Clinical trial NCT05414578: NORDTREAT Prospective Study on Inflammatory Bowel Disease
Official title: The Nordic IBD Study Within Personalized Medicine - Diagnosing and Prediction Using Molecular Characterization of Inflammatory Bowel Disease: the NORDTREAT Prospective Cohort Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Inflammatory Bowel Diseases (IBD)
Crohn Disease (CD)
Ulcerative Colitis (UC)
Keywords: Prospective clinical study
Biomarkers
Diagnosis
Prognosis
Lead sponsor: University of Southern Denmark
Sponsor class: OTHER
Collaborators: name: Nordic Bioscience A/S
name: University Hospital Bispebjerg and Frederiksberg
name: Aalborg University
name: Colitis-Crohn Foreningen
name: Uppsala University
name: Örebro University, Sweden
name: Lovisenberg Diakonale Hospital
name: University of Oslo
name: University of Kiel
name: University Hospital of Southern Denmark
First posted: 2022-06-10
Enrollment: 800
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients referred to the hospital on suspicion of IBD

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Improving the accuracy to diagnose IBD
timeFrame: Baseline (Week 0) and Week 52
measure: Improving the accuracy to define prognosis of IBD
timeFrame: Week 52
Secondary outcomes:
measure: Lack of corticosteroid-free clinical remission at week 12*
timeFrame: Week 12
measure: Lack of corticosteroid-free endoscopic healing at week 52*
timeFrame: Week 52
measure: Disease impact on patients life (daily functioning and quality of life)
timeFrame: Week 52
measure: Disease impact on patients life (perception of health)
timeFrame: Week 52
measure: Disease impact on patients life
timeFrame: Week 52
measure: Disease impact on patients life (fecal incontinence)
timeFrame: Week 52
measure: Mid-term complications
timeFrame: Week 52
measure: Long-term complications
timeFrame: Week 52
measure: Surgery in CD due to obstructive symptoms (stenosis)
timeFrame: Week 52
measure: Anxiety and depression
timeFrame: Week 52
measure: Fatigue Questionnaire
timeFrame: Week 52
measure: Flares
timeFrame: Week 52
measure: Glucocorticoid exposures
timeFrame: Week 52
measure: Adverse drug reactions
timeFrame: Week 52
measure: Increased faecal calprotectin at week 52
timeFrame: Week 52
measure: Time to start of biological therapy
timeFrame: Week 52
measure: Time to onset of event (IBD-related surgery or IBD-related hospitalization)
timeFrame: Week 52
measure: The composite secondary outcome of the proportion of patients who experience severe IBD within 52 weeks after inclusion
timeFrame: Week 52
Other outcomes:
Locations:
city: Aabenraa
country: Denmark
facility: University Hospital of Southern Denmark
city: Esbjerg
country: Denmark
facility: SVS Esbjerg Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Svendborg
country: Denmark
facility: OUH Svendborg Hospital
city: Vejle
country: Denmark
facility: SLB Vejle Hospital
city: Reykjavík
country: Iceland
facility: Landspitali
city: Drammen
country: Norway
facility: Vestre Viken HF
city: Grålum
country: Norway
facility: Østfold Kalnes
city: Oslo
country: Norway
facility: Oslo Universitetssykehus
city: Skien
country: Norway
facility: Sykehuset i Telemark
city: Tønsberg
country: Norway
facility: Sykehuset i Vestfold
city: Eksjö
country: Sweden
facility: Höglandssjukhuset Eksjö
state: Region Jönköpings Län
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset
state: Region Stockholm
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset Uppsala
state: Region Uppsala
city: Linköping
country: Sweden
facility: Universitetssjukhuset i Linköping
state: Region Östergötland
city: Stockholm
country: Sweden
facility: Ersta Sjukhus
city: Örebro
country: Sweden
facility: Universitetssjukhuset Örebro
state: Örebro Län
Study officials:
affiliation: Odense University Hospital
name: Jens Kjeldsen, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of Southern Denmark, Aabenraa
name: Vibeke Andersen, Professor
role: PRINCIPAL_INVESTIGATOR
References: