NORDTREAT Prospective Study on Inflammatory Bowel Disease

Study Overview
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Brief Summary
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Inflammatory bowel disease (IBD), primarily ulcerative colitis (UC) and Crohn's disease (CD), is a chronic disease entity affecting individuals of all ages, and which may severely impact the lives of the patients and their families as well as society. Individuals with IBD may have to live with relapsing symptoms, such as diarrhea, abdominal pain, and fatigue. Further, a substantial proportion of patients develop serious complications such as bowel obstruction and fistula, and some develop complicating liver disease and eventually colorectal cancer. The consequences are that many patients suffer hospitalizations, recurring sick-leave, life-long medication, and surgical interventions. As IBD has become increasingly common in Western populations there is a clear need to improve the outcome from IBD. IBD is a heterogeneous disease entity with substantial differences between patients and personalized medicine may help provide strategies for better treatment . Currently, one of the main unmet needs is the glaring lack of robust biomarkers for individual disease characterization. This lack leads to delayed diagnosis, worse outcomes, increased mortality and an amplified disease burden. Furthermore, diagnosis of IBD is difficult and early diagnosis is crucial as it helps avoid the development of irreversible organ damage. Therefore, there is an emerging focus on the development of simple, non-invasive, and cheap biomarkers to support clinical decision-making in IBD. This Nordic, prospective, clinical study has the aim of identifying markers that are associated with the diagnosis of IBD and prediction of clinical outcomes with various disease manifestations. Importantly, this study will evaluate the markers in a relevant clinical setting, i.e. among patients referred to the hospital for suspicion on IBD using the ECCO Criteria. Specifically the aims of the study are to: Improve the accuracy to diagnose IBD Improve the accuracy to define the prognosis of IBD The study is approved by the local Ethics Committee (S-20200051) and the local Data Agency (20/54594).

Detailed Description
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The primary aim is to identify molecular markers (e.g. in the blood and stools) for discrimination between individuals diagnosed with inflammatory bowel disease (IBD) inclusive Crohn's disease (CD), ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBD-U), and those without (non-IBD). Participants with suspected IBD at baseline, with various disease pathways, will be evaluated again using a 1-year cohort study. Diagnosis and clinical outcome will be evaluated at referral and after 1 year of observation. The secondary aims are, in addition to the molecular information, to investigate whether the inclusion of information on clinical and lifestyle factors as well as combination hereof (e.g. gene-environment interaction analyses) can improve the predictive potential of identifying IBD and distinguish the prognosis. Study design: A prospective Nordic multicenter study on prognostic factors for the diagnosis and characterization of IBD among patients referred to the hospital on suspicion of IBD. A panel of possible prognostic biomarkers for diagnostic purposes will be applied to all participants. Setting: All patients referred due to a suspicion of IBD to the departments of gastroenterology in Odense University Hospital, Svendborg Hospital, Vejle Hospital, Esbjerg Hospital and potentially Hospital of Southern Jutland, Aabenraa will be invited to take part in the study. Participants will be included from January 2022 for a 1-year period or until 800 participants in the Nordic study (up to 400 in Denmark) have been included. The follow-up period is one-year including visits and questionnaires and an additional nine years of follow-up by the use of register data. Biological material will be obtained four times for participants with IBD, at week-2/0, and 12, 26 and 52 after the diagnosis has been established. Participants where IBD is not established (non-IBD) will only have biological material obtained at baseline (that is visit -2/0) and will have a clinical interview after 52 weeks. All participants are treated according to standard clinical practice by the clinical departments. Clinical data consist of personal data, data on health and disease, lifestyle, laboratory measures, and disease activity scores including patient-reported outcome measures (PROMs), clinical assessments, and laboratory data. Each participant will fill out validated questionnaires on disease activity, quality of life, and lifestyle using electronic links. Data management: Study data registered by clinicians, study nurses and technicians will be stored in the web-based case report form (eCRF) Viedoc (Viedoc™, Uppsala, Sweden) or REDCap (Open Patient data Explorative Network (OPEN) at Odense University Hospital) for the diet questionnaire. The questionnaires are in Danish and the participants will have access to the questionnaires via an electronic link sent to their personal, electronic mailbox (REDCap) or via an investigator provided link to MyViedoc. All data will be stored in secure research storage facilities. Statistical methods: We will develop multivariable prediction models relating multiple predictors for a particular individual to the probability of or risk for the presence (diagnosis of IBD at baseline) or future occurrence (prognosis) of a particular outcome such as severe IBD within the first year. Predictors such as biomarkers are covariates, explored as prognostic factors (independent variables). The primary hypothesis is that the final biomarker will define the participant population into two groups each consisting of 50%: a biomarker positive group whereof 80% will be diagnosed with IBD and a biomarker negative group whereof 20% will be diagnosed with IBD. For a comparison of two independent binomial proportions using the likelihood ratio statistic with a Chi-square approximation with a two-sided significance level of 0.05, a total sample size of 800 assuming a ratio biomarker positivity-to-negativity of 1 to 1 has an approximate power of 100% when the proportions of being diagnosed with IBD are 0.8 and 0.2. If we assume that we will have 800 study participants, we will potentially (rule of thumb) be able to build a statistical model with as many as 80 covariates in the multivariable model. The associations of the suspected important biomarkers with other variables will be tested with non-parametric tests: with Spearman rank correlation (rs) for continuous variables, and the Wilcoxon rank-sum test or Kruskal-Wallis test, including a Wilcoxon-type test for trend across ordered groups where appropriate, for categorical variables. In general, logistic regression models will be used with individual marker as the exposure variables and the clinical response as the outcome (dependent variable). The analyses will be adjusted simultaneously for sex, age, and prescribed targeted therapy. Potential interaction between biomarker status (positive/negative) and specific drug type will be analyzed. Covariates (biomarkers) consist of various measures within genetics, transcriptomic, microbiomes, and proteomics. Sample size considerations: Assuming that biomarker positivity constitutes 50% of the individuals enrolled at baseline, if our event rate is 10% on average, a total sample size of 800 patients (i.e. 400 biomarker positive) we will have a very good statistical power (99.7%) to detect a difference between proportions having surgery of 10% points (15% and 5%, respectively). If we decide to split the data set into two (2×400 individuals), in order to first build the model, and subsequently validate it in the second independent dataset, we will have 91.8% statistical power to detect a difference between groups. If the prognostic value of our biomarkers is not that effective separating the number of patients with severe IBD at week 52, we will still have more than 90% power to detect a difference between biomarker groups of 6% points (e.g. 10% and 4%, respectively). Another consideration is the number of events (individuals having severe IBD at week 52) per variable (EPV) considered for inclusion in the multivariable model. For logistic regression modelling the EPV should be at least ten times the number of potential prognostic variables that could be included in the model. As a consequence of this logic, our expected sample size of 800 individuals (having 80 events) will, with reasonable confidence, allow us to create a multivariable model with up to 8 covariates simultaneously. Project organization: NORDTREAT is part of a larger Nordic project (DK, SE, NO and IS) where regular meetings will be held between the partners. Collaborative research and material transfer agreements will be conducted with the national and international collaborators. In addition to the scientific reporting of results, major findings with translational implications will be communicated to health professionals, patient organizations, public health policy makers, and to the general public through various media and news activities.

Official Title
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The Nordic IBD Study Within Personalized Medicine - Diagnosing and Prediction Using Molecular Characterization of Inflammatory Bowel Disease: the NORDTREAT Prospective Cohort Study

Conditions
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Inflammatory Bowel Diseases (IBD), Crohn Disease (CD), Ulcerative Colitis (UC)

Participation Criteria
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Eligibility Criteria
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To be included in the study, the participants must meet the following criteria: Inclusion Criteria: Referred on the suspicion of inflammatory bowel disease Adult (+18 years of age) Written informed consent to participate in the study Exclusion Criteria: A previous known diagnosis of Crohn's disease, ulcerative colitis or IBD-U Unable to provide informed consent Unable to comply with protocol requirements (e.g., for reasons including alcohol and/or recreational drug abuse)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improving the accuracy to diagnose IBD | The primary endpoint in the cross-sectional study will be diagnosis, i.e., IBD (including CD, UC, IBD-U) or non-IBD (patients that are not diagnosed with IBD) at referral. IBD is diagnosed according to the ECCO criteria based on endoscopic, histologic and/or radiological criteria. | Baseline (Week 0) and Week 52 | 
| Improving the accuracy to define prognosis of IBD | The primary endpoint in the longitudinal cohort study will be severe IBD at week 52 defined as: IBD-related surgery or IBD-related hospitalization (except planned procedures) or IBD-related death | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lack of corticosteroid-free clinical remission at week 12* | ● Clinical remission, CD: Patient reported outcome 2 (abdominal pain ≤ 1 and stool frequency ≤ 3) or Harvey Bradshaw Index < 5 ● Clinical remission, UC: Patient reported outcome 2 (rectal bleeding = 0 and stool frequency = 0) or Partial Mayo (< 3 and no score >1) *Both local acting systemic administered (budesonide) and systemic steroids (prednisolon) | Week 12 | 
| Lack of corticosteroid-free endoscopic healing at week 52* | ● Endoscopic healing, CD: Simple endoscopic score in CD < 3 points or absence of ulcerations (e.g. SES-CD ulceration subscores = 0) ● Endoscopic healing, UC: Mayo endoscopic subscore = 0 points, or UC endoscopic index of severity ≤ 1 points *Both local acting systemic administered (budesonide) and systemic steroids (prednisolon) | Week 52 | 
| Disease impact on patients life (daily functioning and quality of life) | ● The Inflammatory Bowel Disease Questionnaire (with a scale from 1-7); where 1 is eg. All of the time and 7 is At no time or 1 is No energy and 7 is Full of energy | Week 52 | 
| Disease impact on patients life (perception of health) | ● Short Form 36 is an 11-item questionnaire on the patient's perception of his/her health (with scales from 1-3, 1-5, 1-6 or yes / no) where e.g. 1 denotes Excellent and 5 denotes Bad or 1 denotes No pain and 6 denotes Very strong pain. | Week 52 | 
| Disease impact on patients life | ● The 14-item version of the IBD Disability Index (modified to be suitable as a self-report) is a questionnaire on IBD and perception of health. The scales range from eg.: Very good / Good / Moderate / Bad / Very bad Yes / No None / Mild / Moderate / Severe / Extreme | Week 52 | 
| Disease impact on patients life (fecal incontinence) | ● Fecal incontinence according to the Wexner score (with a scale from 0-20); where 0 is perfect continence and 20 is complete incontinence. | Week 52 | 
| Mid-term complications | Bowel damage in CD according to the Lémann index IBD-related surgery and hospitalizations defined as: Surgery, UC: any colectomy Surgery, CD: any CD-related surgery Hospitalizations: A composite endpoint combining the total number of IBD-related hospitalizations (including readmissions), and the cumulative length of hospital stay. Disease extension in UC: focus on macroscopic proximal disease extension | Week 52 | 
| Long-term complications | Gastrointestinal and extra-intestinal dysplasia Cancer Mortality | Week 52 | 
| Surgery in CD due to obstructive symptoms (stenosis) | Cumulative number of surgeries in CD due to stenosis | Week 52 | 
| Anxiety and depression | Hospital Anxiety and Depression Scale (HADS) is a 14-item scale with seven items each for anxiety and depression subscales. Scoring ranges from 0 to 3 and a score above 8 denotes anxiety or depression respectively. | Week 52 | 
| Fatigue Questionnaire | The Inflammatory Bowel Disease-Fatigue (IBD-F) Part One is a 5-item scale where scoring ranges from 0 to 4. Zero denotes no fatigue and 4 denotes extreme fatigue. | Week 52 | 
| Flares | Cumulative number of flares at 1 year | Week 52 | 
| Glucocorticoid exposures | Cumulative glucocorticoid exposures at 1 year | Week 52 | 
| Adverse drug reactions | Cumulative number of adverse drug reactions | Week 52 | 
| Increased faecal calprotectin at week 52 | Increased faecal calprotectin is defined as cumulative number of patients with a concentration of faecal calprotectin higher than 250 μg/g | Week 52 | 
| Time to start of biological therapy | Cumulative number of days before start of biological therapy | Week 52 | 
| Time to onset of event (IBD-related surgery or IBD-related hospitalization) | Cumulative number of days before onset of IBD-related surgery or IBD-related hospitalization | Week 52 | 
| The composite secondary outcome of the proportion of patients who experience severe IBD within 52 weeks after inclusion | Cumulative number of patients who experience: Need for medication between diagnosis and one year (immunomodulators, biologicals, steroids) or Need for surgery between diagnosis and one year or Need for hospitalization between diagnosis and one year or Number of relapses between diagnosis and one year. | Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prospective clinical study, Biomarkers, Diagnosis, Prognosis