Feasibility of a Minimally Invasive Diagnostic Algorithm in Suspected Crohn's Disease - a Prospective Comparison of Pan-Enteric Capsule Endoscopy Versus Ileocolonoscopy Plus MR Enterography or Small-Bowel Capsule Endoscopy
Phase: NA
Conditions: Crohn's Disease
Sponsor: Esbjerg Hospital - University Hospital of Southern Denmark

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ANDI study group 
Advanced Non-Invasive Diagnostics in Inflammatory Bowel Disease 
 
 
 
 
Feasibility of a non-invasive diagnostic algorithm in suspected 
Crohn’s disease – a prospective comparison of pan-enteric 
capsule endoscopy versus ileocolonoscopy plus MR 
enterography or small-bowel capsule endoscopy 
 
 
ANDI-3 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary investigator: 
 
Frederik Drejer Thrane, MD 
Department of Internal Medicine 
Esbjerg Hospital – University Hospital of Southern Denmark 
Denmark  
 
frederik.drejer.thrane2@rsyd.dk 
Telephone: +45 2426 9050 
 

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Background 
Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) most often diagnosed in young adults. 
The etiology is unknown, but CD is thought to arise from a dysregulated interaction between the gut 
microbiome and the mucosal immune system in a genetically predisposed individual.1 The incidence in 
Denmark continues to increase and is among the highest in the world. The current incidence is 
9.1/100,000/year corresponding to approximately 500 patients diagnosed each year and up to 18,000 
persons living with CD.2 
Typical symptoms are chronic diarrhea, abdominal pain, and weight loss. A subgroup of patients experience 
extra-intestinal disease such as arthritis, uveitis, pyoderma gangrenosum, erythema nodosum, or primary 
sclerosing cholangitis. CD is characterized by recurrent disease activity and a strong tendency to relapse after 
remission with medical treatment (immunosuppressants) or surgical resection. A small proportion of patients 
experience continuous disease activity.3  
Cardinal lesions are mucosal ulcerations ranging from small aphthous ulcerations to large ulcers and fissures. 
Histologically, the inflammation is transmural and often granulomatous. Typically, CD has a segmental 
distribution, and the entire gastrointestinal tract may be involved. The disease is often located in the terminal 
ileum and right colon (ileocecal CD). In approximately one third of patients, the disease is located in the small 
intestine, and one third has CD restricted to the colon.4 At the time of diagnosis, the majority of patients have 
an inflammatory phenotype, i.e. mucosal ulcerations without stricture, fistula, or abscess.5 In 10-30% of 
patients, however, strictures of varying degrees are present at debut; primarily in patients with CD in the 
small bowel.5-7  
 
Current guidelines for diagnosing Crohn's disease 
Most patients have CD located within reach of the colonoscope, and ileocolonoscopy (IC) with segmental 
biopsies is currently the first-line diagnostic procedure in patients with clinically suspected CD.8 Regardless 
of findings at IC, however, an additional small bowel examination is recommended for evaluation of disease 
extension (e.g. MR enterography or small bowel capsule endoscopy). IC is invasive and reaching the terminal 
ileum is not always possible. Although significant adverse events such as bleeding and perforation are rare 
(< 0.1%),9 up to one third of the patients experience minor adverse events (e.g. abdominal pain and 
bloating),10 and patients prefer less invasive modalities.11, 12 
Fecal calprotectin is an established clinical biomarker for IBD, and it is helpful in selecting patients for further 
diagnostic workup. Concentrations found in healthy individuals range between 10 and 50 mg/kg stool, and a 
fecal calprotectin concentration of ≤ 40 mg/kg confers a ≤ 1% probability of having IBD.13 Several studies 
implicated that fecal calprotectin allowed differentiation between non-IBD and IBD at a cut-off between 100 

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and 200 mg/kg.14 However, an exact cut-off value for the discrimination between IBD and functional bowel 
disease is not established. 
 
Modalities for minimally invasive diagnosis 
Technological advances have recently improved minimally invasive modalities for diagnosing and monitoring 
CD. The primary modalities are capsule endoscopy (CE), MR enterography and intestinal ultrasound (IUS). All 
modalities can visualize both the small intestine and colon in one procedure. 
Visualizing the transmural component of CD (e.g., bowel wall thickening and post-contrast enhancement) is 
a key element of cross-sectional imaging.8 However, patients with newly diagnosed CD most often have 
mucosal ulcerations, and over time, CD can progress to complicated disease involving the entire gut wall.5 
Hence, the diagnostic performance of different modalities differs between patient groups – from mucosal 
lesions at debut best visualized by endoscopy to transmural or penetrating lesions in longstanding disease. 
Correspondingly, recent studies have found an insufficient sensitivity of cross-sectional imaging for the initial 
diagnosis of CD, especially for CD located in the colon.11, 15 
 
Pan-enteric capsule endoscopy 
CE is a patient-friendly and minimally invasive procedure. Compared to cross-sectional imaging, CE allows 
direct and detailed evaluation of the gastrointestinal mucosa with detection of the earliest lesions of CD.16  
Using CE to evaluate the small bowel and colon in a single examination is an attractive diagnostic approach. 
Pillcam colon capsule endoscopy (PCCE) was introduced in 2006 and a pan-enteric capsule endoscope is now 
available in clinical practice (PillCam™ Crohn's capsule, Medtronic, Dublin, Ireland).  
Performing CE of the colon requires optimal cleansing, and the European Society of Gastrointestinal 
Endoscopy currently recommends a regimen consisting of polyethylene glycol (PEG) in two divided doses and 
a booster preparation for propulsion of the capsule through the gastrointestinal tract and maintenance of 
optimal bowel cleansing throughout the entire procedure.17 The extensive bowel preparation required to 
achieve sufficient image quality is a significant limitation. In a recent study by our group, the volume of PEG 
was the main factor affecting the image quality.18 Although few patients were able to ingest the 
recommended volume of PEG (2+2 L), the diagnostic yield for CD was not affected. 
In a prospective study of patients with known CD, PCCE had a sensitivity of 86% for detection of ulcerations 
in the colon and terminal ileum, and lesions outside the reach of the colonoscope were detected in 15% of 
patients.12 There was a moderate correlation between PCCE and IC for assessment of disease severity. 
Leighton et al. compared the diagnostic yield of pan-enteric CE with IC in 66 patients with known active CD.19 
The per-subject diagnostic yield for CD lesions was 83.3% for CE and 69.7% for IC (incremental yield 13.6% 

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(95% CI, 2.6-24.7%). CE detected a greater percentage of lesions in each evaluated segment than IC. The 
overall per-segment diagnostic yield was 40.6% and 32.7%, respectively. In a more recent study by Bruining 
et al., the sensitivity and specificity of CE for active enteric inflammation was 94% and 74%, respectively.20 
The sensitivity of CE was superior to that of MRE for the proximal small bowel and similar for the terminal 
ileum. This study included patients with an established diagnosis of CD. A recent study by our group examined 
patients with clinically suspected CD going through their first diagnostic work-up. The sensitivity and 
specificity for diagnosing ileocolonic CD with MREC was 67.9% (CI 53.7–80.1) and 76.3% (CI 65.2–85.3) 
(terminal ileum 76.9% and 85.6%; colon 27% and 93%) compared to 87.5% (CI 73.2–95.8) and 87.8% (CI 78.2–
94.3) with CE (terminal ileum 96.6% and 87.5%; colon 75.0% and 93.0%).11 The sensitivity of CE was superior 
to that of MREC (P = 0.02). Furthermore, the level of patient discomfort was equal for CE and MREC and 
significantly less than for IC. 
In a retrospective evaluation of histopathological findings, the additional information obtained from biopsies 
was limited after CE performed in patients with clinically suspected CD.21  Biopsies added new diagnostic 
information in only 6.5%, and CE as a single diagnostic procedure was feasible in the majority of patients. 
Biopsies are warranted, however, in patients with an atypical endoscopic appearance or suspected 
malignancy. 
 
Reading the capsule examination with computer assistance 
Analysis of the CE videos is a time-consuming process. The use of artificial intelligence (AI) – especially deep 
learning techniques – has received much attention in recent years. Several clinical areas have been 
investigated, including the ability to analyze endoscopy images and assist in clinical decision making.22-24 A 
recent meta-analysis showed a high sensitivity and specificity of deep learning techniques for ulcer detection 
in the small intestine.23 In contrast, the ability of AI to diagnose CD in the large intestine has not been studied 
to the same extent. Therefore, our group have previously tested the ability of a deep-learning algorithm to 
detect CD lesions in single images of the small intestine or colon captured with CE, determine the localization 
of lesions and the ability to characterize lesions of different severity.25  We obtained excellent agreement 
with the clinical standard, and diagnostic accuracy is equally high for the small intestine and colon. In a recent 
validation study, we examined the diagnostic accuracy of AI-assisted CE reading for the detection of 
inflammatory bowel disease in full-length CE examinations in 131 patients with suspected CD.26 Videos were 
processed by an offline version of the deep learning solution AXARO® (Augmented Endoscopy, Paris, France). 
The AXARO® platform is based on: 1) a user-friendly human-machine interface that ensures efficient use of 
its modules; and 2) an AI core that ensures the different classification and detection tasks. The AI core of 
AXARO® was trained on annotated small bowel CE still frames from a multicenter database, CAD-CAP.27 The 

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output of this AI solution is single images of interest, with and without marking the region of interest. The 
study revealed that the employment of AI assistance in CE reading significantly reduced review time while 
maintaining a high diagnostic accuracy for detection of CD. 
Deep learning approaches have great potential to help clinicians detect, localize and determine the severity 
of CD with CE. Existing data are promising, and AI may have a central role in the future of non-invasive 
diagnosis of CD with CE, although significant development and testing of the technology is needed before 
clinical use. 
 
MR enterography 
Magnetic resonance imaging is characterized by the ability to visualize all manifestations of CD – luminal, 
mural and extraintestinal – with high tissue contrast and without ionizing radiation. MR enterography (MRE) 
is performed with oral and intravenous contrast. Typical manifestations of CD are ulcers, wall thickening, 
relative contrast enhancement, dilated vasa recta (Comb sign), enlarged mesenteric lymph nodes, stenosis, 
prestenotic dilatation, abscess, and fistula. MRE diagnoses CD in the small intestine with a moderate to high 
sensitivity, specificity and inter-observer agreement.16, 28 In contrast, recent studies have demonstrated the 
significantly lower sensitivity of MRE (25-47 %) for diagnosing colonic CD manifestations compared to pan-
enteric CE11, IUS15 and IC11, 15. The wall thickness, relative contrast enhancement and the presence of ulcers 
and edema are independent predictors for endoscopic disease severity.29  
 
Ultrasound 
IUS is an attractive imaging modality as it is non-invasive, associated with minimal to no patient discomfort 
and does not expose the patient to ionizing radiation. Typical findings in CD are wall thickening, loss of wall 
stratification, reduced peristalsis, stenosis, prestenotic dilatation, creeping fat, fistula, and abscess. IUS is 
able to diagnose CD in the terminal ileum and colon with a moderate to high sensitivity and a high specificity, 
although its diagnostic value is highly operator dependent.30, 31 Visualization of the proximal small bowel as 
well as segments of the intestine located in the pelvis may be difficult32 and the examination may be 
compromised by air-filled intestinal loops. The wall thickness and vascularization in affected bowel segments 
evaluated with Doppler IUS correlates with the endoscopic disease activity.9  
 
Small bowel patency 
In a recent meta-analysis by Pasha et al., capsule retention occurred in 2.35% of patients examined for 
suspected CD,33 and retention rates of 4-13% have been reported in patients with symptomatic CD.34 Recent 

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data from centers with extensive experience in capsule endoscopy suggest even lower retention rates in 
patients with suspected CD of around 0,5 %.35 
Different methods exist to determine small bowel patency before CE: 1) clinically, 2) a dissolvable test capsule 
or 3) cross-sectional imaging. Symptoms suggesting small bowel obstruction are abdominal pain (typically 
postprandial), distension, nausea, and vomiting.36 If small bowel stenosis is not firmly excluded, the Pillcam 
patency capsule (Medtronic, Dublin, Ireland) can be used to confirm small bowel patency before performing 
CE. The patency capsule is a dissolvable capsule with the same size as the Pillcam SB3 capsule (26 x 11 mm). 
It is composed of a lactose body with barium added for radio opacity. In each end, the patency capsule has a 
timer plug designed to erode after 30 hours resulting in disintegration of the capsule, and it has been stated 
that all patency capsules are dissolved within 72 hours.37 Capsule endoscopy is considered safe if the patency 
capsule is excreted before 30 hours, an intact capsule is excreted after 30 hours, or passage to the colon of 
an intact patency capsule is radiologically confirmed.  
Herrerias et al. examined the Pillcam patency capsule in 106 patients with radiographic evidence of a small 
bowel stricture.38 Small bowel patency was confirmed in 59, and none of these patients experienced capsule 
retention at a subsequent capsule endoscopy. No severe adverse events could be attributed to the patency 
capsule. Furthermore, Yadav et al. concluded that the Pillcam patency capsule and radiological examination 
were equally reliable for excluding small bowel obstruction or strictures.39 Hence, available studies suggest 
that the Pillcam patency capsule is a safe method for testing small bowel patency before capsule endoscopy, 
even in patients with a radiologically verified stenosis.  
In a study evaluating the accuracy of MRE for prediction of patency capsule retention in patients with 
established small bowel CD, the sensitivity and specificity was 92.3% and 59%, respectively.40 If the decision 
to administer CE was based on imaging and not on patency capsule results, at least 40% of the patients would 
not have undergone CE. Hence, MRE is less accurate in the evaluation of functional small bowel patency, 
frequently overestimating the risk of obstruction. 
Use of IUS in predicting capsule retention is less well studied, although a study of 50 patients with suspected 
small bowel stenosis found a sensitivity and specificity of 92.3% and 72,9%, respectively, for impassable 
stenosis at double-balloon enteroscopy.41 
 
Future perspectives 
Implementing pan‐enteric CE as a first‐line modality in patients with suspected CD could reduce the need for 
IC; changing IC from a first line procedure to a targeted procedure for obtaining biopsies or if CE is incomplete 
or contraindicated. Since pan‐enteric CE visualizes the entire small bowel, this offers a potential single‐
examination strategy yielding the total disease distribution. This strategy might be feasible; especially in 

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young patients with low risk of neoplasia. The potential is a rapid and less invasive, better tolerated and 
possibly cost‐effective diagnostic workup. Future research should develop new diagnostic algorithms using 
minimally invasive technology, examine the feasibility of CE as a first‐line diagnostic procedure, reduce the 
time used for CE analysis (e.g., with AI), implementing pan‐enteric activity scores, and optimize bowel 
preparation, which will add further potential to this modality. Cross sectional imaging should be reserved for 
more advanced stages of CD to harvest the full potential of this modality. 
 
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Hypothesis 
Pan-enteric CE is a feasible, safe and patient friendly first-line diagnostic procedure reducing the need for IC 
and additional diagnostic procedures in patients examined for clinically suspected CD.  
 
Aim 
The aim of this study is to determine the feasibility, efficacy and safety of pan-enteric CE as the first-line 
diagnostic procedure compared to traditional diagnostic work-up with IC plus MRE or small bowel (SB)CE in 
patients with clinically suspected CD. 
 
Inclusion criteria 
 
Clinical suspicion of CD* 
 
Age 18-40 years 
 
Signed informed consent 
 
*A clinical suspicion of CD is based on the following definition: Diarrhea and/or abdominal pain for more 
than 1 month (or repeated episodes of diarrhea and/or abdominal pain) and either fecal calprotectin ≥ 200 
mg/kg or fecal calprotectin ≥ 50 mg/kg plus one or more of the following findings: (1) C-reactive protein 
(CRP) > 5 mg/L, (2) thrombocytosis (> 400 x 109/L), (3) anemia (hemoglobin < 7.0 mmol/L for women and < 
8.0 mmol/L for men or a decrease > 0.5 mmol/L compared to the usual level), (4) prolonged fever (> 37.5 ◦C 
for more than 2 weeks), (6) weight loss (≥ 3 kg or ≥ 5% compared to the normal body weight), (7) perianal 
abscess / fistula or (8) a family history of inflammatory bowel disease. 
 
Exclusion criteria 
 
Previous intestinal resection 
 
Positive serologic markers for celiac disease 
 
Positive stool polymerase chain reaction for pathogenic bacteria 
 
Positive stool polymerase chain reaction for intestinal parasites 

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 
Suspected or established acute bowel obstruction (ileus) 
 
Intake of NSAIDs or acetylsalicylic acid ≤ 4 weeks before inclusion, except low-dose, prophylactic 
acetylsalicylic acid (≤ 150 mg per day) 
 
Intake of opioid or opioid-like medication ≤ 1 week before inclusion 
 
Pregnancy or lactation 
 
Unable to comply with protocol requirements, e.g. for reasons including alcohol or recreational drug 
abuse 
 
Known gastrointestinal disorder other than functional gastrointestinal disorders 
 
Renal failure defined by a plasma-creatinine above the normal reference range  
 
Study design 
This is a pragmatic, prospective, randomized multicenter study comparing a new minimally invasive 
diagnostic algorithm with the traditional diagnostic work-up in patients with clinically suspected CD.  Patients 
referred to medical gastroenterology units at public hospitals in the Region of Southern Denmark are 
screened for participation in the study at the time of referral from primary care or after the first diagnostic 
interview. Participation from centers outside the Region of Southern Denmark is possible if a physician 
responsible for the project can be appointed and centers are able to comply with the protocol requirements. 
Each patient will complete a standardized work-up including medical history, physical examination, blood 
samples and fecal calprotectin. Patients are randomized 2:1 stratified by participating center to a minimally 
invasive strategy with pan-enteric CE (Pillcam Crohn’s) or IC plus MRE or SBCE. All examinations are reviewed 
and described in a standardized fashion.  
 
 
 
Endpoints 
Primary endpoint: 

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1. Diagnostic completeness, defined as the proportion of patients in each group achieving a complete 
gastrointestinal assessment and an unambiguous diagnosis after the first-line work-up strategy without 
need for supplementary examinations. 
 
Secondary endpoints: 
1. Feasibility of pan-enteric CE: Number of patients with suspected CD examined with pan-enteric CE and 
the number of ICs avoided 
2. Additional examinations: Need for additional examinations in the two randomization arms 
3. Safety: Number of severe adverse events, delayed or missed diagnoses 
4. Time to diagnosis: Time from referral or first diagnostic procedure to a final diagnosis and treatment 
5. Disease classification and medical treatments in the two randomization arms 
6. Patient satisfaction: Difference in Gastrointestinal Endoscopy Satisfaction Questionnaire (GESQ) score42 
7. Costs: Expenditure on diagnostic procedures, treatment and loss of productivity 
8. Artificial intelligence: Diagnostic utility of AI algorithms in detection of gastrointestinal pathology using 
pan-enteric CE – sensitivity, specificity, severity, prediction and impact on clinical decision making 
 
Participating centers 
Patients are recruited from the following centers: 
 
Department of Internal Medicine, Esbjerg Hospital – University Hospital of Southern Denmark 
 
Department of Medical Gastroenterology, Odense University Hospital 
 
Department of Internal Medicine, Lillebaelt Hospital – University Hospital of Southern Denmark 
 
Department of Internal Medicine, Hospital Sønderjylland – University Hospital of Southern Denmark 
 
Department of Gastroenterology, Skåne University Hospital Malmö, Lund University, Sweden 
 
Logistics 
Subject identification and informed consent process 
Subjects are identified either by physicians at trial sites when screening referrals to the trial sites on suspicion 
of inflammatory bowel disease or at the first interview with the treating physician, if the suspicion of 
inflammatory bowel disease is first raised here. 
Blood samples, including serologic markers for celiac disease, and stool polymerase chain reaction for 
pathogenic bacteria and parasites are performed in accordance with the standard of care for newly referred 
patients at the site of inclusion. If fecal calprotectin is performed < 4 weeks prior to enrollment in the study, 
a repeated test is not mandatory.  

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Regardless of how the subject is identified, the subject will be offered inclusion in the trial at the first 
interview with the treating physician, if the inclusion criteria and none of the exclusion criteria are met. Oral 
and written information is provided by the treating physician at the trial site, who has been delegated to do 
so by the principal investigator by written agreement. 
Since oral and written information is provided at a scheduled interview with the treating physician in a 
gastroenterology outpatient clinic, the interview takes place undisturbed and the subject has the opportunity 
to bring an assistant to the interview. The subject will also be informed that there is an opportunity to request 
a cooling-off period or a new interview with a repetition of the oral information in the presence of an 
assistant. If the subject does not want a cooling-off period, consent is sought immediately, otherwise after 
at least 24 hours of cooling-off period. The declaration of consent is signed by the patient and the treating 
physician. 
Baseline visit 
Patients undergo a full medical history taking and physical examination by a physician. Patients are randomly 
allocated to a minimally invasive or standard diagnostic algorithm using block randomization in groups of 
two.  
 
Minimally invasive diagnostic work-up 
Pan-enteric CE is performed at the center from which the patient is included. Before CE, patients are 
evaluated for small bowel patency with a thorough clinical assessment, supplemented with the patency 
capsule system if deemed necessary. Assessment of small bowel patency can be supplemented with IUS prior 
to examination with the patency capsule in centers with experience in this procedure. If bowel patency is 
confirmed, pan-enteric CE is performed using standard bowel preparation as described below. If bowel 
patency is not confirmed, the patient will cross over to a standard diagnostic work-up with IC plus MRE. If 
the capsule fails to pass from the stomach to the duodenum during the examination, the procedure will be 
considered failed and the patient will cross over to a standard diagnostic work-up. Endoscopic delivery of the 
capsule to the duodenum is not permitted in this study. 
 
CE is analyzed by central reading performed by an expert reader and lesions of interest are confirmed and 
countersigned by a second expert. In case of disagreement between the first and second expert on findings 
or clinical recommendation after the examination, an evaluation committee of several expert readers will 
provide a final decision. Results are reported standardized as described below, and the treating 

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gastroenterologist is provided with the result. Decisions regarding diagnosis, additional diagnostic work-up 
and treatment are made afterwards by the treating physician.  
 
Standard diagnostic work-up 
Patients go through a diagnostic work-up in accordance with international guidelines including IC with 
segmental biopsies plus a small bowel examination, either MRE or SBCE as selected by the investigating 
clinician. MRE is preferred in patients with suspected complications to CD (stenosis, abscess or fistula). CE is 
preferred in patients without disease complications. Patients are scheduled for IC at one of the participating 
centers using standard bowel preparation and sedation according to local preferences. MREs and SBCEs are 
performed locally at the participating centers. Results are reported in a standardized fashion. After 
completing all diagnostic procedures, the treating gastroenterologist is provided with the results of IC and 
MRE or SBCE, and decisions regarding diagnosis, additional diagnostic work-up and treatment are made. 
 
Follow-up 
Patients are followed clinically for 12 months according to the result of the initial diagnostic work-up: 
 
Non-IBD:  Patients are interviewed by the primary investigator or the study nurse after 12 months.  
 
IBD: Data are collected 3, 6, 9 and 12 months after diagnostic work-up. 
 
 
Artificial intelligence 
Parallel to the standard review of pan-enteric CEs, a secondary AI-supported review will be conducted. Full-
length anonymized videos will be processed and reviewed in a cloud-based deep learning solution such as 
AXARO (Augmented Endoscopy, Paris, France). Results are reported in a standardized fashion and compared 
to the standard review. In cases with disagreement between standard review and AI-assisted review, findings 

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are presented to an IBD expert with experience in CE not involved in the standard or AI review for 
classification of lesions, diagnosis, severity, localization, and need for additional diagnostic work-up.   
 
Treatment 
After completing all bowel examinations, a final diagnosis is made. Patients are discharged (non-IBD) or 
followed in the gastroenterology outpatient clinics by the treating physician. Additional examinations, 
medical or surgical treatment are performed without restrictions.  
 
Blood tests 
Prior to inclusion in the study, the following blood tests are performed in accordance with the standard 
clinical praxis for newly referred patients: Hemoglobin, erythrocyte volume fraction, platelet count, total and 
differential leukocyte count, C-reactive protein, sodium, potassium, albumin, creatinine, alanine 
aminotransferase, alkaline phosphatase, bilirubin, thyrotropin (TSH), transglutaminase IgA, total IgA or 
deamidated gliadin IgG, ferritin, cobalamin and folate. 
 
Stool samples 
Stool samples are examined by polymerase chain reaction for pathogenic bacteria and intestinal parasites, 
and fecal calprotectin is measured as a part of routine clinical praxis. 
 
Biobank 
A biobank is not included in this study. 
  
Number of patients 
We aim to include 165 patients in the study. 
 

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Time perspective 
Inclusion in the study begins 1st of September 2024 and ends 1st of April 2027. Clinical follow-up will continue 
until 1st of September 2027. 
 
Statistical considerations 
The diagnostic completeness of pan-enteric CE and conventional diagnostic work-up depends on the chosen 
inclusion criteria, severity of lesions and disease location. In two previous studies performed by our group 
with similar inclusion criteria, CD was diagnosed in 43% and 39% of patients, respectively.16, 43 The following 
performance measures were derived: 
 
Drop out: Pan-enteric CE was not performed in 10% of patients because of suspected small bowel 
stricture, patient demands or unwillingness to complete the procedure.  
 
Complete procedures: A complete IC and pan-enteric CE was achieved in 86% and 82% of patients, 
respectively. MR-enterography was not completed in accordance with the protocol in 1-5% of patients. 
 
Diagnostic performance: The sensitivity of CE for diagnosing CD in the terminal ileum was significantly 
higher compared to MR (100% vs 81%). The diagnostic yield of CE for detection of CD in the proximal 
small bowel was also higher compared to MR (15-22% vs. 3%). The sensitivity of CE for diagnosing CD in 
the colon was 75% compared to IC. 
 
Expected diagnostic completeness 
Minimally invasive diagnostic work-up: With 10% of patients withdrawn from the procedure, 80% complete 
examinations and a diagnostic procedure in 90%, the expected diagnostic completeness of pan-enteric CE is 
65%.  
Standard diagnostic work-up: With 5% of patients withdrawn from at least one of the procedures, 90% 
complete examinations and diagnostic procedures in 90%, the expected diagnostic completeness of pan-
enteric IC plus MR enterography or SBCE is 77%.  
 
Sample size calculation 
In a randomized controlled non-inferiority trial with a 2:1 ratio of patients examined with CE and standard 
diagnostic procedures (IC + MR enterography or SBCE), significance level 0.05, power 0.8, expected diagnostic 
completeness in samples 0.65, expected diagnostic completeness in controls 0.77 and a margin on risk 
difference scale 0.3, the following number of patients are required to show non-inferiority between two 
diagnostic strategies: 165 (110 in CE arm and 55 controls).  
 

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Data capture and randomization 
Data are collected and stored in a secured REDCap database under OPEN (Open Patient data Explorative 
Network). REDCap also provides a tool for 2:1 randomization of patients for minimally invasive diagnosis or 
standard diagnostic work-up, respectively. 
 
Risks, side effects and disadvantages for the participants 
Modalities selected for this study are all – with the exception of IC – minimally invasive, patient friendly and 
without use of ionizing radiation. Patients with CD often develop small bowel strictures and in known CD, CE 
is associated with a 4-13% risk of capsule retention. However, this study includes patients with suspected CD 
undergoing their first diagnostic work-up, and the risk of capsule retention is significantly lower 
(approximately 2%). A thorough clinical assessment is performed prior to CE and supplemented with the 
patency capsule if a clinical suspicion of stenosis is raised, further minimizing the risk of capsule retention. 
CE is safe if small bowel stenosis is excluded with the patency capsule. 
As IC is associated with discomfort from bowel cleansing and the investigation itself, the procedure is 
conducted using moderate conscious sedation or deep sedation with propofol.  Serious side effects are rare 
with a risk of perforation < 1 per 1,000 colonoscopies. In accordance with international guidelines, IC is 
indicated as the first line diagnostic procedure if patients reject participation in this study.  
Missed or delayed diagnosis of malignancy is a critical adverse event. All patients examined for CD in this 
study are young adults below 40 years of age, and malignancy is rare in this group of patients. In a previous 
study by our group, there were three cases of malignancy and one case of suspected malignancy in 153 
patients with suspected CD. Pan-enteric CE was performed in 2 patients with malignancy, and both cases 
were detected. One patient, a 67-year old woman with a small bowel lymphoma, was misinterpreted as CD, 
but in retrospect, lesions were clearly abnormal and would prompt additional examinations. In a recent 
systematic review, the sensitivity of a complete CE for detection of colorectal cancer was 93%, which was 
comparable to IC.44 CE was considered a safe and effective tool for the detection of colorectal cancer and 
polyps in a screening setting.  
The additional AI-assisted review, will act as another layer of safety in CE – results of this review will never 
stand alone, but will be compared to the standard review. The cloud based software for AI-assisted review, 
are hosted on approved secure servers within the European Union and in compliance with current legislation 
for handling of personal data. Videos used in the analysis are created without identifiers and are deleted 
after review.   
Hence, we believe no increased risk is associated with participation in this study. Participants are covered by 
Patienterstatningen. 

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Ethical considerations 
This study is conducted in accordance with the guidelines for biomedical research involving human subjects 
outlined by the Declaration of Helsinki and after approval from the Regional Ethics Committee for Southern 
Denmark.  
Patients are recruited from medical gastroenterology units at public hospitals in the Region of Southern 
Denmark. Patients are informed orally by the treating physician and in writing and offered time for reflection 
before signing the declaration of consent. The patient is offered another consultation if he or she needs a lay 
representative. Patients may at any time withdraw their consent to participate in the study without it 
impacting the treatment they otherwise receive in the gastroenterology outpatient clinics.  
 
Imaging modalities selected for this study are all – except IC – minimally invasive, patient friendly and without 
use of ionizing radiation. IC is indicated as first line diagnostic procedure if patients reject participation in this 
study. We anticipate that rare cases of malignancy will be detected irrespective of the diagnostic modalities 
performed. We believe no increased risk is associated with participation in this study. We believe the 
additional AI-assisted review will pose no risk to the patients. On the contrary, previous studies have shown 
that AI systems find more pathology than standard analysis by an experienced physician, and any 
disagreement will be review by an expert. Our study examines whether a minimally invasive diagnostic 
strategy is non-inferior to traditional diagnosis using IC as first line procedure. Possibly, IC can be avoided in 
the future for the initial diagnosis of patients with suspected CD. In addition, only one diagnostic procedure 
will be required to visualize CD in both the colon and the small intestine compared to two or more 
examinations performed today. 
 
At any time during the study, a patient can be withdrawn from the study by the treating gastroenterologist 
if indicated. Additional examinations and medical treatment can be performed without restrictions. Thus, 
neither diagnosis nor treatment of the patient will be compromised by participation in this study.  
Current guidelines do not recommend routine use of a patency capsule prior to CE to prevent capsule 
retention in patients with suspected CD.45 In the present study, pan-enteric CE is preceded by a thorough 
clinical assessment, supplemented with the patency capsule system if deemed necessary. This almost 
eliminates the risk of capsule retention. In patients examined with IUS or MRE, the radiologist has to inform 
the primary investigator if one or more of the following findings are identified: 
 
Small bowel stenosis 
 
Abscess or fistula 

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 
Subileus or ileus 
 
Suspected malignancy 
 
Other intra-abdominal conditions requiring acute or subacute intervention 
 
Approval  
The study will be initiated after approval by the Regional Ethics Committee for Southern Denmark and listed 
on the trial register of the Region of Southern Denmark and the ClinicalTrials.gov database. All patients will 
give informed consent before participation, and the study is conducted within the requirements of the Danish 
law. Collaborations with national and foreign research institutions is conducted in agreement with the 
General Data Protection Regulation (GDPR).  
 
Privacy 
Patients will sign written informed consent before participation, and the study is conducted within the 
requirements of the Danish Data Protection Act (DDPA). Clinical data are prospectively collected after 
informed consent has been declared with the exceptions noted in the following section, and personal 
information will not be passed to persons without connection to the study. For collaborations with other 
research institutions, images / videos are anonymized. No personal data or person identifiable information 
will be shown (e.g. faces). For analysis in the AI based software, images are considered pseudo-anonymized 
data, and data processing agreements are made to ensure data safety, compliance with legislation and 
privacy of the participants. Apart from the anonymized images / videos, no clinical or person identifiable 
information is passed on to external partners, and data will not be stored externally after AI review. Only 
doctors involved in this project have access to these data. The primary investigator or sub-investigators at 
participating centers will obtain a medical history, perform a physical examination, and he is informed about 
the results of pan-enteric CE, IC, histopathology and MRE. These data will be stored at a secure server under 
OPEN SDU. Furthermore, digital copies of pan-enteric CEs and videos from the ICs will be sent to the primary 
investigator for subsequent analysis. MR images are saved digitally on the local and regional picture archiving 
and communications system (PACS), and images are accessible for central review by the participating 
radiologist at Department of Radiology, Lillebaelt Hospital. Results of pan-enteric CE, IC and MRE are reported 
in a standardized fashion and sent to the treating gastroenterologist. 
 
Information from medical records 
Transmission without consent 

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Before the patient has signed the declaration of consent, information including personal data from referrals 
to participating centers will be passed on to the investigators in order to determine eligibility for inclusion as 
per the in- and exclusion criteria mentioned above. Referrals marked with a diagnosis code listed in appendix 
1 can be passed on to the investigators. Personal data passed on comprises name, Central Personal Register 
(CPR) number, and the referral text which may include symptoms, physical findings, medications, preexisting 
conditions, and results from previously performed biochemical and imaging examinations. We expect to 
screen 330 referrals during the inclusion period from September 1st 2024 to April 1st 2027. 
 
Transmission with consent 
The following data are collected by interview and review of the medical records: 
 
Demographic, socioeconomic and clinical characteristics 
 
Diagnosis and disease classification 
 
Patient satisfaction after diagnostic procedures 
 
Disease activity (Simple Clinical Colitis Activity Index and Harvey-Bradshaw index) 
 
Biochemistry including fecal calprotectin 
 
Endoscopic procedures 
 
Result of histology 
 
Imaging procedures 
 
Medical treatments 
 
Visits at the outpatient clinic, general practitioner or nurse including time for preparation for 
endoscopic procedures 
 
Hospital admissions 
 
Surgery 
 
Sick leave 
 
Data regarding demographic, socioeconomic and clinical characteristics are necessary to evaluate the results 
of most endpoints and identify previously unrecognized differences in the study results across randomization 
arms. Diagnosis and disease classification, information on medical treatments as well as results from 
endoscopic procedures, histology, and imaging procedures are necessary to determine the main endpoint of 
the study, evaluate differences in disease classification and medical treatments between randomization arms 
and determine expenditures. Data on hospital admissions and sick leave are necessary to determine 
expenditures and loss of productivity. 
 

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By providing consent, the patient allows the investigators and regulatory authorities direct access to 
information in the patient's medical records, including electronic records, in order to view information about 
the patient's health status, which is necessary for the conduct of the research project and for control 
purposes, including self-inspection, quality control and monitoring, which they are obliged to carry out. 
 
 
 
 

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Steering committee responsible for the study 
 
Department of Internal Medicine, Section of Gastroenterology, Esbjerg Hospital – University Hospital of 
Southern Denmark 
- Frederik Drejer Thrane, MD 
- Michael Dam Jensen, Associate Professor, MD, PhD 
- Jacob Broder Brodersen, MD, PhD 
- Torben Knudsen, Professor, PhD, DMSc 
 
Department of Medical Gastroenterology, Odense University Hospital 
- Jens Kjeldsen, Professor, PhD 
 
Department of Radiology, Lillebaelt Hospital Vejle 
- Søren Rafael Rafaelsen, Professor, DMSc 
 
Publications 
Results will be presented at international conferences and published in international journals with an interest 
in CD, endoscopy and imaging. Positive as well as negative and inconclusive results will be published. 
Participating physicians are offered authorship based on each author’s contributions to the work following 
the Vancouver recommendations46. Frederik Drejer Thrane is first author of the main study. Additional 
authorships, including the last author, as well as authorships for subsequent publications deriving from data 
collected according to this protocol are determined by the contribution of each author. Data are reported in 
accordance with the CONSORT guideline for non-inferiority and equivalence randomized trials.  
 
 
 

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Economy  
This study was initiated by the principal investigator and physicians from the participating centers. None of 
the physicians in the steering committee have conflicts of interest in regard to this study. Physicians from the 
participating centers will declare their conflicts of interest. Granted financial support will be deposited on a 
research account at the Hospital of Southwest Jutland (“ANDI-3”, account number SVS.41.8-11.17220) under 
public audit. 
The project has received funding by a grant from Aage og Johanne Louis-Hansens Fond (DKR 1 275 000) and 
an unconditional grant from Tillotts Pharma AG (DKR 200 000). 
Applications for grants from the PhD Fund of the Region of Southern Denmark (DKR 610 000) and the Region 
of Southern Denmark Independent and Strategic Research Fund (DKR 400 000) have been submitted. We will 
apply for a faculty scholarship from the Graduate School of Health Sciences at the University of Southern 
Denmark (DKR 400 000) when other funding has been secured. 
 
 
 
 

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Diagnostic procedures and definitions 
 
Diagnostic criterion for Crohn’s disease 
A single gold standard for the diagnosis of CD is not available. CD is a syndrome diagnosis based on a clinical 
evaluation and a combination of endoscopic, histological, radiological, and/or biochemical investigations. All 
patients included in this study have a clinical presentation suggesting CD, and findings consistent with CD 
with different modalities are outlined below. 
 
Pan-enteric capsule endoscopy 
CE is carried out with the Pillcam Crohn’s capsule (Medtronic, Dublin, Ireland). The following bowel cleansing 
regimen is used: 
 
 
 
Two days before CE: 
Patients should avoid iron supplements and drink additional fluids (up to 2 L) 
 
The day before CE:  
Light breakfast followed by clear liquid diet throughout the day. 
0,5 L Plenvu and 1 L clear noncarbonated nonalcoholic liquid 18.00-19.00. 
The day of CE: 
0,5 L Plenvu and either 240 mg Imogas (simethicone) or 200 mg Minifom 
(dimethicone) 45-75 min. before capsule ingestion. 
30 minutes after 2 mg Resolor (prucalopride) is administered with 0,1 L water. 
The capsule is ingested with a cup of water and either 240 mg Imogas 
(simethicone) or 200 mg Minifom (dimethicone). 
In case the capsule has not reached the small bowel after 1 hour chewing gum 
is chewed for 15 min. x 2 and either 10 mg Metoclopramide or 20 mg 
Domperidone is administered. 
1st boost (when the capsule reaches the small bowel): 1 sachet of Picoprep 
(sodium picosulphate, magnesium oxide, citric acid) in 150 mL water with either 
240 mg Imogas (simethicone) or 200 mg Minifom (dimethicone). Drink 
additional 1 L of clear noncarbonated nonalcoholic liquid. 
2nd boost (3 hours after 1st boost if capsule is still in the body): 1 sachet of 
Picoprep (sodium picosulphate, magnesium oxide, citric acid) in 150 mL water 

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with either 240 mg Imogas (simethicone) or 200 mg Minifom (dimethicone). 
Drink additional 1 L of clear noncarbonated nonalcoholic liquid. 
3rd boost (2 hours after 2nd boost if capsule is still in the body): 20 mg Bisacodyl 
(Dulcolax) as suppository. 
A light meal can be ingested 2 hours after the 3rd boost or after excretion of the 
capsule. 
 
CEs are analyzed by the primary investigator or a specialist in medical gastroenterology with experience in 
capsule endoscopy. The PillCam Reader Software from Medtronic is used for the analysis. Findings are 
reported in a standardized fashion according to the Capsule Endoscopy Minimal Standard Terminology 
(CEMST). It is recorded whether the capsule reaches the colon and anus. The transit times through the 
stomach, small intestine and colon are determined. Pathological findings are localized according to the time 
interval after capsule ingestion and the usual landmarks. The small intestine is divided into thirds based on 
the passage time. The colon is divided into five segments: Cecum, ascending colon, transverse colon, 
descending/sigmoid colon and rectum. The right and left flexures are used as landmarks for this subdivision. 
Disease severity in both small bowel and colon is assessed with the SES-CD and Eliakim score47, while disease 
severity in the small intestine is furthermore assessed with the Lewis score. 
 
Findings at CE consistent with CD: 
 
Multiple (> 3) erosions or aphthous ulcers 
 
Irregular ulcers or fissures 
 
Cobblestone pattern 
 
Luminal narrowing because of inflammation and/or fibrous stenosis 
 
CE report 
A full report including photo documentation is prepared and disclosed to the treating physician. The 
description must state the following findings: 
 
Is the procedure complete? 
 
Image quality (cleanliness level) 
 
Lesions consistent with CD 
 
Localization and severity 
 
Other pathology 
 
Clinical recommendation:  

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1) A complete procedure with sufficient quality and an unambiguous diagnosis requiring no additional 
examinations 
2) Additional examinations recommended because of an incomplete procedure, poor image quality, 
ambiguous lesions or suspected malignancy 
 
 
 

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Complete procedure 
A capsule expelled from the rectum defines a complete CE procedure. An incomplete CE prompts additional 
examinations of the bowel segments not visualized. 
 
Image quality 
The colon cleansing is graded on a 4-point scale: Poor (1): Large amount of fecal residue precludes a complete 
examination. Fair (2): Enough feces or turbid fluid to prevent a reliable examination. Good (3): Small amount 
of feces or turbid fluid not interfering with examination. Excellent (4): No more than small bits of adherent 
feces. A poor image quality prompts additional examinations.  
 
Ileocolonoscopy 
Bowel cleansing and IC is performed according to standard clinical practice and local preferences. The 
following bowel cleansing regimen is an example used at several participating institutions: 
 
Picoprep 10 mg + 3.5 g + 12 g (or Citrafleet 10 mg + 3.5g + 11g):  
 
1 sachet ingested at 6 PM the day before IC followed by 1-2 liters of water 
1 sachet ingested at 6 AM on the day of IC followed by 1-2 liters of water 
 
 A full colonoscopy is documented by identifying two of the following: Visualization of the appendicular 
orifice, tri-angular fold or intubation of the terminal ileum. Intubation of the terminal ileum is documented 
with a biopsy or a photo showing intestinal villi. The length of terminal ileum intubation is estimated and the 
reason for an unsuccessful intubation is recorded. The Simple Endoscopic Score for Crohn's Disease (SES-CD) 
assesses the disease severity. Photo- and video documentation of relevant findings is secured. 
 
Findings at IC consistent with CD: 
 
Multiple (> 3) erosions or aphthous ulcers 
 
Irregular ulcers or fissures 
 
Cobblestone pattern 
 
Luminal narrowing because of inflammation and/or fibrous stenosis 
 
Histopathology 
The histological assessment is performed by pathologists at the participating centers. Biopsies are cut, 

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stained with hematoxylin and eosin and examined under a standard light microscope. The assessment is 
based on the following lesions: 
1) Architectural and surface distortion: Ulceration/erosion, crypt irregularity, mucosal atrophy, mucin 
depletion. 
2) Signs of chronic inflammation: Lamina propria chronic inflammation with lymphocytes and plasma cells, 
basal plasmocytosis, eosinophilic inflammation, epithelioid cell granulomas. 
3) Signs of acute inflammation: Epithelial and lamina propria acute inflammation with neutrophil 
granulocytes, cryptitis, crypt abscesses and crypt destruction granulomas. 
 
Findings at histopathology consistent with CD: 
For surgical specimens, it has been suggested that CD is diagnosed when 3 features are present in the absence 
of granulomas or when granulomas are present with one 1 extra feature. Most experts agree that the same 
definition could be applied to endoscopic biopsies, i.e. epithelioid cell granulomas plus crypt irregularity 
and/or chronic inflammation is suggestive of CD.48-50 The distribution of inflammatory lesions also supports 
a specific diagnosis – segmental inflammation in CD versus continuous inflammation in UC. 
 
Small bowel capsule endoscopy 
SBCE is performed with the Pillcam SB3 (Medtronic, Dublin, Ireland) according to standard clinical practice 
after fasting and, if preferred by the IBD center, with prior bowel preparation (polyethylene glycol). SBCEs 
are analyzed by a specialist in gastroenterology with capsule endoscopy experience. The PillCam Reader 
Software from Medtronic is used for the analysis. Findings are reported standardized according to the 
Capsule Endoscopy Minimal Standard Terminology (CEMST). It is recorded whether the capsule reaches the 
colon. The transit times through the stomach and small intestine are recorded. Pathological findings are 
localized according to the time interval after capsule ingestion and the usual landmarks. The small intestine 
is divided into thirds based on the passage time. Disease severity in the small bowel is assessed with the 
Lewis score. 
 
Findings at SBCE consistent with CD: 
 
Multiple (> 3) erosions or aphthous ulcers 
 
Irregular ulcers or fissures 
 
Cobblestone pattern 
 
Luminal narrowing because of inflammation and/or fibrous stenosis 
 

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MR enterography 
MRE with oral and intravenous contrast is performed as per local protocol at the participating centers. An 
example protocol is provided below: 
Patients attend the Department of Radiology fasting and 1.5 hours before the examination. 1 L of Mannitol 
7.5% solution is ingested 1.5 hours before the examination. 20 mg Buscopan (hyoscine butylbromide) is 
administered intravenously to reduce artifacts from bowel peristalsis. Images are recorded with coronal T2, 
B-FFE, T1, SPIR and axial T1w sequences. Gadolinium 0.1 mmol/kg is administered intravenously for post 
contrast assessment. In addition, a diffusion weighted sequence is performed. The patient is observed in the 
radiology department for 30 minutes after the procedure. Driving is prohibited for 4 hours because of 
accommodation disturbances secondary to Buscopan administration. 
Radiologists analyze MREC at the participating centers. Radiologists are not blinded to the clinical 
information. Pathological findings are localized according to the estimated distance from the ileocecal valve 
or another fixed point. The small intestine is divided into thirds (proximal, middle and distal third) and the 
colon is divided into five segments: Cecum, ascending colon, transverse colon, descending/sigmoid colon and 
rectum. Findings are reported in a standardized fashion, and the treating gastroenterologist is provided with 
a report stating whether MREC is consistent with CD, the localization and severity, and the presence of 
disease complications. Images will be saved digitally on the local and regional picture archiving and 
communications system (PACS). The assessment is based on the following definitions: 
 
Intestinal distension: 
 
Good distension (> 75% of the intestine is sufficiently distended) 
 
Adequate distension (50-75% of the intestine is sufficiently distended) 
 
Poor distension (< 50% of the intestine is sufficiently distended) 
 
Image quality: 
 
Good (diagnostic images without artifact) 
 
Sufficient (diagnostic images with artifacts) 
 
Poor (non-diagnostic images) 
 
Findings at MRE consistent with CD: 
 
Early or minimal disease 
o Superficial ulcerations 
 

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 
Transmural disease 
o Deep ulcers 
o Cobblestone pattern 
o Post-contrast enhancement (the relative contrast enhancement (RCE) is recorded) 
o Wall thickening > 3 mm (the maximum wall thickness is recorded) 
o Stenosis (the relative change of the intestinal caliber (%), stricture grade and occurrence of 
prestenotic dilation is recorded) 
- Definition of small bowel stenosis: > 50% reduction of the intestinal lumen compared to the 
adjacent small intestine. High-grade stenosis is defined by the presence of prestenotic 
dilation > 2.5 cm and/or collapse of the distal segment. 
- Definition of colonic stenosis: > 20% reduction of the intestinal lumen compared to the 
adjacent colon. High-grade stenosis is defined by an intestinal lumen < 11 mm, prestenotic 
dilation > 2.5 cm and/or collapse of the distal segment. 
 
 
Extraintestinal disease: 
o Creeping fat 
o Dilated vasa recta (Comb sign) 
o Enlarged lymph nodes (> 5 mm) 
o Fistula 
o Abscess 
 
 
Ileocolonic disease severity assessed with MaRIA: 
o Ulcer healing < 11 
o Mucosal healing < 7 
 
Patency capsule 
The Pillcam Patency Capsule (Medtronic, Dublin, Ireland) is gold standard for securing small bowel patency 
before CE. The examination is performed according to standard clinical practice after overnight fasting. 
Approximately 24-30 hours after ingesting the patency capsule, the capsule is localized with a low dose CT-
scan (or abdominal x-ray) unless the patency capsule has already been excreted. 
 
Capsule endoscopy is considered safe if: 
 
The patency capsule is excreted before 30 hours 

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 
An intact capsule is excreted after 30 hours 
 
Passage to the colon of an intact patency capsule is radiologically confirmed 
 
Intestinal ultrasound 
Assessment of small bowel patency can be supplemented with IUS prior to examination with the patency 
capsule in centers with experience in this procedure. The examination is performed by the primary 
investigator or a gastroenterologist with experience in IUS, and the examination is focused on detection of 
CD, localization, severity and stenosis precluding CE.  
 
Findings at US consistent with CD: 
 
Wall thickening > 3 mm 
 
Loss of mural stratification  
 
Decreased peristalsis in a pathological bowel segment 
 
Stenosis (wall thickening, luminal narrowing, prestenotic dilatation, atypical hyperperistalsis or subileus) 
 
Reaction in the extraintestinal fat (hyperechoic and non-compressible mass) 
 
Fistula 
 
Abscess