Crohn Disease (CD), Inflammatory Bowel Diseases (IBD), Ulcerative Colitis (UC)
Conditions
Keywords
Biomarker discovery, Biomarker validation, Prospective observational cohort Disease activity, Endoscopic activity, Histologic activity, Treatment monitoring, Treatment response, Risk stratification, Disease progression, Leucine-rich alpha-2 glycoprotein, Fecal calprotectin, Oncostatin M, TL1A, TNFSF15, Multi-omics
Brief summary
The goal of this observational study is to establish a multicenter prospective clinical and biospecimen platform for biomarker discovery and validation in inflammatory bowel disease, including Crohn's disease and ulcerative colitis. Researchers want to learn whether candidate biomarkers or combined biomarker models can help assess intestinal inflammation, monitor response to routine clinical treatment, predict treatment outcomes, and identify participants who may be at higher risk of disease progression. The study may enroll participants with inflammatory bowel disease, unaffected first-degree relatives of participants with inflammatory bowel disease, unrelated healthy controls, and non-IBD disease controls when appropriate. Clinical information and biological samples, including blood, stool, and intestinal tissue, may be collected. Biomarkers measured in blood, stool, intestinal tissue, genetic data, immune profiles, microbiome data, and other multi-omics data may be evaluated. The main questions this study aims to answer are: Can candidate biomarkers or combined biomarker models identify endoscopic disease activity when compared with endoscopic assessment? Can these biomarkers monitor or predict clinical response, clinical remission, endoscopic response, endoscopic remission, imaging response, or biomarker response during routine clinical care? Can these biomarkers help predict treatment failure, disease progression, hospitalization, surgery, treatment escalation, or complex Crohn's disease phenotypes? Participants will not be assigned to any treatment by the study. All treatments and clinical management decisions will be chosen by treating physicians as part of routine medical care.
Detailed description
This is a multicenter prospective observational cohort study designed to establish a clinical data and biospecimen-based platform for biomarker discovery, validation, and multi-omics research in inflammatory bowel disease. The study will enroll participants with inflammatory bowel disease, including Crohn's disease, ulcerative colitis, or IBD-unclassified when applicable, as well as unaffected first-degree relatives, unrelated healthy controls, and non-IBD disease controls when appropriate. The study is not designed to assign or test any study-directed treatment. All medical treatments, including biologic therapies, targeted small-molecule therapies, nutritional therapy, endoscopy, imaging, surgery, and other clinical management decisions, will be determined by treating physicians according to routine clinical practice. The study will observe participants during routine care and collect standardized clinical data, biospecimens, endoscopic findings, histologic findings, laboratory results, imaging findings, treatment exposure information, and follow-up outcomes. The overall purpose of this study is to evaluate whether candidate biomarkers or combined biomarker models can be used to assess disease activity, identify endoscopic and histologic inflammation, monitor response to routine clinical treatment, predict treatment outcomes, and support risk stratification for disease progression. Endoscopic assessment will serve as the primary reference standard for evaluating biomarker performance for objective intestinal inflammation. The study is intended to function as an open biomarker discovery and validation platform. It will evaluate both pre-specified biomarkers and additional candidate biomarkers identified through genetic, pharmacogenetic, immune, microbiome, transcriptomic, proteomic, metabolomic, single-cell, tissue-based, spatial, or other multi-omics analyses. Pre-specified biomarker domains may include blood-based biomarkers, stool-based biomarkers, tissue-based biomarkers, genetic markers, immune-related markers, microbiome-derived markers, and multi-omics-derived candidate biomarkers. Examples may include leucine-rich alpha-2 glycoprotein, fecal calprotectin, C-reactive protein, oncostatin M, TL1A/TNFSF15-related markers, TNFSF15 genotype, selected HLA or other pharmacogenetic markers when available, and additional biomarkers selected from exploratory omics analyses. The primary analysis will evaluate the diagnostic performance of candidate biomarkers or combined biomarker models for endoscopic disease activity. Reference measures may include SES-CD, standardized small-bowel endoscopic assessments, capsule endoscopy scores, Mayo endoscopic score, UCEIS, or other accepted endoscopic assessments when applicable. Performance measures may include area under the receiver operating characteristic curve, sensitivity, specificity, predictive values, and biomarker cut-off values. Cut-off values may be explored in discovery datasets and evaluated in internal and external validation cohorts. A second core analysis will evaluate whether baseline biomarker profiles, longitudinal biomarker changes, or combined biomarker models can monitor or predict treatment response during routine clinical care. Treatment response outcomes may include clinical response, clinical remission, endoscopic response, endoscopic remission, imaging-defined response or remission, fecal calprotectin response, C-reactive protein response, treatment escalation, treatment failure, hospitalization, surgery, or relapse when available. Secondary analyses will evaluate biomarker performance against specific clinical and objective outcomes. These may include histologic disease activity and histologic remission; clinical remission rate and clinical response rate using disease-specific clinical definitions; concordance with fecal calprotectin as an established stool-based comparator biomarker; concordance with C-reactive protein as an established blood-based comparator biomarker; cross-sectional imaging-defined radiologic response and remission using MRE or CTE when available; intestinal ultrasound-defined response and remission or transmural healing; and disease progression or poor outcomes. The study will also include family-based and exploratory analyses. The inclusion of unaffected first-degree relatives is intended to support analyses of genetic susceptibility, shared environmental exposure, immune profiles, microbiome features, and other biomarkers related to inflammatory bowel disease. Exploratory analyses may assess genetic or pharmacogenetic markers, multi-omics-derived biomarkers, and biomarker profiles associated with complex Crohn's disease phenotypes, including perianal fistula, stricturing disease, penetrating disease, surgery, treatment escalation, or treatment failure. Previously collected biospecimens and clinical data from prior ethics-approved prospective studies may be included as discovery datasets when permitted by the original consent, ethics approval, and the current platform protocol. Later enrolled participants from the same research network may be used as an internal validation cohort. Participants from collaborating centers or external datasets may be used as an external validation cohort when available. This discovery and validation framework is intended to improve reproducibility, reduce overfitting, and evaluate the generalizability of candidate biomarkers and biomarker-based prediction models. Statistical analyses may include descriptive statistics, group comparisons, correlation analyses, regression models, survival analyses, mixed-effects models for longitudinal data, receiver operating characteristic analyses, threshold exploration, model calibration, model discrimination, reclassification analyses, decision curve analyses, and internal or external validation. The long-term goal is to provide a standardized clinical and biospecimen platform to support objective disease monitoring, treatment prediction, risk stratification, and future precision medicine research in inflammatory bowel disease.
Interventions
None listed
Sponsors
Sixth Affiliated Hospital, Sun Yat-sen University
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Eligibility Criteria: Inclusion Criteria: 1. General inclusion criteria for all participants: * Age 14 years or older. * Able to provide written informed consent; for minors, consent from a legal guardian and assent from the participant will be obtained according to local ethics requirements. * Willing to provide clinical information and/or biospecimens, which may include blood, stool, intestinal tissue, or other available biological samples. * Able to participate in study-related data and sample collection according to the study protocol. 2. Participants with inflammatory bowel disease: * Diagnosed with inflammatory bowel disease, including Crohn's disease, ulcerative colitis, or IBD-unclassified when applicable, according to accepted national or international diagnostic criteria. * May be newly diagnosed, previously diagnosed, under routine follow-up, or receiving routine clinical treatment. * Clinical data, treatment exposure information, laboratory results, endoscopic findings, histologic findings, imaging findings, biospecimens, and follow-up outcomes may be available or collected. 3. Unaffected first-degree relatives of participants with inflammatory bowel disease: * Biological first-degree relatives of participants with inflammatory bowel disease, including parents, siblings, or offspring. * No prior diagnosis of inflammatory bowel disease at enrollment. * Willing to provide clinical information and/or biospecimens for family-based genetic, environmental, immune, microbiome, and multi-omics analyses. 4. Unrelated healthy controls: * Individuals without a diagnosis of inflammatory bowel disease. * No first-degree biological relationship to enrolled participants with inflammatory bowel disease. * No known active gastrointestinal inflammatory disease at enrollment. 5. Non-IBD disease controls: * Individuals with gastrointestinal symptoms or other non-IBD conditions who undergo clinical evaluation but are not diagnosed with inflammatory bowel disease. * Clinical information and/or biospecimens may be collected as disease controls when appropriate.
Exclusion criteria
* Refusal or inability to provide informed consent or required assent when applicable. * Active severe infection or chronic infectious disease that may substantially affect biomarker interpretation, including active tuberculosis, active hepatitis B or C, HIV infection, or other clinically significant active infection. * Pregnancy or lactation at the time of enrollment. * Severe mental illness, cognitive impairment, or other condition that prevents cooperation with study procedures. * Known primary extraintestinal autoimmune disease or systemic inflammatory disease that is considered the main disease and may substantially confound biomarker interpretation. * Current or recent participation in another interventional clinical trial that may substantially affect the study biomarkers or outcome assessments, as judged by the investigator. * History of malignant tumor or other severe comorbidity that may substantially affect study participation or biomarker interpretation, as judged by the investigator. * Inadequate biospecimen quality, missing key clinical information, or inability to complete essential study assessments for the relevant analysis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Diagnostic Performance of Candidate Biomarkers or Combined Biomarker Models for Endoscopic Disease Activity | At paired biospecimen and endoscopy assessments, with biospecimen collection within 30 days before or after endoscopy; assessed from enrollment through 52 weeks per participant | Diagnostic performance of pre-specified and newly identified candidate biomarkers or combined biomarker models for identifying endoscopic disease activity in inflammatory bowel disease. Endoscopic assessments will serve as the primary reference standard. Reference measures may include SES-CD, standardized small-bowel endoscopic assessments, capsule endoscopy scores, Mayo endoscopic score, UCEIS, or other accepted endoscopic assessments when applicable. Performance measures will include AUC, sensitivity, specificity, positive predictive value, negative predictive value, and biomarker cut-off values. Cut-off values will be explored in discovery datasets and evaluated in internal and external validation cohorts. |
| Predictive Performance of Candidate Biomarkers or Combined Biomarker Models for Treatment Response | From treatment baseline to induction assessment at approximately 12 to 16 weeks; maintenance assessment up to 52 weeks when available | Predictive performance of baseline candidate biomarkers, longitudinal biomarker changes, or combined biomarker models for response to routine clinical treatment will be evaluated. Treatment response outcomes may include clinical response, clinical remission, endoscopic response, endoscopic remission, inflammatory marker response, imaging response, treatment escalation, treatment failure, hospitalization, surgery, or relapse when available. Treatments are not assigned by the study and are recorded only as routine-care clinical exposures. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Diagnostic Performance of Candidate Biomarkers or Combined Biomarker Models for Histologic Disease Activity and Remission | At paired biospecimen and histologic assessments, with biospecimen collection within 30 days before or after tissue sampling; assessed from enrollment through 52 weeks per participant when available | Diagnostic performance of candidate biomarkers or combined biomarker models for histologic disease activity and histologic remission will be evaluated when tissue samples or pathology results are available. For ulcerative colitis, histologic activity may be assessed using Nancy Histological Index, Geboes score, Robarts Histopathology Index, or local pathology assessment when available. For Crohn's disease, active histologic inflammation may be assessed using standardized or study-defined pathology criteria when available. Performance measures may include AUC, sensitivity, specificity, predictive values, and biomarker cut-off values. |
| Concordance and Predictive Performance of Candidate Biomarkers or Combined Models for Clinical Remission Rate | At treatment baseline and routine-care follow-up assessments, including induction assessment at approximately 12 to 16 weeks and maintenance assessment up to 52 weeks per participant when available | Concordance and predictive performance of candidate biomarkers or combined biomarker models for clinical remission rate will be evaluated. Clinical remission rate is the proportion of participants achieving disease-specific clinical remission at follow-up. For Crohn's disease, remission will be defined uniformly as CDAI \<150. HBI will not define this registered endpoint and may be used only for supportive analyses. For ulcerative colitis, remission will be defined as partial Mayo score \<=2 with no individual subscore \>1 and rectal bleeding subscore =0. Analyses will compare biomarker levels and changes with remission status and remission rate. |
| Concordance and Predictive Performance of Candidate Biomarkers or Combined Models for Clinical Response Rate | At treatment baseline and routine-care follow-up assessments, including induction assessment at approximately 12 to 16 weeks and maintenance assessment up to 52 weeks per participant when available | Concordance and predictive performance of candidate biomarkers or combined biomarker models for clinical response rate will be evaluated. Clinical response rate is the proportion of participants achieving disease-specific clinical response at follow-up. For Crohn's disease, response will be defined uniformly as a CDAI decrease of at least 100 points from treatment baseline. HBI will not define this registered endpoint and may be used only for supportive analyses. For ulcerative colitis, response will be defined as a partial Mayo score decrease of at least 2 points and at least 30% from baseline, with rectal bleeding subscore decrease of at least 1 point or absolute rectal bleeding subscore of 0 or 1. |
| Concordance Between Candidate Biomarkers or Combined Models and Fecal Calprotectin for Intestinal Inflammatory Activity | At paired biospecimen and fecal calprotectin assessments at baseline, induction assessment at approximately 12 to 16 weeks, and maintenance assessment up to 52 weeks per participant when available | Concordance between candidate biomarkers or combined biomarker models and fecal calprotectin (FC) as an established stool-based comparator biomarker for intestinal inflammatory activity will be evaluated. FC will be measured in micrograms/g and analyzed as a continuous variable and by categories: \<150, 150-250, and \>250 micrograms/g when applicable. Analyses will assess cross-sectional concordance and longitudinal trend consistency between biomarker changes and FC changes. FC response may be defined as at least 50% decrease from baseline among participants with elevated baseline FC, and FC normalization as \<150 micrograms/g. FC will not serve as the primary reference standard. |
| Concordance Between Candidate Biomarkers or Combined Models and C-Reactive Protein for Systemic Inflammatory Activity | At paired biospecimen and C-reactive protein assessments at baseline, induction assessment at approximately 12 to 16 weeks, and maintenance assessment up to 52 weeks per participant when available | Concordance between candidate biomarkers or combined biomarker models and C-reactive protein (CRP) as an established blood-based comparator biomarker for systemic inflammatory activity will be evaluated. CRP will be measured in mg/L and analyzed as a continuous variable and by normal versus elevated status. CRP normalization will be defined as below the local laboratory upper limit of normal, with \<5 mg/L used for standardized analyses when applicable. CRP response may be defined as at least 50% decrease from baseline among participants with elevated baseline CRP. Analyses will assess cross-sectional concordance and longitudinal trend consistency. CRP will not serve as the primary reference standard. |
| Predictive Performance of Candidate Biomarkers or Combined Models for Cross-Sectional Imaging-Defined Radiologic Response Rate | From treatment baseline MRE or CTE to follow-up MRE or CTE at approximately 12 to 16 weeks and up to 52 weeks per participant when available | Predictive performance of candidate biomarkers or combined biomarker models for cross-sectional imaging-defined radiologic response rate will be evaluated in participants with Crohn's disease who have paired baseline and follow-up MRE or CTE. Imaging modality will be MRE or CTE depending on availability. For MRE, radiologic response may be defined as at least 50% reduction in index-segment or global MaRIA score, or decrease of an active segment from MaRIA \>=7 to \<7. For CTE, radiologic response may be defined as reduction or resolution of active inflammatory features in the index segment, including wall thickening, mural hyperenhancement, stratification, inflammatory fat stranding, or inflammatory mass, without new or worsening complications. |
| Predictive Performance of Candidate Biomarkers or Combined Models for Cross-Sectional Imaging-Defined Radiologic Remission Rate | From treatment baseline MRE or CTE to follow-up MRE or CTE at approximately 12 to 16 weeks and up to 52 weeks per participant when available | Predictive performance of candidate biomarkers or combined biomarker models for cross-sectional imaging-defined radiologic remission rate will be evaluated in participants with Crohn's disease who have follow-up MRE or CTE. Imaging modality will be MRE or CTE depending on availability. For MRE, radiologic remission may be defined as all evaluable bowel segments having MaRIA \<7, with no active penetrating complication when applicable. For CTE, radiologic remission may be defined as absence of active mural inflammatory features in evaluable diseased segments, including no active hyperenhancement, stratification, inflammatory fat stranding, inflammatory mass, abscess, phlegmon, or new penetrating complication. Fixed fibrotic stricture without active inflammation will be recorded separately. |
| Predictive Performance of Candidate Biomarkers or Combined Models for Intestinal Ultrasound-Defined Response Rate | From treatment baseline intestinal ultrasound to follow-up intestinal ultrasound at approximately 12 to 16 weeks and up to 52 weeks per participant when available | Predictive performance of candidate biomarkers or combined biomarker models for intestinal ultrasound-defined response rate will be evaluated when paired IUS data are available. IUS response may be defined as a relative reduction in bowel wall thickness of at least 25% from baseline in the index segment, or multifactorial improvement including bowel wall thickness reduction plus at least one-grade improvement in color Doppler signal or another IUS inflammatory parameter. Supportive analyses may use an absolute bowel wall thickness reduction of at least 1 mm. Outcomes will include IUS response rate, change in bowel wall thickness, color Doppler signal, IBUS-SAS when available, and biomarker predictive performance. |
| Predictive Performance of Candidate Biomarkers or Combined Models for Intestinal Ultrasound-Defined Remission or Transmural Healing Rate | From treatment baseline intestinal ultrasound to follow-up intestinal ultrasound at approximately 12 to 16 weeks and up to 52 weeks per participant when available | Predictive performance of candidate biomarkers or combined biomarker models for IUS-defined remission or transmural healing rate will be evaluated when follow-up IUS data are available. IUS-defined remission or transmural healing may be defined as normalization of bowel wall thickness to 3 mm or less in all evaluable involved segments, with absent or normal color Doppler signal when applicable. A stricter supportive definition may require normalization of multiple IUS parameters, including bowel wall thickness, Doppler signal, bowel wall stratification, mesenteric inflammatory fat, and absence of active IUS-detected complications. Outcomes will include IUS remission or transmural healing rate and biomarker predictive performance. |
| Predictive Performance of Candidate Biomarkers or Combined Models for Disease Progression and Poor Outcomes | From enrollment to the end of available follow-up, up to 5 years per participant when available | Predictive performance of baseline candidate biomarkers, longitudinal biomarker changes, or combined biomarker models for disease progression and poor outcomes will be evaluated. Outcomes may include new or progressive stricturing Crohn's disease, penetrating disease, perianal disease progression, treatment escalation, treatment failure, hospitalization, surgery, relapse, or other study-defined adverse outcomes. Analyses may include time-to-event models, logistic regression, discrimination, calibration, and validation metrics. |
Countries
China
Contacts
CONTACTWei Wang, MD & PhD
Outcome results
None listed