Challenges and Opportunities in IBD Clinical Trial Design

Dubinsky, Marla; Collins, Rory; Abreu, María T.; Jairath, Vipul; Lindsay, James O.; Mérad, Miriam; Ng, Siew C.; Panaccione, Remo; Panés, Julián; Sands, Bruce E.; Siegal, Corey A.; Singh, Siddarth; Vermeire, Séverine; Ahuja, Vineet; Allez, Matthieu; Ananthakrishnan, Ashwin N.; Bemelman, Willem A.; Braun, Jonathan; Colombel, Jean–Frédéric; Danese, Silvio; D’Haens, G; D’Hoore, André; Dignaß, Axel; Dotan, Iris; Gassul, M; Griffiths, Anne M.; Halfvarson, Jonas; Hanauer, Stephen B.; Kotze, Paulo Gustavo; Koutroubakis, Ioannis Ε.; Loftus, Edward V.; Louis, Édouard; Magro, Fernando; Mantzaris, Gerassimos J.; Mary, Jean‐Yves; McGovern, Dermot P.; Munkholm, Pia; O’Moráin, Colm; Peyrin–Biroulet, Laurent; Prantera, Cosimo; Ran, Zhihua; Siegmund, Britta; Silverberg, Mark S.; Stange, Eduard F.; Targan, Stephan; Tysk, Curt; Travis, Simon; Vatn, M H; Yamamoto-Furusho, Yesus; Aarts, Janske M.; Abhyankar, Brihad; Ahmad, Harris; Aranda, Richard; Arora, Vipin; Benjacoub, Jalil; Berg, Sofie; Besuyen, R.; Bojic, Daniela; Carriero, Valerio; Cataldi, Fabio; D’Agay, Laurence; Delgado-Aros, Sílvia; Giannasca, Paul J.; Goyal, Kavitha; Greinwald, Roland; Gropper, Savion; Kageyama, Shunsuke; Laoun, R; Levesque, Barrett G.; Lissoos, Trevor; Modesto, Irene; Mohrbacher, Ralf; Müeller, Ralph; Naegeli, April N.; Naik, Snehal; Nguyen, D. Viet; Niezychowski, Wojciech; O’Brien, Caitriona; Odnoletkova, Irina; Oortwijn, Alessandra; Park, Kun K.T.; Radziszewski, Waldemar; Salese, Leonardo; Spleiss, Johannes; Stancati, Andrea; Tatro, Amanda R.; Thompson, Jennifer L.; Hofmann, Robert; Zambrano, Javier; Zhou, Wen; Zigmont, Ellen

doi:10.1053/j.gastro.2021.03.065

Cited by 16 publications

(5 citation statements)

References 19 publications

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“…However, dosing at 90 µg/kg every 2 weeks was stopped in HVs due to intolerable DLAEs occurring in several participants; 90 µg/kg every 2 weeks was therefore above the MTD in HVs. The attrition rate generated in this study is one parameter among several others to be taken into consideration for powering large phase 2 studies and beyond 27 28. Interestingly, differences in PK for different populations (eg, HVs vs inflammatory bowel disease, patients witth IBD) is not unique to efmarodocokin alfa, and has been seen with anrukinzumab29 and infliximab 30.…”

Section: Discussionmentioning

confidence: 93%

Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and patients with ulcerative colitis

Wagner

Mansfield

Lekkerkerker³

et al. 2023

Gut

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BackgroundThe interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallisable fragment (Fc) of human IgG4for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions.MethodsThis randomised, phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (n=24) at 30–90 µg/kg doses given once every 2 weeks or monthly (every 4 weeks) for 12 weeks (6:2 active:placebo per cohort).ResultsThe most common adverse events (AEs) were on-target, reversible, dermatological effects (dry skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 μg/kg once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally dose-proportional across the dose levels, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22-responsive genes in colon biopsies were induced with active treatment, and microbiota composition changed consistent with a reversal in baseline dysbiosis. As a phase 1b study, efficacy endpoints were exploratory only. Clinical response was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active-treated and 0/6 placebo-treated patients.ConclusionEfmarodocokin alfa had an adequate safety and pharmacokinetic profile in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the colonic epithelium. Results support further investigation of this non-immunosuppressive potential inflammatory bowel disease therapeutic.Trial registration numberNCT02749630.

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Section: Discussionmentioning

confidence: 93%

Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and patients with ulcerative colitis

Wagner

Mansfield

Lekkerkerker³

et al. 2023

Gut

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“…Cross et al (27) reported several challenges in recruitment in their home telemanagement trial related to difficulty in randomization and blinding and defining a control group who receive variable degree of BAC. Several other factors can contribute to low recruitment in clinical trials of IBD, with ongoing efforts to improve trial design, processes, and methodology to improve recruitment (28–31). Whether these interventions can be readily implemented and be similarly effective in a population enriched in negative social determinants of health such as racioethnic minorities, low literacy level, and limited affordability is a major knowledge gap that merits future studies.…”

Section: Discussionmentioning

confidence: 99%

Digital Health Technologies for Remote Monitoring and Management of Inflammatory Bowel Disease: A Systematic Review

et al. 2021

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INTRODUCTION: Digital health technologies may be useful tools in the management of chronic diseases. We performed a systematic review of digital health interventions in the management of patients with inflammatory bowel diseases (IBD) and evaluated its impact on (i) disease activity monitoring, (ii) treatment adherence, (iii) quality of life (QoL) measures, and/or (iv) health care utilization. METHODS: Through a systematic review of multiple databases through August 31, 2020, we identified randomized controlled trials in patients with IBD comparing digital health technologies vs standard of care (SoC) for clinical management and monitoring and reporting impact on IBD disease activity, treatment adherence, QoL, and/or health care utilization or cost-effectiveness. We performed critical qualitative synthesis of the evidence supporting digital health interventions in patients with IBD and rated certainty of evidence using Grading of Recommendations Assessment, Development and Evaluation. RESULTS: Overall, we included 14 randomized controlled trials (median, 98 patients; range 34—909 patients; follow-up <12 months) that compared web-based interventions, mobile applications, and different telemedicine platforms with SoC (clinic-based encounters). Although overall disease activity and risk of relapse were comparable between digital health technologies and SoC (very low certainty of evidence), digital health interventions were associated with lower rate of health care utilization and health care costs (low certainty of evidence). Digital health interventions did not significantly improve patients' QoL and treatment adherence compared with SoC (very low certainty of evidence). Trials may have intrinsic selection bias due to nature of digital interventions. DISCUSSION: Digital health technologies may be effective in decreasing health care utilization and costs, though may not offer advantage in reducing risk of relapse, QoL, and improving treatment adherence in patients with IBD. These techniques may offer value-based care for population health management.

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“… 10 However, patient recruitment is a significant challenge in IBD clinical trials, partly because physicians are focused on procedures rather than recruitment. 24 Interobserver variability and endoscopist inexperience may also lead to misevaluation of disease severity, resulting in inappropriate patient enrolment or incorrect treatment arm assignment. 20 Recruitment inefficiencies may result in the loss of participants from a relatively small pool of eligible patients, creating the need for larger cohorts and increasing clinical trial costs.…”

Section: Current Status Of Endoscopy In Ibd Clinical Trialsmentioning

confidence: 99%

Artificial Intelligence in Inflammatory Bowel Disease Endoscopy: Implications for Clinical Trials

Ahmad

East

Panaccione

et al. 2023

Journal of Crohn's and Colitis

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Artificial intelligence shows promise for clinical research in inflammatory bowel disease endoscopy. Accurate assessment of endoscopic activity is important in clinical practice and inflammatory bowel disease clinical trials. Emerging artificial intelligence technologies can increase efficiency and accuracy of assessing the baseline endoscopic appearance in patients with inflammatory bowel disease and the impact that therapeutic interventions may have on mucosal healing in both of these contexts. In this review, state-of-the-art endoscopic assessment of mucosal disease activity in inflammatory bowel disease clinical trials is described, covering the potential for artificial intelligence to transform the current paradigm, its limitations, and suggested next steps. Site-based artificial intelligence quality evaluation and inclusion of patients in clinical trials without the need for a central reader is proposed; for following patient progress, a second reading using AI alongside a central reader with expedited reading is proposed. Artificial intelligence will support precision endoscopy in inflammatory bowel disease and is on the threshold of advancing inflammatory bowel disease clinical trial recruitment.

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Challenges and Opportunities in IBD Clinical Trial Design

Cited by 16 publications

References 19 publications

Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and patients with ulcerative colitis

Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and patients with ulcerative colitis

Digital Health Technologies for Remote Monitoring and Management of Inflammatory Bowel Disease: A Systematic Review

Artificial Intelligence in Inflammatory Bowel Disease Endoscopy: Implications for Clinical Trials

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