Clinical Trial Design Considerations for Hospitalised Patients With Ulcerative Colitis Flares and Application to Study Hyperbaric Oxygen Therapy in the NIDDK HBOT-UC Consortium.

BACKGROUND: Patients with ulcerative colitis (UC) who are hospitalised for acute severe flares represent a high-risk orphan population. AIM: To provide guidance for clinical trial design methodology in these patients. METHODS: We created a multi-centre consortium to design and conduct a clinical trial for a novel therapeutic intervention (hyperbaric oxygen therapy) in patients with UC hospitalised for moderate-severe flares. During planning, we identified and addressed specific gaps for inclusion/exclusion criteria; disease activity measures; pragmatic trial design considerations within care pathways for hospitalised patients; standardisation of care delivery; primary and secondary outcomes; and sample size and statistical analysis approaches. RESULTS: The Truelove-Witt criteria should not be used in isolation. Endoscopy is critical for defining eligible populations. Patient-reported outcomes should include rectal bleeding and stool frequency, with secondary measurement of urgency and nocturnal bowel movements. Trial design needs to be tailored to care pathways, with early intervention focused on replacing and/or optimising responsiveness to steroids and later interventions focused on testing novel rescue agents or strategies. The PRECIS-2 framework offers a means of tailoring to local populations. We provide standardisation of baseline testing, venous thromboprophylaxis, steroid dosing, discharge criteria and post-discharge follow-up to avoid confounding by usual care variability. Statistical considerations are provided given the small clinical trial nature of this population. CONCLUSION: We provide an outline for framework decisions made for the hyperbaric oxygen trial in patients hospitalised for UC flares. Future research should focus on the remaining gaps identified.

Drug-Induced Acne in Inflammatory Bowel Disease: A Practical Guide for the Gastroenterologist.

Drug-induced acne is a common side effect to a wide array of pharmacological therapies and is characterized by a monomorphic, papulopustular eruption typically affecting the face, scalp, and the upper thorax. Corticosteroids and Janus kinase inhibitors (JAKi) are commonly used for the treatment of inflammatory bowel disease (IBD) and are known to aggravate a prior tendency to acne or trigger the development of new acneiform eruptions. Recent attention on managing drug-induced acne has been driven by the increasing use of JAKi, an expanding therapeutic class in IBD and several other immune-mediated inflammatory diseases. Both randomized controlled trials and real-world studies have identified acne as one of the most common treatment-emergent adverse events in JAKi. Left untreated, this common skin reaction can significantly impact patient self-esteem and quality of life leading to poor treatment adherence and suboptimal IBD control. This review examines the characteristics of drug-induced acne in IBD treatments, provides a practical guide for gastroenterologists to manage mild to moderate occurrences, and highlights when to seek specialist dermatology advice. Such approaches enable early treatment of a common and often distressing adverse event and optimizes the management of IBD by preventing the premature discontinuation or dose reduction of efficacious IBD drugs.

Personalized (N-of-1) Clinical Trials for Inflammatory Bowel Disease: Opportunities and Challenges.

BACKGROUND & AIMS: Heterogeneity of treatment effects in inflammatory bowel disease (IBD) means that many individuals or patient subgroups depart from the average for whom the outcomes from traditional randomized trials may not be applicable. The N-of-1 trial is a design in which a single patient is followed over time with the treatments being randomized from period to period with the intention of finding the most effective treatment for that patient. The aim was to investigate the utility of N-of-1 trials in IBD. METHODS: To identify relevant articles for this scoping review, a MEDLINE literature search was conducted through the PubMed platform for articles published in the English language using the search terms "inflammatory bowel disease," "Crohn's disease," "ulcerative colitis," "N-of-1 trials," "single case designs," and "personalized trials." RESULTS: N-of-1 trials have seen a resurgence across several medical disciplines, driven by a need for more personalized medicine and patient-centered health care; their use in IBD is scarce with only 3 trials identified. Studies involving multiple N-of-1 trials can generate robust evidence for each participant and average effect estimates. The N-of-1 trial may hold potential for studying patients with IBD that are excluded from or underrepresented by randomized trials, such as those with extraintestinal manifestations, pouchitis, and proctitis. Although methodologically sound and akin to the rigor of a randomized controlled trial, the crossover periods inherent to the study design can be perceived as burdensome by patients and researchers. CONCLUSIONS: The N-of-1 trial design provides a patient-centered means of objectively determining individual response to therapy.

Nested Randomized Controlled Trials in Large Databases: An Opportunity for Inflammatory Bowel Disease?

Although randomized controlled trials (RCTs) are the gold standard for investigating the efficacy and safety of interventions, they present major operational challenges due to their complexity, time-consuming nature, and high costs. To address some of these difficulties, RCTs nested in cohorts (RCTsNC) have been developed to enable patient enrolment and randomization from existing databases. RCTsNC is an emerging trial design, which has been successfully utilized across several medical disciplines but not inflammatory bowel disease (IBD). This narrative review outlines the principles of RCTsNC and discusses the numerous advantages it affords for IBD, including harnessing longer-term longitudinal data for safety and efficacy assessment, and enhanced recruitment and follow up processes. Leveraging pre-existing cohorts and their organizational structures improves patient acceptance and is more economical compared to traditional randomized trials. Observational data for IBD, derived from research (cohort and case-control studies) and non-research sources (electronic health records and registries), provides access to comprehensive records for a large number of IBD patients. It permits researchers to address knowledge gaps in IBD where traditional RCTs have had a limited role, such as specific sub-populations typically excluded from pivotal trials, or assessing the effect of environmental exposures on disease course. This review also details caveats of this study design that include the risk of selection bias and constraints related to comparisons with placebo. In conclusion, RCTsNC offers a promising opportunity IBD research given the challenges of the current IBD RCT landscape.

Systematic review: Methotrexate-A poorly understood and underused medication in inflammatory bowel disease.

BACKGROUND: Methotrexate, an immunosuppressant used for the treatment of inflammatory bowel disease (IBD) for over 30 years, remains underused compared to thiopurines. AIMS: To review the efficacy, safety, optimal dosing and delivery regimens of methotrexate in adults with IBD. METHODS: We conducted a systematic review of studies involving patients with IBD treated with methotrexate from inception to August 2023. All studies were included from the MEDLINE database via PubMed. RESULTS: For Crohn's disease, we included eight randomised controlled trials (RCTs) and 17 observational studies. Parenteral methotrexate effectively increased remission rates in steroid-dependent patients at 25 mg/week for 16 weeks and at 15 mg/week for maintenance. Methotrexate can be used in combination with anti-tumour necrosis factor (TNF) agents to reduce immunogenicity. Data comparing thiopurines and methotrexate remain scarce. For ulcerative colitis (UC), we included five RCTs and 10 observational studies were included; there was no evidence to support the use of methotrexate in (UC). We extracted safety data from 17 studies; mild-to-moderate adverse effects were common. The incidence of liver fibrosis or cirrhosis was low. CONCLUSION: Methotrexate is effective at inducing and maintaining remission in steroid-refractory Crohn's disease and can reduce anti-TNF-induced immunogenicity when used in combination therapy. Data regarding tolerance and safety are reassuring. These findings challenge preconceived ideas on methotrexate and suggest that it is a valid first-line conventional option for the treatment of mild-to-moderate Crohn's disease.

Target Trial Emulation: Improving the Quality of Observational Studies in Inflammatory Bowel Disease Using the Principles of Randomized Trials.

The past decade has seen a substantial increase in the number of randomized controlled trials (RCTs) conducted in inflammatory bowel disease (IBD). Randomized controlled trials are the gold standard method for generating robust evidence of drug safety and efficacy but are expensive, time-consuming, and may have ethical implications. Observational studies in IBD are often used to fill the gaps in evidence but are typically hindered by significant bias. There are several approaches for making statistical inferences from observational data with some that focus on study design and others on statistical techniques. Target trial emulation is an emerging methodological process that aims to bridge this gap and improve the quality of observational studies by applying the principles of an ideal, or "target," randomized trial to routinely collected clinical data. There has been a rapid expansion of observational studies that have emulated trials over the past 5 years in other medical fields, but this has yet to be adopted in gastroenterology and IBD. The wealth of nonrandomized clinical data available through electronic health records, patient registries, and administrative health databases afford innumerable hypothesis-generating opportunities for IBD research. This review outlines the principles of target trial emulation, discusses the merits to IBD observational studies in reducing the most common biases and improving confidence in causality, and details the caveats of using this approach.

Target trial emulation uses observational data to mimic the principles of an ideal or "target" randomized trial. This framework offers several opportunities to strengthen the quality of observational research in inflammatory bowel disease by reducing common sources of bias.

Acute severe ulcerative colitis trials: the past, the present and the future.

Acute severe ulcerative colitis (ASUC), characterised by bloody diarrhoea and systemic inflammation, is associated with a significant risk of colectomy and a small risk of mortality. The landmark trial of cortisone in 1955 was pivotal for two reasons: first, for establishing the efficacy of a drug that remains a first-line therapy today and, second, for producing the first set of disease severity criteria and clinical trial endpoints that shaped the subsequent ASUC trial landscape. Trials in the 1990s and at the turn of the millennium established the efficacy of infliximab and ciclosporin, but since then, there has been little progress in drug development for this high-risk population. This systematic review evaluates all interventional randomised controlled trials (RCTs) conducted in patients hospitalised with severe UC. It provides an overview of the efficacy of treatments from past to present and assesses the evolution of trial characteristics with respect to study populations, eligibility criteria and study designs over time. This review details ongoing RCTs in this field and provides a perspective on the challenges for future clinical trial programmes and how these can be overcome to help deliver novel ASUC therapies.

Navigating the complexities of drug development for inflammatory bowel disease.

Inflammatory bowel disease (IBD) - consisting of ulcerative colitis and Crohn's disease - is a complex, heterogeneous, immune-mediated inflammatory condition with a multifactorial aetiopathogenesis. Despite therapeutic advances in this arena, a ceiling effect has been reached with both single-agent monoclonal antibodies and advanced small molecules. Therefore, there is a need to identify novel targets, and the development of companion biomarkers to select responders is vital. In this Perspective, we examine how advances in machine learning and tissue engineering could be used at the preclinical stage where attrition rates are high. For novel agents reaching clinical trials, we explore factors decelerating progression, particularly the decline in IBD trial recruitment, and assess how innovative approaches such as reconfiguring trial designs, harmonizing end points and incorporating digital technologies into clinical trials can address this. Harnessing opportunities at each stage of the drug development process may allow for incremental gains towards more effective therapies.

Biomarkers in inflammatory bowel disease: a practical guide.

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn's disease (CD), is a costly condition in terms of morbidity and healthcare utilization, with an increasing prevalence now approaching 1% in the Western world. Endoscopic assessment of IBD remains the gold standard for diagnosis, evaluation of treatment response and determination of post-operative recurrence, but is expensive and invasive. Biomarkers can facilitate non-invasive disease assessment, with C-reactive protein and faecal calprotectin as the most widely available biomarkers in current clinical practice. This narrative review summarizes the evidence for their use in both UC and CD and offers practical guidance for healthcare providers taking into account the limitations of biomarker interpretation. We present evidence for the future use of novel biomarkers in IBD and discuss how biomarker discovery could deliver the goal of precision medicine in IBD.

Biomarkers in inflammatory bowel disease: a practical guide Inflammatory bowel disease (IBD) is a term used to describe two conditions, ulcerative colitis (UC) and Crohn's disease (CD). These two diseases cause inflammation of the bowel, which can lead to diarrhoea, abdominal pain and bleeding from the back passage. The best way of assessing how active a patient's IBD is, is by performing a camera test called a colonoscopy. However, having a colonoscopy is inconvenient, comes with some risks to the patient, and uses a lot of healthcare resources. 'Biomarkers' are proteins detectable in body fluids (such as blood, poo and urine) which can give information to medical staff about how active a patient's disease is, without the need for colonoscopy. In this article, we give guidance about how best to use these tests, and when they might not be so useful. We also discuss new biomarkers and ways in which they could be used in the future to predict which treatments patients might respond to best.

JAK inhibitors for inflammatory bowel disease: recent advances.

Inflammatory bowel disease (IBD) commonly requires immunosuppressive treatments to induce and maintain durable remission. Janus kinase inhibitors (JAKis) are a novel group of orally administered, small molecule drugs that work by attenuating multiple cytokine signalling pathways to mediate dysregulated immune responses involved in the pathogenesis of IBD. Tofacitinib, filgotinib and upadacitinib have demonstrated efficacy against placebo and are licensed for the treatment of moderate to severe ulcerative colitis; upadacitinib is the only JAKi also currently approved for the treatment of Crohn's disease. Safety concerns stratified by age have led to class-wide regulatory restrictions for JAKi use across all inflammatory diseases. It is important for gastroenterologists managing patients with IBD to be aware of the key pivotal trial outcomes, to identify appropriate patients in whom to commence a JAKi, and to understand the safety considerations and ways to mitigate these risks in the patients they treat. This review provides a contemporaneous overview of this emerging therapeutic class and provides a practical guide for healthcare practitioners for initiating and monitoring JAKi in IBD.

JAK inhibitors for the treatment of inflammatory bowel disease: results of an international survey of perceptions, attitudes, and clinical practice.

BACKGROUND: Janus kinase inhibitors (JAKi) are small molecule drugs with demonstrated efficacy in inflammatory bowel disease (IBD). However, widespread utilisation may be hindered by safety concerns. AIMS: This is the first study assessing risk-benefit perceptions and clinical practices of those using JAKi for IBD. METHODS: A prospective, cross-sectional study was conducted using a 23-item survey distributed to IBD healthcare providers worldwide. RESULTS: Of 385 respondents from 48 countries, 72% were tertiary-centre based and 50% were gastroenterologists with ≥10 years experience. JAKi were commonly used outside market authorisation (31%), though many (17%) were unconfident discussing JAKi risk-benefit profile and 7% had never prescribed JAKi. If venous thromboembolism risks were present, 15% preferentially referred for surgery than initiate JAKi; 21% would do this even if the patient was already anticoagulated. For patients relapsing on dose reduction, 8% would switch treatment rather than dose escalate. Conversely, 45% felt that cardiovascular safety concerns from post-marketing studies were irrelevant to IBD. Despite the lack of detailed, long-term safety data, safety profiles of JAK1-selective drugs were perceived to be favourable to tofacitinib by most (62%). CONCLUSION: The study indicates that while clinical practice appears to be in keeping with international guidance, a significant minority remain deterred by safety concerns.

Ulcerative colitis.

Ulcerative colitis is a lifelong inflammatory disease affecting the rectum and colon to a variable extent. In 2023, the prevalence of ulcerative colitis was estimated to be 5 million cases around the world, and the incidence is increasing worldwide. Ulcerative colitis is thought to occur in people with a genetic predisposition following environmental exposures; gut epithelial barrier defects, the microbiota, and a dysregulated immune response are strongly implicated. Patients usually present with bloody diarrhoea, and the diagnosis is based on a combination of clinical, biological, endoscopic, and histological findings. The aim of medical management is, first, to induce a rapid clinical response and normalise biomarkers and, second, to maintain clinical remission and reach endoscopic normalisation to prevent long-term disability. Treatments for inducing remission include 5-aminosalicylic acid drugs and corticosteroids. Maintenance treatments include 5-aminosalicylic acid drugs, thiopurines, biologics (eg, anti-cytokines and anti-integrins), and small molecules (Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators). Although the therapeutic options are expanding, 10-20% of patients still require proctocolectomy for medically refractory disease. The keys to breaking through this therapeutic ceiling might be the combination of therapeutics with precision and personalised medicine.

Review article: Externally derived control arms-An opportunity for clinical trials in inflammatory bowel disease?

BACKGROUND: One of the greatest challenges in the current IBD clinical trial landscape is, perhaps, the recruitment and retention of eligible participants. Seamless testing of promising investigational compounds is paramount to address unmet needs, but this is hindered by a number of barriers, particularly patient concerns of placebo assignment. AIMS: To review the use of novel trial designs leveraging externally derived data to synthetically create control groups or augment existing ones, and to summarise the regulatory position on the use of external controls for market authorisation. METHODS: We conducted a PubMed literature search without restriction using search terms such as 'external controls' and 'historical controls' to identify relevant articles. RESULTS: External controls are increasingly being used outside the context of cancer and rare diseases, including IBD, and increasingly recognised by regulatory bodies. Such designs, particularly in earlier phase trials, can inform key nodes in drug development and permit evaluating efficacy of interventions without combating the ethical and numerical enrolment challenges described. However, the lack of randomisation and blinding subjects them to significant bias. Groups require robust statistical and computational approaches to ensure patient-level data across groups are adequately balanced. CONCLUSIONS: While this approach has several pitfalls, and is not robust enough to replace traditional randomised, placebo-controlled trials, it may offer a compromise to address key research questions at a more rapid pace, with fewer patients, and lower cost.

An update on the safety of long-term vedolizumab use in inflammatory bowel disease.

INTRODUCTION: Vedolizumab (Entyvio) is a humanized monoclonal antibody that disrupts the interaction between α4ß7 integrin on circulating T-lymphocytes and MAdCAM-1 on the vascular endothelium to prevent their egress to sites of gut inflammation. It has proven therapeutic efficacy for the treatment of moderate-to-severe Crohn's disease, ulcerative colitis, and pouchitis. AREAS COVERED: This narrative review assesses the safety profile of vedolizumab from the registration trial programs, open-label extension studies, observational real-world data, and pooled safety analyses. This includes an evaluation of the long-term overall safety in special populations typically underrepresented in clinical trials. EXPERT OPINION: Vedolizumab is an effective therapy for inflammatory bowel disease with a well-established safety profile. No unexpected long-term safety signals have been identified. Safety data in pregnancy, in pediatric and elderly populations, in patients undergoing surgery, and in patients with a prior history of cancer are reassuring. Due to its safety merits, we propose that vedolizumab is an excellent candidate for advanced combination treatment with an anti-cytokine approach using another biologic or novel small molecule inhibitor. This is important in patients with medically refractory IBD, in patients at high risk of developing disease-related complications, or in patients with concomitant uncontrolled immune-mediated inflammatory diseases.

How achievable are STRIDE-II treatment targets in real-world practice and do they predict long-term treatment outcomes?

Objective: The second iteration of the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) initiative recommends use of the Simple Endoscopic Score for Crohn's disease (SES-CD) as a treatment target for patients with CD. We aimed to assess whether the STRIDE-II endoscopic endpoints are achievable and whether the degree of mucosal healing (MH) affects long-term outcomes. Design/method: We performed a retrospective observational study between 2015 and 2022. Patients with CD who had baseline and follow-up SES-CD scores after biological therapy initiation were included. The primary outcome was treatment failure, defined as the need for: (1) change of biological therapy for active disease (2) corticosteroid use (3) CD-related hospitalisation or (4) surgery. We compared rates of treatment failure with the degree of MH achieved. Patients were followed up until treatment failure or study end (August 2022). Results: 50 patients were included and followed up for median 39.9 (34.6-48.6) months. Baseline characteristics: 62% male, median age 36.4 (27.8-43.9) years, disease distribution (L1: 4, L2: 11, L3: 35, perianal: 18). The proportion of patients achieving STRIDE-II end-points were: SES-CD≤2-25 (50%) and >50% reduction in SES-CD-35 (70%). Failure to achieve SES-CD≤2 (HR 11.62; 95% CI 3.33 to 40.56, p=0.003) or >50% improvement in SES-CD (HR 30.30; 95% CI 6.93 to 132.40, p<0.0001) predicted treatment failure. Conclusion: Use of SES-CD is feasible in real-world clinical practice. Achieving an SES-CD≤2 or a greater than 50% reduction, as set out by STRIDE-II, is associated with reduced rates of overall treatment failure including CD-related surgery.

Patient and Public Involvement in Research: Lessons for Inflammatory Bowel Disease.

Participatory research, also referred to as patient and public involvement, is an approach that involves collaborating with patients affected by the focus of the research, on the design, development and delivery of research to improve outcomes. There are two broad justifications for this: first, that it enhances the quality and relevance of research, and second, that it satisfies the ethical argument for patient inclusion in decisions about them. This synergistic and collaborative effort, which bridges the divide between researchers and participants with the lived condition, is now a mainstream activity and widely accepted as best practice. Although there has been a substantial increase in the literature over the past two decades, little has been published on how participatory research has been used in inflammatory bowel disease [IBD] research and little guidance as to how researchers should go about this. With an increasing incidence and prevalence worldwide, combined with declining study enrolment in an era of perennial unmet need, there are a multitude of benefits of participatory research to IBD patients and investigators, including research output that is informed and relevant to the real world. A key example of participatory research in IBD is the I-CARE study, a large-scale, pan-European observational study assessing the safety of advanced therapies, which had significant patient involvement throughout the study. In this review, we provide a comprehensive overview of the benefits and challenges of participatory research and discuss opportunities of building strategic alliances between IBD patients, healthcare providers and academics to strengthen research outcomes.

Amoebic colitis masquerading as inflammatory bowel disease for a decade.

Nil.

Positioning intestinal ultrasound in a UK tertiary centre: significant estimated clinical role and cost savings.

Objective: Intestinal ultrasound (IUS) is an inexpensive, non-invasive method of diagnosing and monitoring inflammatory bowel disease (IBD). We aimed to establish the proportion of lower gastrointestinal endoscopies (LGIEs) and magnetic resonance enterographies (MREs) that could have been performed as IUS, the potential pathology miss-rates if IUS was used and the associated cost savings. Methods: All MREs and LGIEs performed for either assessment of IBD activity or investigation of possible IBD, performed at a single UK tertiary centre in January 2018, were retrospectively reviewed against predetermined criteria for IUS suitability. Case outcomes were recorded and cost of investigation if IUS was performed instead was calculated. Results: 73 of 260 LGIEs (28.1%) and 58 of 105 MREs (55.2%) met the criteria for IUS suitability. Among potential IUS-suitable endoscopy patients, one case each of a <5 mm adenoma and sessile serrated lesion were found; no other significant pathology that would be expected to be missed with IUS was encountered. Among IUS-suitable MRE patients, no cases of isolated upper gastrointestinal inflammation likely to be missed by IUS were found, and extraintestinal findings not expected to be seen on IUS were of limited clinical significance. The predicted cost saving over 1 month if IUS was used instead was £8642, £25 866 and £5437 for MRE, colonoscopy and flexible sigmoidoscopy patients, respectively. Conclusion: There is a significant role for IUS, with annual projected cost savings of up to almost £500 000 at our centre. Non-inflammatory or non-gastrointestinal pathology predicted to be missed in this cohort was of limited clinical significance.