Identification of Predictive Biomarkers for Response to Biologic Therapies and Tofacitinib in Inflammatory Bowel Disease

Study Overview
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Brief Summary
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Prospective, multicentre trial which the biologic treatment will be initiated by clinical indication. The treatment selection anti-TNFα (infliximab, adalimumab or golimumab), vedolizumab, ustekinumab and tofacitinib will be made at the discretion of the clinician. There will be no random assignment of treatment. The drugs will be used in the approved indications and conditions of use.

Detailed Description
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Background IBD, including CD and UC, is a chronic disorder of unknown etiology that involves a pathological response of the immune system, resulting in chronic inflammation of the gastrointestinal tract. IBD generally affects young patients, being a highly disabling disease. Unfortunately IBD has no current treatment, so the therapeutic goal is to keep the inflammatory process under control in order to prevent the onset of symptoms and the development of further complications. The complexity and costs associated with the treatment of IBD make it a very relevant disease. Specifically in the USA, where it is one of the five diseases with the greatest social burden, with an annual cost of 1,700 million dollars for health services. In Europe, the annual costs (direct and indirect) associated with IBD exceed 25,000 million euros. Together, this highlights the strategic importance of IBD for society, including both patients and the health system. IBD prevalence is high, affecting more than 1.6 million inhabitants in the US and more than 2.2 million in Europe. On the other hand, its incidence varies widely depending on the different countries. Nevertheless, in a generalized manner, it is increasing rapidly, probably due to the westernization of lifestyles. Indeed, a large multicenter study leaded by the host institution suggests that the current incidence is greater than previously described. In addition, the cost associated with IBD diagnosis and treatment is increasing over time, either because of the costs associated with the treatment itself or due to the greater complexity of the diagnostic tests and tools to which these patients are subjected. Despite the increasingly frequent use of immunosuppressant drugs, the need for surgery due to IBD has not changed substantially in recent decades. It has been suggested that early initiation of treatment with immunosuppressants and biologics to induce remission would prevent the onset of complications of the disease. However, this widely applied strategy would lead to overtreatment of patients who would have had a benign course of the disease. On the other hand, the current treatment strategy is similar in almost all patients with IBD: it starts, in general, with the less aggressive drugs, progressively moving to more potent therapies when previous treatments have failed. In this way, the window of opportunity to prevent complications in more complex patients is often lost. Thus, because there are no prognostic factors that have proven useful in clinical practice, the selection of a treatment for each patient remains empirical, adapted according to clinical evolution and difficulties of each case. Anti-TNFα drugs have been shown to be effective for induction of remission and maintenance thereof in patients with IBD. In 2014, the use of vedolizumab was approved, both for CD and UC, whose therapeutic targets are α4β7 integrins. In 2016, ustekinumab, directed against the p40 subunit shared by interleukins 12 and 23, was approved in patients with CD, thus increasing the therapeutic arsenal against IBD. All these biologic drugs have a high cost, so they pose a great economic burden for health systems. However, approximately only one third of patients will achieve remission. At present, the medical community does not have reliable criteria for selecting which patients will benefit from any of the above-mentioned drugs. Thus, the variables (epidemiological, clinical, analytical, etc.) usually used to predict patients' response to biological therapy have shown little utility. Therefore, it is a priority in the study of IBD the identification of those molecular and cellular pathways involved in the onset of IBD in each patient, in order to make a more rational use of resources. Achieving that goal will allow us to indicate the most appropriate treatment to each individual, hence avoiding administering drugs to patients who will not respond (which implies an inadequate use of resources and an unjustified risk of adverse effects). The identification of biomarkers with capacity to predict clinical response to biologic drugs is, therefore, an area of great interest. In this context, omic techniques allow massive searches at various levels, including DNA (genomics) and its modifications (epigenome), RNA (transcriptome), proteins (proteome), bacterial composition (microbiome), etc. This project aims to deepen this aspect through the use of 2 massive last-generation approaches that will identify the signaling routes (proteomics) and the immune cell subsets (mass cytometry) involved in the response to biologic drugs. This will ultimately lead to the identification, in an unbiased manner, of novel predictive biomarkers for response to biologic therapies in IBD. Study population Group 1: Patients with IBD that will start treatment with a biologic drug or tofacitinib according to medical criteria in the context of the usual clinical practice. Group 2: Individuals without IBD in whom an ileocolonoscopy is performed and is normal. Definitions Endoscopic activity: In patients with CD, it will be evaluated using the Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD); Endoscopic activity will be considered when the SES-CD is ≥3. In operated patients, or in those where the endoscopic exploration is incomplete, the SES-CD will be calculated according to the explorable segments, considering the previously described activity criterion. In patients with UC, it will be evaluated by the Mayo endoscopic sub-score; endoscopic activity will be considered as ≥2. The assessment of endoscopic activity will be carried out centrally by sending anonymized endoscopic images. Endoscopic response (main endpoint): In patients with CD, the endoscopic response will be defined as a >50% decrease in the SES-CD14 weeks after starting the biologic treatment. As a secondary variable, endoscopic response will be also defined as a decrease ≥3 points in the SES-CD (considered as a clinically significant endoscopic improvement). There is consensus that the evaluation of the response to treatment (and therefore the consideration of a patient as a primary non-responder) should not be performed before week 12-14 (in patients treated with anti-TNFα drugs). In patients with UC, the endoscopic response will be defined as a decrease of ≥1 point in the Mayo endoscopic sub-score 14 weeks after starting the biologic treatment. Endoscopic remission: In patients with CD, endoscopic remission will be defined as a SES-CD ≤2, 14 weeks after starting the biologic treatment. In patients with UC, endoscopic remission will be defined as an endoscopic subscript ≤1, 14 weeks after starting the biologic treatment. Clinical activity: In patients with CD, it will be evaluated using the Crohn's Disease Activity Index (CDAI). Clinical remission will be considered as a CDAI <150 points 14 weeks after starting the biologic treatment; and clinical response, reduction of CDAI by 100 (R-100) or 70 points (R-70). In patients with UC it will be evaluated by the partial Mayo index. Clinical remission will be considered as a partial Mayo index ≤2, with all the scores (of the partial index) of 1 as a maximum and with a sub-score of rectal bleeding of 0, 14 weeks after starting the biologic treatment; and clinical response, the decrease of 3 or more points (of the partial index) with respect to the baseline situation. Sample size The sample size for the laboratory analyses will be 30 in each of the subgroups of patients: 1) CD treated with anti-TNFα drugs; 2) CD treated with vedolizumab; 3) CD treated with ustekinumab; 4) UC treated with anti-TNFα; 5) UC treated with vedolizumab; 6) UC treated with tofacitinib. Since the total number of patients is 180, the inclusion for each of the 17 participating centers will be approximately 9 patients, a perfectly viable figure in the allocated timeframe. It is estimated that the percentage of endoscopic response (primary endpoint) is 30% so in each subgroup there will be 10 responding patients and 20 patients with treatment failure, an adequate number for the evaluation of biomarkers predictors of response. In addition, 30 healthy controls will be included to compare the obtained results in the IBD patients. Development of the study The present study is organized in 3 visits: visit 1, prior to initiating the treatment; visit 2, at 14 weeks after starting treatment; and visit end of study. The investigators will use their proved expertise in previous clinical trials to coordinate and monitor all the research centers using the online AEG-RedCap platform. Data collection forms will be provided to all the centers prior to start the study. The overall duration of the study is estimated at 3 years (20 months of inclusion + 4 months of follow-up + 12 months for analysis).

Official Title
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Identification of Predictive Biomarkers for Response to Biologic Therapies and Tofacitinib in Inflammatory Bowel Disease by Proteomic and Mass Cytometry Approaches

Conditions
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Inflammatory Bowel Diseases, Crohn Disease, Ulcerative Colitis

Intervention / Treatment
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* Biological: Infliximab or adalimumab or golimumab or vedolizumab or ustekinumab or tofacitinib


Participation Criteria
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Eligibility Criteria
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Group 1: Patients with IBD Inclusion Criteria: Over 18 years. Diagnosis of IBD according to the criteria of the European Crohns and Colitis Organization (ECCO). Have indication of treatment with a biologic drug or tofacitinib. Be the first received drug with a given mechanism of action (anti-TNFα, anti-α4β7, anti-p40 or Janus kinase (JAK) inhibitor). Have endoscopic activity of IBD within 1 month of starting the biologic treatment (see definitions section: SES-CD ≥ 3 in CD and endoscopic sub-index of May ≥ 2 in UC). In the case of CD, receive the biologic treatment by luminal activity (not perianal). Exclusion Criteria: Under 18 years old. Having an immune-mediated disease other than IBD at the baseline visit. Having a neoplasm or an active infection at the time of the baseline visit. Pregnancy or lactation. Alcohol or drug abuse. Ostomy. Abdominal surgery in the last 6 months. Colectomy in patients with UC. Active infection with hepatitis B, C or HIV virus. Indication of biologic treatment for a cause other than IBD. Indication of biologic treatment to prevent postoperative recurrence in CD. Have previously received a drug with the same mechanism of action of the drug indicated by your doctor (anti-TNFα, anti-α4β7, anti-p40 or JAK inhibitor). Refusal to give consent for participation in the study. Group 2: patients without IBD Inclusion Criteria: - Patients not diagnosed with IBD, or other inflammatory, allergic, malignant or autoimmune diseases, where a ileocolonoscopy is performed due to the normal clinical practice. Exclusion Criteria: Under 18 years old. Advanced chronic disease or any other pathology that prevents the follow-up of the protocol of this study. Pregnancy or lactation. Active infection with hepatitis B, C or HIV virus. Alcohol or drug abuse. Finding of macroscopic alterations during the ileocolonoscopy, or finding of relevant inflammatory alterations in the biopsies obtained during the ileocolonoscopy. Refusal to give consent for participation in the study.

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Patients with treatment<br>Infliximab (Infusion 5mg/kg milligram(s)/Kilogram-Intravenous use) per clinical practice, or adalimumab (Subcutaneus 40 mg milligram(s)) per clinical practice, or golimumab (subcutaneus 50 mg milligram(s)) per clinical practice, or vedolizumab (infusion 300 mg milligram(s)) per clinical practice or ustekinumab (subcutaneous 90 mg milligram(s)) per clinical practice or tofacitinib (oral 5mg bid oral) per clinical practice | Biological: Infliximab or adalimumab or golimumab or vedolizumab or ustekinumab or tofacitinib<br>* Infliximab (Infusion 5mg/kg milligram(s)/Kilogram-Intravenous use) per clinical practice or adalimumab (Subcutaneus 40 mg milligram(s)) per clinical practice or golimumab (subcutaneus 50 mg milligram(s)-subcutaneus) per clinical practice or vedolizumab (infusion 300 mg milligram(s)) per clinical practice or ustekinumab (subcutaneous 90 mg milligram(s)) per clinical practice or tofacitinib (oral 5mg bid)<br>|
| No Intervention: healthy control<br>Patients without treatment | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify predictive tissue and blood biomarkers for response to biologic therapies and tofacitinib in Crohn´s disease and ulcerative colitis | will be calculated for each of the selected biomarkers: sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify non-invasive blood biomarkers of endoscopical inflammation | will be calculated for each of the selected biomarkers: sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio | 14 weeks | 
| Evaluate the effect of the treatment on the immune subsets and study the signaling pathways specifically modulated | To achieve this outcome will be used endoscopic response defined in CD patients as a decrease of 50% in SES-CD(78) 14 weeks after starting treatment and defined in UC patients as a decrease ≥1 point in the mayo score (82) 14 weeks after starting treatment | 14 weeks | 
| Generate a collection of biological simple (Blood sample, urine sample, stool sample, biopsy simple) | these samples will be use to reach the outcomes of this study and will be used in future studies | 14 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-TNF, inflammatory bowel diseases, Crohn Disease, Ulcerative Colitis, Infliximab, Adalimumab, Golimumab, Vedolizumab, Ustekinumab, Tofacitinib