrup and Anastasios Kou-
laouzidis 
Endoscopy unit, Nyborg Hospital 
Trine Nielsen, Anne-Mette Frisch Andersen and Ann-
Louise Wessel Petersen 
Capsule readers 
Benedicte Schelde-Olesen, Thomas Bjørsum-Meyer, Is-
sam Al-Najami and Alexandra Agache 
Patient representatives 
Ulrik Larsen and Helle Lund 
 
 
 

 
Page 4 of 20 
 
Short summary 
The Department of Surgery at Odense University Hospital (OUH) carries out approximately 10,000 colonos-
copies each year, and this number is continuously increasing. Since 2014, the screening for colorectal cancer 
(CRC) has resulted in a significant increase in the colonoscopy workload. Conventional optical colonoscopy 
(OC) is a hospital-based procedure that can require sedation or analgesics and is often considered uncom-
fortable, intimidating, or even painful. The diagnostic yield of OC can be as low as 3-5% in some patient 
groups, which means that an endoscopist may need to perform 20 to 30 colonoscopies to identify one case 
requiring treatment. Physical or cultural barriers can also deter patients from attending appointments, lead-
ing to missed cancers or precancerous lesions. To address these challenges, an alternative pathway is needed 
to reduce the colonoscopy burden on the healthcare system while ensuring fewer findings are missed.  
One solution is to use Colon Capsule Endoscopy (CCE) as a triage tool. This procedure can be performed in 
outpatient healthcare centers and requires less equipment than an OC. However, CCE offers no therapeutic 
capability, and individuals with clinically significant findings will still require an OC. A low reinvestigation rate 
(<25%-30%) is desirable for patient preference and the economy.  
Therefore, DanCap will introduce a new pathway that relies on CCE for routine colorectal examinations of 
symptomatic patients who are expected to have a low rate of positive findings and, consequently, a low 
reinvestigation rate, and asses the cost of this new pathway. 
Background 
As the sensitivity of OC and CCE is constantly increasing (1) and progressively smaller-size pathologies are 
detected, the association between detected lesions and patients’ short- and long-term outcomes is becoming 
more uncertain (2). In some cases, such as with the resection of diminutive polyps, the number needed to 
treat to save one person (approx. 8.000) is very close to the number needed to cause one procedure-related 
death (10.000) (3, 4). Therefore, there is an increasing need to filter OC candidates and define a realistic 
threshold for treating or ignoring lesions. The DanCap study fulfils this need by introducing a renewed ap-
proach to the diagnostic pathways using CCE. This approach offers out-of-hospital, accurate bowel diagnos-
tics that allow for the decongestion of endoscopic services, as seen in the UK. It has an upscaling potential 
for national and international redesign of bowel diagnostics (5-7).  
The foundation of the CCE, the PillCam® Colon Capsule2, was introduced approximately 15 years ago (8). 
Several clinical trials have demonstrated the strengths and weaknesses of CCE as compared to OC (9, 10). 
The Scottish and English Services have shown the feasibility of routine use of CCE (to date, collectively deliv-
ered 15.000 capsules). (11) Additionally, results from the large-scale CareForColon2015 trial, investigating 
the application of CCE in CRC screening, will soon be published (12). The UK CCE-based services confirmed 
already known data with real-world equivalents regarding CCE's safety and high diagnostic quality (13).  
However, there are remaining concerns, primarily due to the high (45-60%) re-investigation rate, which 
makes the patient experience and cost-efficiency of CCE-based services inferior to that of the conventional 
OC counterpart (14). Based on these recent findings, setting up a routine diagnostic pathway for further eval-
uation of CCE in the clinical routine of patients with a low frequency of positive findings, including cost-effi-
ciency assessment, is highly relevant. Here, introducing methods to predict a patient’s findings may be extra 
relevant in the future. Currently, studies suggest that the use of faecal haemoglobin concentration or the 
microbiome composition may be useful biomarkers for colorectal cancer or precursor lesions (15-20). The 
predictive potential of these biomarkers in a diagnostic pathway has yet to be sufficiently tested, and more 
evidence is needed before clinical application is possible.  

 
Page 5 of 20 
 
Aim & hypothesis 
Our study aims to investigate the DanCap pathway as a viable solution for CCE-based diagnostics in sympto-
matic patients, considered to have a high need for endoscopic evaluation due to the symptoms compatible 
with neoplastic disease, as referred from general practice (GP). This approach is expected to be cost-effective 
and maintain high clinical quality while relieving the burden on endoscopy wards in a Danish setting.  
The study will provide data for pathway cost analysis of the CCE-based pathway compared to the traditional 
colonoscopy pathway based on a realistic medicine outcomes assessment. 
 
The secondary aims are to: 
1) Compare the polyp detection rate (PDR) and CRC detection rates in both groups  
2) Investigate the role of FIT-testing and microbiome analyses in CCE-based diagnostics for predictive pur-
poses 
Methods 
Study Design 
DanCap is a two-armed prospective clustered case-crossover randomized controlled trial investigating the 
use of CCE in routine clinical practice in symptomatic patients referred for colonic examination, which is usu-
ally done by OC in current practice. The project is planned to start September 1st, 2024, and finish August 
31st, 2025. 
All patients referred for a 2-week diagnostic lower gastrointestinal (GI) procedure (symptoms compatible 
with neoplastic disease) will be considered for inclusion. Participants will either be investigated by CCE at 
home or by colonoscopy at OUH. Patients will be included in parallel groups and be allocated 1:1. 800 con-
secutive patients referred from GPs will be randomized in clusters determined by the GP clinic provider num-
ber. At the start of the project, odd provider numbers will be referred to OC, and even provider numbers will 
be referred to CCE. After the inclusion of the first 200 consecutive CCE patients, the two arms will be 
swapped, i.e., patients from clinics with even provider numbers are referred for OC, and odd provider num-
bers are referred for CCE. A complete list of all GP clinics can be seen in Appendix B. The project inclusion is 
expected to last one year. Ten patients in total can be included per week in the CCE arm at the beginning of 
the study. Depending on capacity, this capacity can potentially be increased when the study has been initi-
ated. The number of polyps and cancers detected in the two diagnostic pathways will be measured. 
Study Population 
 
 
All participants with symptoms from the lower GI tract who are referred to OUH by GPs located in Funen, 
Denmark, for a colonic assessment will be invited to the study. After invitation, the patients will be included 
and excluded based on the following criteria. 
 
 
 
 
 

 
Page 6 of 20 
 
Inclusion Criteria 
Patients must meet the following criteria for inclusion in the study (Table 1). 
Table 1: Inclusion criteria  
Criteria 
1. Older than 18 years 
2. Symptomatic patient referred for colonoscopy assessment 
3. Able to provide oral and written informed consent 
Exclusion Criteria 
Patients will be excluded from CCE based on the criteria in Table 2; and from investigation with OC based on 
the standard protocols in effect. The project secretary will ensure the absence of any exclusion criteria when 
contacting the patients to confirm study participation. Any uncertainties will be discussed with and handled 
by a project doctor at the research unit. Any participants excluded from the study will be treated as per 
routine clinical procedures outside of the project.  
Table 2: Exclusion criteria  
Criteria 
1. Require hospital admission for inpatient colonoscopy 
2. Previous OC with poor bowel preparation within the last 5 years 
3. Patient is unable to provide oral and written informed consent 
4. History of stenosis of the gastrointestinal tract 
5. Previous major surgery of the gastrointestinal tract* 
6. Patient has a pacemaker/defibrillator 
7. Patient is pregnant or breastfeeding 
8. Known allergies to the bowel preparation regimen 
9. Have severe kidney disease 
10. Known chronic constipation 
*excluding appendectomy, gallbladder removal, partial colectomy 
 
Patient flow 
The following steps outline the patient flow for participants in both the CCE and colonoscopy arms. The first 
three steps are represented by the current clinical routine for symptomatic patients (symptoms compatible 
with neoplastic disease) referred for endoscopic investigation. 
1. Patients are referred to the endoscopic unit by a GP.  
2. The referral is received, and a secretary forwards the referral for triage by a specialist doctor. 
3. A list of referrals is inspected by a specialist doctor who is on duty in the Nyborg department from ap-
proximately 07:45 to 09:00 on weekdays. Any referral that meets the criteria for a colonoscopy proce-
dure is a candidate for this study.  
3.1. In the current clinical routine setting, after these steps, patients get information, the date for the sched-
uled colonoscopy and the bowel preparation kit sent by mail according to the date for the colonoscopy. 
A few days before the scheduled colonoscopy, the patients receive a call from the endoscopy nurses, 
who confirm the appointment date and answer any patient questions regarding the procedure, bowel 
preparation, diet, etc. We are adding a recruitment letter and a phone call by one of the secretaries to 
this clinical routine. This setup is necessary because the current time limits for our diagnostic processes 
for cancer are established by legal decree, and traditional approaches to inclusion (i.e. written material 
as the initial point of contact) are not applicable if we are to meet the established guarantees 

 
Page 7 of 20 
 
(kræftpakkeforløb). The referrals are assigned for examination by the triaging doctor, who will perform 
the preliminary exclusion based on the inclusion and exclusion criteria.  
4. Following triage, the patient will receive an electronic recruitment letter informing them about the 
DanCap study and about an upcoming informative phone call from a secretary scheduled for the follow-
ing day.  
5. The next day, the secretary calls the study candidates, informs them about the project and asks the pa-
tients if they prefer getting more information at this call or in a physical/virtual meeting. Either way, the 
patients who manifest interest will receive information about the study by mail. 
5.1. If patients prefer to be informed over the phone, the secretaries will continue explaining all the relevant 
information about the study. If the patients want to participate or manifest interest, they will receive an 
information letter with the study invitation (Appendix E), an initial questionnaire (Appendix F), and a 
consent form (Appendix H) through mail. After 24 hours of contemplation, the secretaries will contact 
the patients who had uncertainties and ask if they have any further questions, if they want more details 
at a physical meeting where they can also come accompanied or if they have decided already. If the 
patient has decided, they will be allocated to either the intervention or control arm based on their pre-
vious randomization by GP clinic provider number and receive a date and place for the colonic examina-
tion in their mail.  
5.2. If patients prefer to be informed in a physical meeting, it will be scheduled at one of the Odense Univer-
sity Hospital (OUH) regional outpatient clinics (Nyborg, Odense or Svendborg) after a maximum of 2 
work days. The patients are informed that they have the right to be accompanied by a person of his/her 
choice if they want to. Here, the discussion will be conducted by one of our clinical researchers and will 
take place in a location we are establishing exclusively for private talks so that we can ensure that the 
discussion will be undisturbed. 
6. After acceptance to participate in the study, the individual is informed that he/she has a 24-hour consid-
eration period before any further steps will be set in motion (bowel preparation and FIT test delivery). If 
they wish to withdraw from the study at any time, they can call the secretary.  
7. If a participant cannot attend the scheduled CCE for any reason (other than intolerance of bowel prepa-
ration), he/she can call and make another appointment. 
8. Written consent will be given before any trial-related procedures are initiated. This is marked by the 
patient's arrival at the clinic where he/she is scheduled for his/her colonic investigation.  
9. Patients follow their designated pathway and complete the related procedures. 
10. The final investigation report is handled by the assigned doctor at the Department of Surgery. 
Patients who reject participation in the study will return to the standard diagnostic pathway (they will re-
ceive a date and time for a colonoscopy and be sent the bowel preparation regimen).  
Intervention Group (CCE)  
See Appendix D for the study flow of the intervention group participants and Appendix K for a descrip-
tion of the patient course. 
Patients who accept participation in the study will be asked if it’s possible to complete the faecal sample for 
the FIT sampling and to start bowel cleansing according to the instructions (Appendix I). Twice a week, the 
included patients will attend the in-hospital clinic in groups of five persons. They will bring their completed 
FIT sample, completed questionnaire, and the signed consent form. At the clinic, it will also be available blank 
copies of the forms in case patients need other ones.  A project nurse will administer the capsules to the 
patients in the morning, and the patients can leave after. When the capsule investigation is completed (ex-
cretion of capsule) or the day after capsule ingestion (whichever occurs first), patients must return their belt 
and receiver to the Department of Surgery, OUH. After a few days, the patient will receive an electronic letter 

 
Page 8 of 20 
 
(per routine clinical practice) from the project doctor with the results and information regarding upcoming 
steps (Appendix D). Those with positive findings or an incomplete investigation will be given a new appoint-
ment according to the current clinical routine. A second questionnaire, Q2 (Appendix G), will be sent to the 
patient 2 weeks after the completed procedure.  
Control Group 
See (Appendix J) for the study flow of the control group participants. 
Patients who accept participation in the study will be asked to start bowel cleansing according to the in-
structions. They will bring their completed questionnaire and the signed consent form to the scheduled co-
lonoscopy. At the clinic, it will also be available blank copies of the forms in case patients need other ones. 
They will continue to follow the routine clinical setup for outpatient colonoscopy and will only receive, by 
digital post, after 2 weeks from the procedure, an extra second questionnaire Q2 (Appendix G).   
Data Collection and Management 
Intervention group  
A paper-based questionnaire (Q1) is handed to the patients, asking about basic personal information (includ-
ing name, social security number, contact info, transport to hospital, age, and sex) and procedural infor-
mation (CCE or OC). The patients complete the Q1 questionnaires. They are handed over to the nurse han-
dling the patient’s examination at the endoscopic unit, after which it is forwarded to the SATC-C research 
unit. A questionnaire concerning the post-investigation period (Q2) (including questions about occupation 
and consequences of the procedure) will be electronically distributed to participants on the public commu-
nication platform “Digital Post” two weeks after the procedure. All clinical data retrieved from the electronic 
patient journals and the Q1 will be manually entered into a RedCap database by SATC-C project staff. Patient 
replies from Q2 will automatically be entered in the RedCap database. The CCE videos will be reviewed by 
trained doctors from the Department of Surgery, OUH.  
Control group 
For control group participants investigated by OC, the medical record will be examined for colonoscopy 
findings, pathology results and reported complications (both during and after the procedure) approxi-
mately four weeks after the examination. A paper-based questionnaire received before the colonoscopy 
procedure (Q1), the same as received by the intervention group, will be collected by nurses at the endo-
scopic unit and forwarded to the SATC-C research unit. A questionnaire concerning the post-investigation 
period (Q2) (including questions about occupation and work-related consequences of the procedure) will 
be electronically distributed to participants on the public communication platform “Digital Post” two weeks 
after the procedure. All clinical data retrieved from the electronic patient journals and the Q1 will be manu-
ally entered into a RedCap database by SATCC project staff. Patient replies from Q2 will automatically be 
entered in the RedCap database. 
Stool samples & microorganisms  
Participation in the study is not conditioned by taking the FIT test. If patients agree to submit the faecal 
sample, it will only be analysed for traces of blood, and the haemoglobin concentration and the microbiota 
composition. We will conduct this analysis considering that recent studies suggested these this values can be 
useful biomarkers for colorectal cancer or precursor lesions (15-20). The FIT sample collection KIT is already 
an integrated part of colorectal cancer screening in Denmark. The collection kits contain a vial, a spatula for 
collection of stool and minor collection aids. Patients will be asked to collect one sample containing approx-
imately 1 gram of faeces.  

 
Page 9 of 20 
 
The stool sample will be analysed at the Department of Biochemistry at Vejle Hospital in accordance with 
standard analytical protocols. After the samples have been tested for traces of faecal haemoglobin and the 
concentration determined, the samples will be frozen and transported to the laboratory in Aalborg 
(DNASense, Aalborg, Denmark). Here it will be examined of all DNA from microorganisms in the sample (no 
human DNA will be examined) to determine the entire composition of the microbiome. A similar examination 
of microorganisms of tissue samples from colonoscopy (from both intervention and control group) will be 
undertaken. After pathological assessment (clinical routine), these samples will be frozen and shipped to the 
laboratory in Aalborg (DNASense, Aalborg, Denmark), where the DNA of microorganisms on the samples will 
be analysed. The results of all analyses will be used to study whether either blood or microbiome composition 
predicts diagnostic outcomes (cancer or precursor lesions) and could be used in future interventions for this 
purpose. 
After this analysis, the biological material (stool sample and tissue) will be destroyed. The bacterial DNA (non-
biological material) will be stored for research purposes in accordance with current data protection legisla-
tion in freezing facilities at the Department of Microbiology, OUH. No human DNA or biological material will 
be stored, hence no biobank is needed. The electronic test results from both laboratories will be transferred 
electronically to secure storage at OUH for further statistical analyses.  
Patient journal information 
We need to include 800 patients. We expect a 10% to decline participation or be ineligible for inclusion. 
Therefore, we theoretically need to access 880 journals in total, whereof we expect approximately 100-120 
of these to be accessed before written consent is obtained during the inclusion period. 
Before written consent: 
The status of patients with symptoms that need a colonic investigation will be confirmed during a phone call 
with the secretaries after oral information about the project and interest in participating are manifested. The 
conversation will inform and identify eligible patients (based on inclusion or exclusion criteria). The secretar-
ies will be assisted at any point by the clinical research staff. The name, CPR-number and procedure date of 
the patient is registered in the hospitals electronic patient management system (EPJ/Bookplan) on a proce-
dure schedule. Those in the intervention arm will be registered on a separate CCE list, where research staff 
will have access to this basic information. Those in the control arm will be registered as per standard clinical 
practice. No information will be collected by researchers from the patient journals before written consent is 
obtained, but it may become necessary to confirm or elaborate on patient input on inclusion/exclusion cri-
teria based on the phone call, at which time the patient journal may be accessed for the following infor-
mation:  
1. History of gastrointestinal surgery (incl. stenosis) (ICD10: KJ)  
2. History of colonoscopy procedures (incl. stenosis) (ICD10: KUJF) 
3. Implanted pacemaker/defibrillator (ICD10: KFPF, KFPH) 
4. Allergies to bowel preparation (ICD10: Z88) 
5. Severe kidney disease (ICD10:  DN17-DN19) 
6. Chronic obstipation (ICD10: DK590A) 
Here information will be passed on to research doctors with the purpose of evaluating inclusion/exclusion 
criteria.  
 
 

 
Page 10 of 20 
 
After written consent: 
Data relating to the clinical procedures conducted in the study will be collected from patient journals. This 
data is not accessible outside the patient journal system, and access will be necessary to ensure that we can 
meet both the primary and the secondary aim(s). Patient consent gives the principal investigator and in need, 
sponsors and sponsors representatives, as well as any control authority, direct access to obtain information 
in the patient's medical record, including electronic medical records, to see information about the subject's 
health conditions necessary in the implementation of the research project as well as for control purposes 
including self-monitoring, quality control and monitoring, which they are obliged to perform. 
The following types of data will be collected from the patient journals:  
1. Procedural information and results from OC 
2. Procedural information and results from CCE 
3. Pathology report from OC specimens 
4. Lab results relating to the performed procedures 
5. Follow-up procedures (OC after CCE, Computer tomography colonography, Magnetic resonance in-
vestigation) 
6. Information from the GP referral  
7. Result from the FIT analysis (Haemoglobin concentration, microbiome components) 
8. Reported complications from OC or CCE, both during and after the procedure  
9. Administrative information (Expenses - for bowel preparation kit and delivery, consumables used per 
patient; manpower – time spent by any medical and connected staff member on every task project-
related; time and expenses for cleaning and maintaining the scopes and related information). 
Outcomes 
The primary outcome is the costs of the suggested CCE-based pathway compared to the routine clinical path-
way. Secondary outcomes include the clinical quality parameters, PDR, FIT concentration, microbiome com-
position, diagnostic performance, and reinvestigation rate. All outcomes are detailed in Table 3 below: 
Table 3: Aims with correspondent outcomes, defined by groups and data type. Blue represents the primary aim, and red represents 
the secondary aims.  
Study arm 
Outcome 
Description 
Both 
Cost of CCE-pathway compared to OC-path-
way 
Cost analysis  
Intervention 
Diagnostic tool evaluation / Performance 
evaluation 
NPV, PPV, Sensitivity, Specificity 
Intervention 
Reinvestigation rate of CCE 
Technically insufficient examinations or plus number of ex-
aminations followed by second-stage OC due to positive CCE 
findings 
Both 
Comparative analysis of detection rates for 
CCE  and OC  
PDR in both pathways, categorized as “<6 mm”, “6-9 mm” 
and “>9 mm” 
Intervention 
Predictive value of FIT  
Concentration of faecal haemoglobin and the risk of findings 
Intervention 
Gut microbiome  
The composition of the microbiome and the risk of findings 
ABBREVIATIONS: CCE: Colon/Camera capsule endoscopy; OC: Optical Colonoscopy; PDR: Polyp detection rate 
 

 
Page 11 of 20 
 
Pathway-cost analysis   
The objectives of the cost analysis encompass each aspect of the process for patients and staff and scrutinize 
the direct costs associated with both pathways, evaluating factors such as dropout rates and cancellations. 
The cost analysis will be measured in various ways, dependent on tool-specific aspects, as presented in Table 
4. The main focus of the pathway cost analysis is hospital-related costs to identify possible cost benefits/def-
icits of CCE appliances in routine clinical practice.    
Relevant factors for analysis 
Timeline 
(No. of day 
from GP re-
ferral) 
Hospital-related costs 
of CCE 
CCE-related cost-fac-
tors 
Hospital-related costs 
of OC 
OC-related cost-fac-
tors 
Day 1 
Secretary allocates re-
ferred patients to vet-
ting doctor 
 
Sample-size to esti-
mate time spent for 
patients allocated to 
triage by doctor  
Secretary allocates re-
ferred patients to vet-
ting doctor 
 
Sample-size to esti-
mate time spent for 
patients allocated to 
triage by doctor 
Doctors time spent on 
vetting referred pa-
tients to CCE pathway 
 
Sample-size to esti-
mate time spent for 
patients allocated to 
CCE 
Doctors time spent on 
vetting referred pa-
tients to OC pathway 
(normal practice) 
Sample-size to esti-
mate time spent for 
patients allocated to 
OC 
 
Day 2 
Secretary calls patient 
for inclusion and study 
information 
Not relevant for cost-
analysis 
Secretary calls patient 
for inclusion and study 
information 
Not relevant for cost-
analysis 
 
Day 6-7 
Expenses for bowel 
preparation medication 
 
Expenses for bowel 
preparation medica-
tion 
 
 
Nurse calls patient for 
CCE bowel preparation 
information. 
Sample-size to esti-
mate time spent call-
ing CCE patients 
Nurse calls patient for 
OC bowel preparation 
information. 
Sample-size to esti-
mate time spent call-
ing OC patients 
 
Day of In-
vestigation 
Collection of Q1 
 
Collection of Q1 
 
Pre-procedural tasks 
 
1Nurse-time spent on 
group information 
before capsule ad-
ministration 
 
2Nurse-time spent on 
administrate the cap-
sule, per patient (re-
tracted from “Book-
plan”) 
Pre-procedural tasks 
 
Materials: 
1Maintenance of scope 
2Blanket for patient 
 
Secretaries: 
1Time spent on book-
ings and patient con-
tact 
 
Nurses: 
(Two nurses at each 
operating room) 
1Time spent preparing 
patient, equipment, 
logging in patient jour-
nal, etc. 
 
 
Doctors: 

 
Page 12 of 20 
 
1Time spent informing 
and preparing patient 
 
Procedural tasks 
1Nurse-/doctor-time 
spent on procedural 
questions per phone  
Procedural tasks 
(Normal/Negative OC) 
Materials: 
1Procedural items; 
gloves, plastic 
apron/cover, glasses, 
masks, plastic for co-
lonoscope, IV cannula, 
paper cover for bed, 
exploration gel, hand 
disinfection, soap, 
valves, suction equip-
ment,  
 
Nurses: 
(Two nurses at each 
OR) 
1Time spent at OR 
 
Doctors: 
1Time spent on colon-
oscopy 
 
 
 
Procedural tasks 
(Abnormal/Positive 
OC) 
*Same as above for 
staff and material, and 
the additional cost-fac-
tors specified for the 
below mentioned ab-
normality 
 
For incomplete proce-
dure: 
1Second OC with dou-
ble bowel prep. 
2OC and hospital ad-
mission 
3CT-colonography 
4OC in full anaesthesia   
 
For biopsies: 
1Forceps, sample glass 
2Time spent by doctor 
marking samples and 
filing pathology requi-
sition 
3Pathology resources  
 
For polypectomies: 
1Simple; snare 
2Advanced; EMR 
 
For cancers: 

 
Page 13 of 20 
 
1Surgery, chemother-
apy, etc. 
Post-procedural tasks 
(Normal/Negative CCE) 
Doctors: 
1Time spent evaluat-
ing CCE video, CCE 
report and uploading 
report to EPJ 
2Time spent dictating 
or writing a note in 
patient journal 
 
 
 
Post-procedural tasks 
 
Materials: 
1Wipes for cleaning OR 
2Cleaning endoscopy 
equipment (water, 
chemicals, machines 
 
Secretaries: 
1Time spent writing 
patient pathway sum-
mary (“epikrise”) and 
procedure-related re-
porting in patient jour-
nal 
 
Nurses: 
(Two nurses at each 
OR) 
1Time spent reporting 
in patient journal 
2Time spent cleaning 
and preparing OR 
3Time spent observing 
patient post-operative 
 
 
Doctors: 
1Time spent informing 
the patient 
2Time spent reporting 
in patient journal 
3Time spent uploading 
video to Endobase 
 
 
Post-procedural tasks 
(Abnormal/Positive 
CCE) 
*Same as above for 
staff and addition-
ally: 
 
Doctors: 
1Contacting patients 
by phone (if relevant; 
cancers) 
2Referring patient to 
secretary for follow-
up OC 
 
Secretaries: 
1Referring patient to 
OC 
 
 
Day after In-
vestigation 
Post-procedural tasks 
Secretaries: 
 
 

 
Page 14 of 20 
 
1Time spent pro-
cessing monitor from 
delivery at Svend-
borg or Odense to 
Nyborg by internal 
mail (sample size 
evaluation) 
 
Nurses: 
(Two nurses at each 
OR) 
1Time spent cleaning 
monitor and upload-
ing video to EPJ 
 
Days after 
Investigation 
Collection of Q2 
 
Collection of Q2 
 
ABBREVIATIONS: CCE: Colon/Camera capsule endoscopy; OC: Optical Colonoscopy; Q1: Questionnaire 1; OR: Operating Room; 
Q2: Questionnaire 2 
ADDITIONAL: Sample sizes: 25-30 procedures 
Statistical Analysis of Secondary Outcomes 
Descriptive statistics, X2 for categorical outcomes and a t-test for numerical outcomes will be employed to 
compare the intervention and the control arm. Fischer’s exact test will be employed to compare the results 
of the metagenomic analyses of the microbiome. A multivariate logistic regression model will be employed 
to allow adjustments of potential confounding factors. Due to the risk of clustering by GP unit, we will con-
sider robust statistical models to address this issue.  
Sample Size Estimation 
To meet the primary aim and compare the costs of the CCE-based pathway to standard clinical practice, the 
major unsolved issue is the reinvestigation rate and cost compared to OC and to build a practical integration 
of the pathway into the routines of the endoscopy unit. Compared with OC, there is a wish to verify PDR in a 
Danish cohort. A standard sample size calculation is irrelevant. The cost analysis is based on the reinvestiga-
tion rate and the number of patients with positive findings in each group. It is estimated from the Scottish 
and English experience that the frequency of relevant positive pathological findings is 10-20%. The frequency 
of technically unacceptable examinations will be 10-15%. Polyps are allocated into three groups of approxi-
mately equal size:  <6 mm, 6-9 mm and >9 mm. The number of cancers will be too low, and we would need 
to include several thousand to achieve > 10 cases. In discussions with health economics, it has been agreed 
that at least ten in each group will allow for a fairly accurate and detailed cost analysis. Including 2x400 
patients will ensure at least ten patients in the smallest group. 
Interim Analysis & Monitoring 
We will perform an interim analysis to assess quality (video quality, completion rate, and adverse events), 
reinvestigation rates, complications, clinical routines, and pathways after including 100 CCE patients. The 
project steering group will then decide whether to continue or shut down the study based primarily on the 
reinvestigation rate, which should never exceed 35%.  

 
Page 15 of 20 
 
Quality control on the capsule video readings will be conducted during the study to ensure consistent quality 
on the manual CCE assessment. In addition, we will also seek to employ a set of newly developed diagnostic 
AI algorithms, developed in a collaboration between OUH and the University of Southern Denmark, on all 
videos as an extra precaution. The algorithms are developed and validated as part of the AICE project 
(www.AICEproject.eu). The algorithms will strictly be used as a quality assurance and support tool and will 
not be part of the clinical decision-making process.   
Deviation from standard treatment and care 
All patients will receive a colonoscopic investigation following clinical routine guidelines indications. The 
only deviation will be regarding timelines (deviation only for a few days) in case the patients need a second 
investigation due to findings requiring therapeutic actions. We should also consider that delays can happen 
per clinical routine due to non-responders, poor bowel preparation, uninterrupted anticoagulants, etc.  
Study group & feasibility 
The described platform has been developed as a collaboration of the Surgical Research Unit SATC-C, the De-
partment of Surgery, OUH in partnership with the board of OUH directors and the Region of Southern Den-
mark. It is built upon solid research and experience we have collected during the last 9 years (21), combined 
with published results from international partners and colleagues. The CCE research has been developed 
through numerous trials, including the activity of our Centre of Excellence ‘CICA’ (CICA-research.com) and 
the Horizon Europe project ‘AICE’ (aiceproject.eu). 
The SATC-C has a long history of delivering studies on CCE and has recently completed a seminal trial on using 
CCE in the screening population (CareforColon 2015). (12) Therefore, both SATC-C and CICA are ideally 
placed, in terms of expertise and vision, to deliver this study. Eventually, the study's outcome will allow a 
much-needed cost-benefit analysis that will pave the way for integrating CCE into regular clinical routine.  
The unit, under the guidance of Professor Koulaouzidis, is known internationally for CCE expertise, and the 
overall benefit of the study will provide continuous development for the medical & nursing staff. Lastly, the 
overall CCE process platform will be integrated into the clinical routine if acceptable cost is proven. 
Ethics 
Patients will receive information before providing consent and will only be included in trial-related proce-
dures after both oral and written consent has been obtained. They will be allowed to withdraw their consent 
at any time with no consequence to their further diagnostics. Patients will receive no compensation for par-
ticipation. 
Colon camera capsules have been on the market for around 15 years. They are CE-marked. European guide-
lines exist for their use in selected cases (but not for the indication of this study). Tens of thousands of colon 
capsule investigations have been conducted, and CCE is now implemented in routine clinical diagnostics in 
Scotland and England. Existing evidence suggests that the quality in terms of sensitivity, complication rates, 
and patient preference is equal to or superior to OC. The procedure is considered safe and ethical. Patients 
in the intervention arm of the trial will gain a therapeutic advantage by being given the chance to undergo 
CCE instead of OC, allowing them a less straining, less invasive and clinically efficient mode of undergoing 
diagnostics. Should the study results prove acceptable, future patients will hopefully be given the same op-

 
Page 16 of 20 
 
tion as patients in the DanCap trial, potentially with the addition of predictive biomarkers (FIT and microbi-
ome composition analysis) that can further improve the quality of the diagnostic procedure. Patients in the 
control arm will use healthcare facilities as normal, and the quality of their diagnostic course will not be 
impacted. Patients will not be compensated for the participation but will be covered by “patienterstat-
ningen”.  
Before inclusion, potential participants will be offered information from project staff (secretaries, nurses, 
doctors, researchers). When included, the participants will receive information regarding the investigation 
and have the opportunity to change their decision and receive standard treatment at all times. 
If additional findings are detected during quality control, a project doctor will assess them, and subsequent 
patient management will be in accordance with the established clinical standards dictated in the protocol.  
The microbiome analyses using genome sequencing will not be conducted on human DNA. The analyses will 
only include the DNA of the microorganisms of the faecal sample. The material will be destroyed immediately 
after we conduct the stool sample analysis.  
Data Management 
The trial will be initiated after approval from the regional ethics committee. It will be conducted according 
to the Helsinki Declaration. All data will be handled according to the General Data Protection Regulation 
(GDPR) and the Data Protection Act. The project is registered internally in the Region of Southern Denmark 
(intern fortegnelse over forskningsprojekter). 
Data on participants will be collected from electronic patient charts. Only relevant and required information 
for conducting the study is collected and entered into a RedCap electronic database via OPEN at OUH. Par-
ticipation is always completely voluntary, and patients can exit the study. The Data Protection Regulation and 
the Data Protection Act are complied with. 
The CCE examinations, including all intestinal images taken by the camera capsule, will be stored in the es-
tablished GAIA database (19/30116). The results of the metagenomic analyses will be transferred to the GAIA 
database and stored in a secure storage environment. These results will be coupled with the other data from 
the project for research purposes.  
Only project staff with a legitimate research purpose will be granted access to the database. This access will 
be limited to essential staff. The Data Protection Regulation and the Danish Data Protection Act will be com-
plied with.  
Procedure-related risks and disadvantages 
Some patients report difficulties swallowing the capsule because of its size. Fluid displacement can happen 
due to bowel preparation. Complications of CCE are expected to be minimal following the existing literature.  
In a large meta-analysis, complications were reported in 4.1% of CCE examinations, and all were documented 
as mild to moderate, the most common being nausea and abdominal pain (22). Other possible side effects of 
the bowel preparation are dizziness and general discomfort. Severe complications in terms of capsule aspi-
ration (blocking the respiratory tract) and retention (blocking the GI tract) are extremely rare. These patients 
cannot undergo MR-investigations while the capsule is retained in the body. These complications can some-
times lead to endoscopic or surgical removal of the capsule. The existing evidence suggests that the rate of 
major complications related to CCE is significantly lower than that of colonoscopy. 

 
Page 17 of 20 
 
One of the disadvantages of CCE is that if the patient needs a subsequent colonoscopy (due to significant 
findings or incomplete/inadequate CCE investigation), he/she will be exposed to a new bowel preparation 
and the risks associated with colonoscopy. Severe bleeding after polypectomy and bowel perforation are 
serious complications of colonoscopy, with an incidence of less than one out of 1000 examinations.  
To diminish possible side effects and complications of CCE, we screen the patients, excluding those at risk for 
developing complications (e.g., capsule retention). Furthermore, we inform and thoroughly explain the entire 
process and procedure to the patients. We also carefully monitor the patients undergoing a CCE or OC. Pa-
tients undergoing colonoscopies are offered sedatives during the examination to diminish discomfort. 
Realistic medicine perspectives 
There is currently a discussion on the “Realistic Medicine” aspect of diagnostic procedures in Denmark and 
other European countries (23, 24). There is accumulating evidence that over-treatment, defined as providing 
high-risk procedures without a clear benefit for the patient, increases dramatically in frequency. It is interna-
tionally acknowledged that the higher sensitivity of diagnostic tests must go together with sound definitions 
of the treatment thresholds (25). Therefore, the existing national guideline that recommends removing all 
polyps seen during colonoscopy is outdated (26). Polyps with no or very little risk of harm can now be iden-
tified before resection and should be left untreated. The combination of CCE and “Realistic Medicine” will 
improve patient outcomes without increasing treatments with no clear patient benefit. The DanCap protocol 
employs Realistic Medicine, leaving diminutive polyps (<6 mm) untreated. This prevents an increase in ther-
apeutic colonoscopies, which will improve patient safety, preference, and the healthcare economy. During 
the next 2-4 years, this approach will be further developed by the pragmatic use of Artificial Intelligence (AI) 
in image analysis (www.aiceproject.eu/www.cica-research.com). 
Combining the established higher sensitivity of CCE for advanced lesions with a decision to disregard low-risk 
polyps will result in a favourable diagnostic course for patients. It will lead to the resection of approximately 
the same number of polyps as in current practice but with a higher percentage of high-risk polyps and a lower 
percentage of low-risk polyps.  
Dissemination  
After completion of the study, we plan to publish two articles in (preferably) high-impact journals. One article 
on primary and secondary outcomes and another on the study protocol. Results will be published in case of 
positive, negative or inconclusive results. The trial will be registered at clinicaltrial.gov. 
Financial Considerations Initiative for the study was taken by Trial Manager Anastasios Koulaouzidis. The 
trial protocol originates from the Surgical Research Unit, Department of Surgery, Odense University Hospital, 
Svendborg. The study costs will be covered by OUH, Region of Southern Denmark, with a grant of 1.8 million 
DKK and funds from CICA (a tentative budget is attached). Funding is administered by an account subject to 
public audit. The Trial manager has no financial affiliation with study subjects. Participants will not receive 
any monetary compensation for their participation. Loss of earnings and transportation costs will not be 
covered. Patients will not be compensated or receive any monetary benefits for participating in the study.  
Cooperation  
The project will be conducted in close cooperation with OUH. Who will deliver the capsules and bowel prep-
aration and withstand the patients during CCE, while the research unit will internally analyze the CCE videos 

 
Page 18 of 20 
 
and report the findings. Endoscopic capsules are received from Medtronic at a reduced price without condi-
tions or involvement in the protocol or operation of the project. 
References 
1. 
Mollers T, Schwab M, Gildein L, Hoffmeister M, Albert J, Brenner H, et al. Second-generation 
colon capsule endoscopy for detection of colorectal polyps: Systematic review and meta-analysis of clinical 
trials. Endosc Int Open. 2021;9(4):E562-E71. 
2. 
Deane C, Walker C, Ryan B, O'Connor A, O'Donnell S, Breslin N, et al. High diagnostic yield 
despite a lower completion rates for inpatient versus outpatient colon and pan-intestinal capsule 
endoscopy: a nested case-control study. BMC Gastroenterol. 2023;23(1):61. 
3. 
Bretthauer M, Loberg M, Wieszczy P, Kalager M, Emilsson L, Garborg K, et al. Effect of 
Colonoscopy Screening on Risks of Colorectal Cancer and Related Death. N Engl J Med. 2022;387(17):1547-
56. 
4. 
Huffstetler AN, Fraiman J, Brownlee S, Stoto MA, Lin KW. An Estimate of Severe Harms Due 
to Screening Colonoscopy: A Systematic Review. J Am Board Fam Med. 2023;36(3):493-500. 
5. 
MacLeod C, Hudson J, Brogan M, Cotton S, Treweek S, MacLennan G, et al. ScotCap - A large 
observational cohort study. Colorectal Dis. 2022;24(4):411-21. 
6. 
NHS rolls out capsule cameras to test for cancer [press release]. england.nhs.uk, 11-03-2021 
2021. 
7. 
Inform N. Colon capsule endoscopy nhsinform.scot: NHS Scotland; 2023 [updated 25-01-
2023; cited 2024. Available from: https://www.nhsinform.scot/tests-and-treatments/non-surgical-
procedures/colon-capsule-endoscopy/. 
8. 
Jalayeri Nia G, Arasaradnam RP, Koulaouzidis A. Clinical utility of colon capsule endoscopy: a 
moving target? Therap Adv Gastroenterol. 2023;16:17562848231195680. 
9. 
Deding U, Cortegoso Valdivia P, Koulaouzidis A, Baatrup G, Toth E, Spada C, et al. Patient-
Reported Outcomes and Preferences for Colon Capsule Endoscopy and Colonoscopy: A Systematic Review 
with Meta-Analysis. Diagnostics (Basel). 2021;11(9). 
10. 
Bjoersum-Meyer T, Skonieczna-Zydecka K, Cortegoso Valdivia P, Stenfors I, Lyutakov I, 
Rondonotti E, et al. Efficacy of bowel preparation regimens for colon capsule endoscopy: a systematic 
review and meta-analysis. Endosc Int Open. 2021;9(11):E1658-E73. 
11. 
Selnes O, Thorndal C, Hansen LØ, Eskemose SR, Koulaouzidis A. Conference Report: The 
FutuRE oF MinimalLy InvasivE GI and Capsule DiagnosTics (REFLECT) Nyborg, Denmark, October 2023. 
Diagnostics. 2024;14(5):458. 
12. 
Kaalby L, Deding U, Kobaek-Larsen M, Havshoi AV, Zimmermann-Nielsen E, Thygesen MK, et 
al. Colon capsule endoscopy in colorectal cancer screening: a randomised controlled trial. BMJ Open 
Gastroenterol. 2020;7(1). 
13. 
Bond S, Kyfonidis C, Jamieson M, Maguire R, McCann L, Watson A, et al. Evaluation of an 
Innovative Colon Capsule Endoscopy Service in Scotland From the Perspective of Patients: Mixed Methods 
Study. J Med Internet Res. 2023;25:e45181. 
14. 
Bjoersum-Meyer T, Spada C, Watson A, Eliakim R, Baatrup G, Toth E, et al. What holds back 
colon capsule endoscopy from being the main diagnostic test for the large bowel in cancer screening? 
Gastrointest Endosc. 2022;95(1):168-70. 
15. 
Deding U, Kaalby L, Steele R, Al-Najami I, Kobaek-Larsen M, Plantener E, et al. Faecal 
haemoglobin concentration predicts all-cause mortality. European journal of cancer (Oxford, England : 
1990). 2023;184:21-9. 
16. 
Kaalby L, Deding U, Al-Najami I, Berg-Beckhoff G, Bjørsum-Meyer T, Laurberg T, et al. Faecal 
haemoglobin concentrations are associated with all-cause mortality and cause of death in colorectal cancer 
screening. BMC Med. 2023;21(1):29. 

 
Page 19 of 20 
 
17. 
Barnett KN, Clark GRC, Steele RJC, Fraser CG. Faecal haemoglobin estimated by faecal 
Immunochemical tests-an indicator of systemic inflammation with real clinical potential. Diagnostics. 
2021;11(11). 
18. 
Libby G, Fraser CG, Carey FA, Brewster DH, Steele RJC. Occult blood in faeces is associated 
with all-cause and non-colorectal cancer mortality. Gut. 2018;67(12):2116-23. 
19. 
Wirbel J, Pyl PT, Kartal E, Zych K, Kashani A, Milanese A, et al. Meta-analysis of fecal 
metagenomes reveals global microbial signatures that are specific for colorectal cancer. Nature medicine. 
2019;25(4):679-89. 
20. 
Justesen US, Nielsen SL, Jensen TG, Dessau RB, Møller JK, Coia JE, et al. Bacteremia With 
Anaerobic Bacteria and Association With Colorectal Cancer: A Population-based Cohort Study. Clin Infect 
Dis. 2022;75(10):1747-53. 
21. 
Koulaouzidis A, Baatrup G. Current status of colon capsule endoscopy in clinical practice. Nat 
Rev Gastroenterol Hepatol. 2023;20(9):557-8. 
22. 
Wang YC, Pan J, Liu YW, Sun FY, Qian YY, Jiang X, et al. Adverse events of video capsule 
endoscopy over the past two decades: a systematic review and proportion meta-analysis. BMC 
gastroenterology. 2020;20(1):364. 
23. 
ScotCap Clinical Leads C. Follow-up of small and diminutive colonic polyps-How to balance 
the risks in the COVID-19 era. Colorectal Dis. 2021;23(12):3061-4. 
24. 
Koulaouzidis G, Robertson A, Wenzek H, Koulaouzidis A. Colon capsule endoscopy: the 
evidence is piling up. Gut. 2022;71(2):440-1. 
25. 
Lu M, Wang L, Zhang Y, Liu C, Lu B, Du L, et al. Optimizing Positivity Thresholds for a Risk-
Adapted Screening Strategy in Colorectal Cancer Screening. Clin Transl Gastroenterol. 2021;12(8):e00398. 
26. 
Asheer ZE, Bisgaard T, Mjaland O, Angenete E, Bulut O, Souzani KL. Scandinavian surveillance 
follow-up programmes in patients with malignant colorectal polyps. Dan Med J. 2021;68(2). 
 
 
 

 
Page 20 of 20 
 
Appendices 
 
Overview  
A. Protocol Summary 
B. GP Clinics 
C. Workflow DanCap staff 
D. CCE flowchart 
E. CCE patient information 
F. Questionnaire 1 
G. Questionnaire 2 
H. Consent 
I. Bowel preparation 
J. Colonoscopy flowchart 
K. CCE patient course 
L. Recruitment letter