Recommendations for Broadening Eligibility Criteria in Inflammatory Bowel Disease Clinical Trials.

BACKGROUND: Clinical trial recruitment for patients with inflammatory bowel disease (IBD) has become more challenging over time. We aimed to develop recommendations for broadening IBD clinical trial eligibility to improve the inclusion of a more representative patient population in a more efficient timeline. METHODS: We applied the RAND/UCLA Appropriateness Method focused on broadening IBD clinical trial eligibility. A literature review was performed for 7 domains, each representing a different area related to trial recruitment. Based on these domains, 32 statements were developed. A questionnaire was sent to IBD specialists to anonymously vote on each statement with regards to its appropriateness and feasibility. After the first round of voting, participants met for a moderated discussion to review all statements. At the end of the discussion a second round of anonymous voting led to the final recommendations. RESULTS: The final round of voting resulted in 26 statements. All were rated as feasible and 25 of 26 rated as appropriate. Recommendations generally are to be more inclusive of complicated disease phenotypes, more liberal around safety criteria, to recognize the importance of non-invasive imaging and biomarkers, to minimize the washout period and to not enforce a minimum or maximum number of prior medications, to allow a recently recorded colonoscopy to count as a baseline study, and to be less restrictive of age. CONCLUSION: Recommendations to broaden clinical trial eligibility were found to be both appropriate and feasible with a high degree of agreement amongst an international group of IBD specialists.

Efficacy and Safety of Ustekinumab for Chronic Pouchitis: A Prospective Open-label Multicenter Study.

BACKGROUND & AIMS: Seventeen percent of patients with ulcerative colitis that undergo proctocolectomy with pouch surgery will develop chronic pouchitis. We evaluated the efficacy of ustekinumab for these patients. METHODS: We performed a prospective study of patients with chronic pouchitis receiving ustekinumab intravenously at baseline (∼6 mg/kg) and 90 mg ustekinumab subcutaneously every 8 weeks thereafter. The Modified Pouchitis Disease Activity Index (mPDAI) was assessed at baseline and weeks 16 and 48. The primary endpoint was the proportion of patients achieving steroid-free remission (mPDAI <5 and reduction by ≥2 points) at week 16. Secondary endpoints included the proportion of patients achieving remission at week 48, the proportion of patients achieving response (reduction of mPDAI by ≥2 points) at weeks 16 and 48, and change in mPDAI. RESULTS: We enrolled 22 patients (59% male; median age, 42.2 years). Remission was achieved in 27.3% at week 16 and 36.4% at week 48. Response was achieved in 54.5% both at weeks 16 and 48. The median mPDAI decreased from 8 (interquartile range [IQR], 7-10) to 7 (IQR, 4-9) at week 16 (P = .007) and 4 (IQR, 1.75-7.25) at week 48 (P < .001). The clinical mPDAI subscore decreased from 3.5 (IQR, 2-4) to 2 (IQR, 1-3) at week 16 (P = .009) and 1 (IQR, 0-2.25) at week 48 (P = .001). The endoscopic mPDAI subscore decreased from 5.5 (IQR, 4-6) to 4 (IQR, 3-6) at week 16 (P = .032) and 3 (IQR, 1.75-4.25) at week 48 (P = .001). CONCLUSION: Ustekinumab was efficacious in one-half of the patients suffering from chronic pouchitis. Ustekinumab should therefore be positioned in the treatment algorithm of chronic pouchitis. (ClinicalTrials.gov Number NCT04089345).

Analysis of Clinical Trial Screen Failures in Inflammatory Bowel Diseases (IBD): Real World Results from the International Organization for the study of IBD.

BACKGROUND: Recruitment for randomized controlled trials (RCTs) in IBD have substantially dropped over time. This study aimed to assess reasons why IBD patients are not included in sponsored multicenter phase IIb-III RCTs. METHODS: All IOIBD members (n=58) were invited to participate. We divided barriers to participation as follow: 1) reasons patients with active IBD were not deemed appropriate for a RCT; 2) reasons qualified patients did not wish to participate; 3) reasons for screen failure (SF) in patients agreeing to participate. We assess those in a 4-week prospective study including, consecutively, all patients with symptomatic disease for whom a treatment change was required. In addition, we performed a 6-month retrospective study to further evaluate reasons for SF. RESULTS: A total of 106 patients (60 male (56.6%), 63 Crohn's disease [CD] (59.4%)), from 10 centers across the world, were included in the prospective study. A RCT has not been proposed to 65 of them (mainly due to eligibility criteria). Of the 41 patients to whom a RCT was offered, 8 refused (mainly due to reluctance to receive placebo) and 28 agreed to participate. Among these 28 patients, 5 failed their screening and 23 were finally included in a RCT. A total of 107 patients (61 male (57%), 67 CD (62.6%)), from 13 centers worldwide, were included in our retrospective study of SFs. The main reason was insufficient disease activity. CONCLUSION: This first multicenter study analyzing reasons for non-enrollment in IBD RCTs shown that we lose patients at each step. Eligibility criteria, the risk of placebo assignment and insufficient disease activity were part of the main barriers.

Screening Failure in a Large Clinical Trial Centre for Inflammatory Bowel Diseases: Rates, Causes, and Outcomes.

BACKGROUND: Patients with inflammatory bowel diseases (IBD) sometimes require investigational medicinal therapy in a clinical trial. Before enrollment, patients must meet strict eligibility criteria, hampering recruitment rates. We investigated the rates, causes, and outcomes of screening failure (SF) in a tertiary IBD center. METHODS: We reviewed all IBD patients screened for sponsored multicenter phase 1-3 induction studies with available global SF rates between January 2008 and March 2021. We compared our SF rates with the global SF rates. Causes of SF were categorized into disease activity, hematology, chemistry, microbiology, protocol violation, and withdrawal of consent. Patient outcomes were categorized into rescreening for the same trial, screening for another trial, (re)introduction of commercially available therapy, surgery, or watchful waiting. RESULTS: During the study period, 642 local screenings were performed as part of 53 studies. We identified an overall SF rate of 17.1%, compared with 39.2% in the global study population (P < .00001). Causes of SF at our center included ineligible disease activity (36.4%), microbiology (25.5%), protocol violation (16.4%), withdrawal of consent (9.1%), chemistry (6.4%) and hematology (6.4%). Thirty SFs could have been avoided by prescreening that was more thorough. After SF, 34 patients were rescreened for the same trial, 17 screened for another trial, 38 initiated approved therapy, 9 were referred for surgery, and 12 did not receive further therapy. CONCLUSIONS: A significant proportion of IBD patients consenting to clinical trials fail their screening. Main causes of SF are ineligible disease activity and abnormal finding on microbiology. Approximately one-fourth of SFs could have been avoided by prescreening that was more thorough.

Using provocative design to foster electronic informed consent innovation.

BACKGROUND: The development of technological applications in clinical research, such as electronic informed consent (eIC), is on the rise. The involvement of end users throughout the design process of eIC is of utmost importance to improve the current informed consent process. METHODS: Using a provocative design, we conducted interviews with 30 clinical research participants. Provotypes were used as a starting base to discuss various aspects relevant to eIC. By providing a medium to encourage divergent thinking, participants' views and concerns were solicited. Thematic analysis was undertaken using NVivo. RESULTS: The majority of participants placed trust in the principal investigator or the hospital to perform the role of eIC hosting party. Differing opinions were reported on the amount of information required related to stakeholders' access to an eIC system, and thus, to participants' personal data, to enable trust in an eIC system. Nevertheless, this study indicates a general willingness of participants to share personal data with physicians and pharmaceutical companies on an international level, and to receive requests for new research studies via an eIC system. Participants suggested to tailor an eIC system based upon their preferences, for example, regarding whom they want to share their personal data with. Moreover, they expressed a desire to choose how they can contact the research team, and to indicate which study-related information they would like to receive electronically. In addition, positive opinions were voiced on the integration of a test to assess participants' understanding before providing their eIC. CONCLUSIONS: Following a research through design approach, insights have been generated which inform the design of eIC. Provotypes were designed to help participants think beyond what is familiar to them. Study findings revealed that not all situations were perceived as provocative, because of participants' motivation to advance scientific research and the trust they place in the research team. Nevertheless, the use of provocative design resulted in additional insights, generated by clinical research participants, which could be considered in the further design of eIC.

Multi-model averaging improves the performance of model-guided infliximab dosing in patients with inflammatory bowel diseases.

Infliximab dosage de-escalation without prior knowledge of drug concentrations may put patients at risk for underexposure and trigger the loss of response. A single-model approach for model-informed precision dosing during infliximab maintenance therapy has proven its clinical benefit in patients with inflammatory bowel diseases. We evaluated the predictive performances of two multi-model approaches, a model selection algorithm and a model averaging algorithm, using 18 published population pharmacokinetic models of infliximab for guiding dosage de-escalation. Data of 54 patients with Crohn's disease and ulcerative colitis who underwent infliximab dosage de-escalation after an earlier escalation were used. A priori prediction (based solely on covariate data) and maximum a posteriori prediction (based on covariate data and trough concentrations) were compared using accuracy and precision metrics and the classification accuracy at the trough concentration target of 5.0 mg/L. A priori prediction was inaccurate and imprecise, with the lowest classification accuracies irrespective of the approach (median 59%, interquartile range 59%-63%). Using the maximum a posteriori prediction, the model averaging algorithm had systematically better predictive performance than the model selection algorithm or the single-model approach with any model, regardless of the number of concentration data. Only a single trough concentration (preferably at the point of care) sufficed for accurate and precise prediction. Predictive performance of both single- and multi-model approaches was robust to the lack of covariate data. Model averaging using four models demonstrated similar predictive performance with a five-fold shorter computation time. This model averaging algorithm was implemented in the TDMx software tool to guide infliximab dosage de-escalation in the forthcoming prospective MODIFI study (NCT04982172).

Longitudinal monitoring of STAT3 phosphorylation and histologic outcome of tofacitinib therapy in patients with ulcerative colitis.

BACKGROUND: Tofacitinib is the first in class, pan-JAK inhibitor approved for ulcerative colitis (UC). Clinical efficacy has been shown, but long-term real-life endoscopic and histologic data are lacking. AIM: To investigate the effects of tofacitinib in patients with refractory UC focussing on endoscopic, histologic and molecular outcomes, including STAT3 phosphorylation (pSTAT3) detection in the spatial context of mucosal inflammation METHODS: We prospectively monitored 59 highly refractory patients (96.7% anti-TNF exposure, 91.7% vedolizumab exposure) initiating tofacitinib at two IBD referral centres and assessed outcome at the end of induction and after 48 weeks of therapy. Endoscopic improvement was defined as a Mayo endoscopic subscore ≤1, endoscopic and histologic remission as Mayo endoscopic subscore 0 and Nancy histologic score 0. Multiplex immunohistochemistry with multispectral imaging was used to assess pSTAT3. RESULTS: Endoscopic improvement was achieved by 24.4% and 30.5% of patients at weeks 8 and 48, respectively. Endoscopic and histologic remission rates were 11.1%, 23.7 and 16.7%, 21.4%, respectively. Endoscopic improvement at week 8 was significantly associated with treatment continuation in the long-term (72.7% vs 20.6%, p = 0.003). Although we observed a gradual decrease of mucosal pSTAT3 levels in both remitters and non-remitters (p < 0.05), no association with treatment outcome could be demonstrated. However, lamina propria pSTAT3 was significantly associated with the Nancy Histologic index (p = 0.004). CONCLUSION: Tofacitinib can induce and maintain endoscopic and histologic remission in up to one-quarter of highly refractory UC patients. Longitudinal monitoring of nuclear pSTAT3 in mucosal tissue compartments reflects distinctive on-target effects, independently of long-term treatment outcomes.

Safety and efficacy of combining biologics or small molecules for inflammatory bowel disease or immune-mediated inflammatory diseases: A European retrospective observational study.

BACKGROUND AND AIMS: Few data are available regarding the combination of biologics or small molecules in inflammatory bowel disease (IBD) patients. We report safety and efficacy of such combinations through a retrospective multicentre series. METHODS: Combination therapy was defined as the concomitant use of two biologics or one biologic with a small molecule. Patient demographics, disease characteristics and types of combinations were recorded. Safety was evaluated according to the occurrence of serious infection, opportunistic infection, hospitalisation, life-threatening event, worsening of IBD or immune-mediated inflammatory diseases (IMID), cancer and death. Efficacy was evaluated as the physician global assessment of the combination and comparison of clinical/endoscopic scores of IBD/IMID activity prior and during combination. RESULTS: A total of 104 combinations were collected in 98 patients. Concomitant IMID were present in 41 patients. Reasons for starting combination therapy were active IBD (67%), active IMID or extra-intestinal manifestations (EIM) (22%), both (10%) and unclassified in 1. Median duration of combination was 8 months (interquartile range 5-16). During 122 patient-years of follow-up, 42 significant adverse events were observed, mostly related to uncontrolled IBD. There were 10 significant infections, 1 skin cancer and no death. IBD disease activity was clinically improved in 70% and IMID/EIM activity in 81% of the patients. Overall, combination was continued in 55% of the patients. CONCLUSIONS: Combination of biologics and small molecules in patients with IBD and IMID/EIM seems to be a promising therapeutic strategy but is also associated with a risk of opportunistic infections or infections leading to hospitalisation in 10%.

Chronic Antibiotic-Refractory Pouchitis: Management Challenges.

BACKGROUND: Pouchitis is the most common long-term complication in patients with ulcerative colitis who underwent restorative proctocolectomy with ileal pouch-anal anastomosis. The incidence of acute pouchitis is 20% after 1 year and up to 40% after 5 years. Chronic antibiotic-refractory pouchitis develops in approximately 10% of patients. AIM: To present a narrative review of published literature regarding the management of chronic antibiotic-refractory pouchitis. METHODS: Current relevant literature was summarized and critically evaluated. RESULTS: Clear definitions should be used to classify pouchitis into acute versus chronic, and responsive versus dependent versus refractory to antibiotics. Before treatment is started for chronic antibiotic-refractory pouchitis, secondary causes should be ruled out. There is a need for validated scoring systems to measure the severity of the disease. Because chronic antibiotic-refractory pouchitis is a rare condition, only small studies with often a poor study design have been performed. Treatments with antibiotics, aminosalicylates, steroids, immunomodulators and biologics have shown to be effective and safe for chronic antibiotic-refractory pouchitis. Also, treatments with AST-120, hyperbaric oxygen therapy, tacrolimus enemas, and granulocyte and monocyte apheresis suggested some efficacy. CONCLUSION: The available data are weak but suggest that therapeutic options for chronic antibiotic-refractory pouchitis are similar to the treatment strategies for inflammatory bowel diseases. However, randomized controlled trials are warranted to further identify the best treatment options in this patient population.

Health Literacy and Quality of Life in Young Adults From The Belgian Crohn's Disease Registry Compared to Type 1 Diabetes Mellitus.

Background and Aims: The management of chronic inflammatory bowel diseases in youth is challenging. We aimed to determine health literacy (HL), quality of life (QoL) and clinical outcomes in young adults from the BELgian CROhn's disease registry (BELCRO) in comparison to type 1 diabetes mellitus (DM) as a control. Methods: In this prospective and observational study, young adults with Crohn's disease (CD) diagnosed < 18 years and with > 5 years disease duration and a comparable group of patients with DM completed validated HL, QoL and work productivity and activity impairment questionnaires (HLS-EU-Q16, EQ-5D-5L and WPAI). HL was scored as sufficient (13-16), problematic (9-12) or inadequate (0-8). QoL was dichotomized into "no problems" (EQ-5D level 1) or "problems" (EQ-5D levels 2 to 5). Non-parametric (Mann-Whitney U) analyses and Spearman correlations were performed. Results: A total of 52 CD (median [IQR] age of 25.0 [23.8-27.0], 64% male) and 50 DM (age 20.0 [19.0-22.0], 50% male) patients were included. HL was 14.0 [11.0-16.0] for CD and 14.0 [11.3-14.8] for DM (p = 0.6) with similar proportions of sufficient (60 vs. 68%, p = 0.4), problematic (34 vs. 26%, p = 0.3) and inadequate HL (both 6%, p = 1). Although QoL was comparable for CD and DM (77.0 [68.8-82.0] vs. 75.0 [65.0-80.0] %, p =0.4), CD had a trend for higher pain/discomfort (50 vs. 32%, p = 0.06). HL and QoL correlated in CD (r = 0.6, p < 0.001) and DM patients (r = 0.6, p < 0.001). Fewer CD patients with recent hospitalization/surgery had sufficient HL (31 vs. 69%, p = 0.01) and had lower QoL (70.0 [60.0-77.0] vs. 80.0 [70.0-85.0], p = 0.04) compared to those without. Conclusions: Selected young Belgian adults suffering from CD for >5 years have similar and sufficient HL compared to DM patients. However, CD patients requiring hospitalization/surgery have lower HL, which indicates the need for targeted educational programs.

Influence of Drug Exposure on Vedolizumab-Induced Endoscopic Remission in Anti-Tumour Necrosis Factor [TNF] Naïve and Anti-TNF Exposed IBD Patients.

BACKGROUND AND OBJECTIVES: Vedolizumab has demonstrated efficacy and safety in patients with Crohn's disease [CD] and ulcerative colitis [UC]. Endoscopic outcome data are limited, especially in anti-tumour necrosis factor [TNF] naïve patients. The present study compared endoscopic outcome in anti-TNF naïve and exposed patients, and explored if this was affected by drug exposure. METHODS: We retrospectively analysed all patients initiating vedolizumab at our tertiary referral centre since 2015. For UC, endoscopic improvement was defined as a Mayo endoscopic subscore ≤1 at week 14. For CD, endoscopic remission was defined as absence of ulcerations at week 22. Vedolizumab trough concentrations were measured at week 6, week 14 and during maintenance. RESULTS: A total of 336 patients were identified [53.3% CD], 20% of them being anti-TNF naïve. Endoscopic improvement was achieved by 56.1% of UC patients and endoscopic remission by 39.1% of CD patients. Endoscopic outcomes were significantly better in anti-TNF naïve vs exposed patients [all: 67.2% vs 42.0%, p = 0.0002; UC: 74.4% vs 50.0%, p = 0.02; CD: 57.1% vs 35.8%, p = 0.03]. Achievement of endoscopic end points significantly impacted long-term treatment continuation [p = 9.7 × 10-13]. A better endoscopic outcome was associated with significantly higher drug exposure in both CD and UC. CONCLUSIONS: The results of this observational, single-centre real-life study suggest that vedolizumab may induce endoscopic remission in both CD and UC. Although anti-TNF naïve patients had a significantly better outcome, 42% of anti-TNF exposed patients still benefited endoscopically. A clear exposure-endoscopic response relationship exists, but not all patients will benefit from treatment intensification. Hence, predictive biomarkers remain necessary. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Ustekinumab Exposure-outcome Analysis in Crohn's Disease Only in Part Explains Limited Endoscopic Remission Rates.

BACKGROUND AND AIMS: Ustekinumab, an anti-IL12/23p40 monoclonal antibody, has been approved for Crohn's disease [CD]. Real-life data in CD patients receiving ustekinumab intravenously [IV] during induction, followed by subcutaneous [SC] maintenance, are lacking. We assessed efficacy of ustekinumab and studied exposure-response correlations. METHODS: We performed a prospective study in 86 CD patients predominantly refractory or intolerant to anti-tumour necrosis factor agents and/or vedolizumab. All received ustekinumab 6 mg/kg IV induction, with 90 mg SC every 8 weeks thereafter. Endoscopic response (50% decrease in Simple Endoscopic Score for CD [SES-CD] at Week 24), endoscopic remission [SES-CD ≤2], and clinical remission [daily stool frequency ≤2.8 and abdominal pain score ≤1] were assessed at weeks 4,8,16, and 24. Further serial analyses included patient-reported outcomes [PRO2], faecal calprotectin [fCal], and ustekinumab serum levels. RESULTS: SES-CD decreased from 11.5 [8.0-18.0] at baseline to 9.0 [6.0-16.0] at week [w]24 [p = 0.0009], but proportions of patients achieving endoscopic response [20.5%] or endoscopic remission [7.1%] were low. Clinical remission rates were 39.5% at w24. After IV induction, fCal dropped from baseline [1242.9 µg/g] to w4 [529.0 µg/g] and w8 [372.2 µg/g], but increased again by w16 [537.4 µg/g] and w24 [749.0 µg/g]. A clear exposure-response relationship was observed, both during induction and during maintenance therapy, with different thresholds depending on the targeted outcome. CONCLUSIONS: In this cohort of refractory CD patients, ustekinumab showed good clinical remission rates but limited endoscopic remission after 24 weeks. Our data suggest that higher doses may be required to achieve better endoscopic outcomes.