Clinical Trials In Inflammatory Bowel Disease Research Articles

Outcomes in Adult Inflammatory Bowel Disease Clinical Trials: Assessment of Similarity Among Participants with Adolescent-Onset and Adult-Onset Disease.

Most pediatric IBD studies are performed after medications are approved in adults and the majority of participants in these studies are adolescents. We hypothesized that adolescent-onset IBD is not fundamentally different than adult-onset IBD. If this is correct, the value of delaying access to novel drugs in adolescents becomes questioned. Data from 11 randomized, double-blind, placebo-controlled adult phase 2 and 3 trials of 4 biologics were analyzed. Participants were categorized as having adolescent- or adult-onset disease (diagnosed 12 to <18, or ≥18 years). Multivariable modelling explored the association between age at diagnosis and response to treatment after adjustment for disease duration, extent, and severity at baseline. Data from dose arms were pooled to evaluate similarity of therapeutic response between adolescent- and adult-onset IBD within the same trial (not between doses or across trials). Ratios of odds ratios between the two groups were evaluated. Data from 6,283 study participants (2,575 with Crohn's disease [CD], 3,708 with ulcerative colitis [UC]) were evaluated. Of 2,575 study participants with CD, 325 were 12-<18 years old at diagnosis; 836 participants (32.4%) received placebo. Of 3,708 participants with UC, 221 were 12-<18 years old at diagnosis; 1,212 (33%) were receiving placebo. The majority of the ratios of ORs were within two-fold, suggesting that responses in adolescent and adult-onset participants are generally similar. Data presented lend support for extrapolating efficacy of biologics from adults to adolescents with IBD, which would facilitate earlier labeling and patient access.

P952 Why do patients with Inflammatory Bowel Disease Take Part in Pharmaceutical Clinical Trials? A qualitative study of Clinical Trial Participants

Abstract Background Recruitment rates to clinical trials in inflammatory bowel disease (IBD) continue to decline. A better understanding of motivations to participate as well as recommendations to reduce barriers to enrolment from a patient perspective may assist in design of future clinical trials. Methods We developed a 32-item electronic questionnaire to explore motivations, experiences and recommendations of patients with IBD, who have participated in pharmaceutical clinical trials in a tertiary centre in Canada. Results We distributed a total of 82 emails with surveys based on the patient details available to the study team. Using the DillMan Total Design Survey method, participants were followed up one week after the initial email with a reminder phone-call and we received 46 responses (56.1% response rate). Participants were mostly, male (58.7%), non-Hispanic white (93.5%), with a mean age of 45.5 years (SD 10.9). Most participants decided to participate in a clinical trial to benefit future patients with IBD (63.0%). Self-reported knowledge of the possibility of being assigned to placebo on a scale from 0 (no knowledge) to 100 (extremely knowledgeable) was a median of 100 (IQR 100-100) (Table 1). Half of participants (50.0%) reported they were worried about the possibility of receiving placebo, although the majority (63.0%) understood they could improve on placebo. The most challenging aspect reported was the number and length of questionnaires (32.6%), as well of the number of colonoscopies (30.4%). Strategies to increase enrolment recommended by participants were reduction in the chance of receiving placebo (43.5%), facilitating inclusion of patients who have failed multiple therapies (43.5%), allowing virtual visits (39.1%), including subtypes of disease that have traditionally been excluded in clinical trials (e.g., ostomies, fistula) (34.8%), and improving outreach to underrepresented populations (28.3%) (Figure 1). The vast majority (80.4%) reported their experience of participation to be better than expected and would recommend taking part in a clinical trial to other patients with IBD (97.8%). Conclusion Patients with IBD who took part in pharmaceutical trials reported a high level of satisfaction overall. The top three recommendations from patients to improve clinical trial design were reducing the chance of receiving placebo, allowing inclusion of patients who have failed multiple therapies and allowing for virtual visits to reduce travel burden to the clinical trial site. These results should help inform the design of patient centric clinical trials in IBD.

Iron oxide nanoparticles for inflammatory bowel disease: Recent advances in diagnosis and targeted drug therapy

Gastrointestinal tract (GI) is the second largest and essential organ in the body responsible for the absorption of nutrients and removal of wastes from the body. The proper functioning of GI is pivotal for healthy lifestyle as it regulates various metabolic processes directly or indirectly. The compromised intestinal permeability and other metabolic disorders are the major factors contributing to inflammatory bowel disease (IBD). The ulcerative colitis (UC) and Crohn's disease (CD) are the types of IBD characterized by chronic inflammation in the GI tract and carries a higher risk to develop colon cancer. Early diagnosis of IBD using pro-inflammatory cytokines as biomarkers is often challenging. Iron oxide nanoparticles (IONPs) are gaining increasing attention as they offer early and reliable confirmation of the type of IBD. Moreover, IONPs that are either encapsulated to conjugated or even engineered, can render site specific drug delivery and thus reduce high-dose induced toxic effects at the non-target sites. In this focused review, we review emphasize the diagnostic, therapeutic, theranostic applications of IONPs for IBD. In addition, current research involving studies on IONPs in experimental IBD models and clinical trials are also reviewed. The IONPs proven to have higher biodistribution in the cell compared to other conventional drug delivery systems. The surveyed literature conclusively establishes the magnificent properties, and broad-spectrum applicability of IONPs, which can be promptly used for both diagnosis and therapy including image guided drug delivery to the colon region.

Geographic Inequities in Access to Phase 3 Clinical Trials for Inflammatory Bowel Disease in the United States

Randomized controlled trials (RCTs) are an important mode of access to treatments for patients with inflammatory bowel diseases (IBDs) (eg, Crohn's disease [CD], ulcerative colitis [UC]), and a critical step in the regulatory process toward the approval of new therapies. Prior studies examining disparities in RCT participation for patients with IBD have importantly focused on racial and age-related disparities.1,2 Lack of geographic access to trials may be an important barrier to participation and a source of inequity. The aim of our study was to geographically map access to phase 3 clinical trials in IBD within the United States, and identify the impact of rural residence and socioeconomic status on access to trials.

Long Washout Periods Between Biologics for Inflammatory Bowel Disease Clinical Trials Are Unnecessary: A Canadian Retrospective Cohort Study.

To assess the safety of early vs late biologic switch in patients with inflammatory bowel disease. In this retrospective study, we included patients with inflammatory bowel disease who underwent biologic switch between January 2014 and July 2022 at a tertiary center. The primary outcome was any infection by 6 months. There was no statistically significant difference between patients who had early biologic switch (≤30 days, n = 51) and late switch (>30 days, n = 77) in either infectious or noninfectious adverse events by 6 and 12 months. Early biologic switch is safe. A prolonged washout period between 2 biologics is unnecessary.

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

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.

P277 Predicting disease relevant features in Crohn’s Disease and Ulcerative Colitis from Haematoxylin &amp; Eosin stained whole slide images using self-supervised deep learning

Abstract Background Histopathological endpoints are evolving as a treatment target in Inflammatory Bowel Disease (IBD). Use of histology to screen entrants could add value in IBD clinical trials; for example, by refining eligibility criteria to ensure studies recruit patients with definitive active inflammation at the microscopic level. Several histopathological indices have been developed, but the relative complexity of available scores hinders the development of an AI algorithm without large-scale labour-intensive annotation by a pathologist. We aimed to develop computer vision tools to assist decoding the complex clinical disease features at the histological level for both Crohn’s Disease (CD) and Ulcerative Colitis (UC). This will inform understanding of disease pathology and patient stratification to support clinical trial development strategies. Methods A total of 1397 clinically annotated Haematoxylin &amp; Eosin (H&amp;E) images were included from 418 CD and 218 UC patients enrolled in a multicentred longitudinal Study of a Prospective Adult Research Cohort with IBD (SPARC IBD) obtained from the IBD Plexus program of the Crohn’s &amp; Colitis Foundation. We developed an image quality control (QC) algorithm to automatically identify image and tissue processing/staining artefacts negatively impacting analysis (e.g., out-of-focus, tissue folds, overstained regions) and excluded these regions (Fig. 1). Next, a self-supervised learning (SSL) deep learning computer vison model was developed and trained to predict disease relevant features including disease diagnosis and lesional macroscopic appearance (inflammation, erosions and ulcers). Finally, to better understand the model’s predictions, we generated heatmap overlays on the tissue that show regions which the model considers to be most predictive (Fig. 2) and shared these with pathologists for qualitative evaluation. Results We find that the SSL model performs well on different downstream classification tasks such as UC vs CD (area under curve (AUC) = 0.79) and normal vs lesional tissue (AUC = 0.76). Specialist pathologist collaboration further confirmed that the heatmap overlays identified clinically relevant tissue features, including inflammatory cell infiltrates (Fig. 2). Conclusion These encouraging results support further exploration of this deep-learning algorithm to distinguish disease specific characteristics in this set of images from CD and UC patients. Further work is ongoing to validate the heatmap approach on endoscopic scores, we also plan to validate our model on IBD clinical trial datasets.

P539 Patient Preferences for Inflammatory Bowel Disease Treatments: Development of a European Preference Survey using a Discrete Choice Experiment

Abstract Background There is a growing consensus across stakeholders on the value of patient preference (PP) studies, as recognized by the European Medicines Agency and the European Network for Health Technology Assessment. This study aimed to develop a PP survey to quantitatively evaluate which characteristics are most important to inflammatory bowel disease (IBD) patients, so that the results can inform the medicinal product life cycle (MPLC). Methods Following the PREFER recommendations, a four-step approach was followed to develop the PP survey: 1) stated preference method selection, 2) attribute and level development, 3) survey implementation, and 4) survey piloting. Throughout the different steps of the survey development, an advisory board (AB) consisting out of patients, patient organizations, gastroenterologists, IBD nurses, and statisticians were consulted. Results First, a discrete choice experiment (DCE) was chosen as the preferred elicitation method because it allows to reach the objectives of the survey, namely to: 1) quantify the relative importance of different attributes, 2) elicit the trade-offs patients make, and 3) measure preference heterogeneity. Second, a scoping literature review of IBD clinical trials, available IBD treatments, and previously published preference studies was performed. Discussions on these characteristics with patients (n=11) during focus group discussions (FGDs) using the nominal group technique revealed the following patient prioritized characteristics: prevent surgery, long-term clinical remission, improved quality of life, occurrence of urgency, and improved labor rate. Based upon the results of the FGDs, a preliminary list of possible attributes for inclusion in the DCE was refined during AB meetings. This list was iteratively adapted until consensus was found on 14 attributes, their levels, and corresponding explanations (Figure 1). Third, the DCE survey was designed to include these 14 attributes using partial profiles next to measures about sociodemographic variables, health literacy, and treatment experience. Fourth, piloting the study with IBD patients (n=4) revealed that the survey was comprehensible, had a good flow, and contained graphics that supported the content. Only minor text edits were needed. Conclusion It is key to develop a PP survey in partnership with patients and other members of the AB. This survey will be rolled out across Europe in 11 different languages and will increase understanding of which treatment aspects are most important to IBD patients. These aspects should be included in drug development and evaluation so that the MPLC can be more patient-centered and future treatments will target aspects that are most important to IBD patients themselves.

Anti-inflammatory effects of vagal nerve stimulation with aspecial attention to intestinal barrier dysfunction.

The vagus nerve (VN), the longest nerve of the organism innervating the gastrointestinal tract, is a mixed nerve with anti-inflammatory properties through its afferents, activating the hypothalamic-pituitary adrenal axis, and its efferents through the cholinergic anti-inflammatory pathway inhibiting the release of pro-inflammatory cytokines (e.g., TNFα) by splenic and gut macrophages. In addition, the VN is also able to modulate the permeability of the intestinal barrier although the VN does not innervate directly the intestinal epithelium. Targeting the VN through VN stimulation (VNS) has been developed in experimental model of intestinal inflammation and in inflammatory bowel disease (IBD) and might be of interest to decrease intestinal permeability in gastrointestinal disorders with intestinal barrier defect such as IBD, irritable bowel syndrome (IBS), and celiac disease. In this issue of neurogastroenterology and motility, Mogilevski et al. report that a brief non-invasive transcutaneous auricular VNS in healthy volunteers consistently reduces the permeability of the small intestine induced by intravenous administration of the stress peptide corticotropin releasing hormone, known to increase intestinal permeability and to inhibit the VN. In this review, we outline the mechanistic underpinning the effect of stress, of the VN and VNS on intestinal permeability. In particular, the VN can act on intestinal permeability through enteric nerves, and/or cells such as enteric glial cells. We also review the existing evidence of the effects VNS on intestinal permeability in models such as burn intestinal injury and traumatic brain injury, which pave the way for future clinical trials in IBD, IBS, and celiac disease.

Definition of mild to moderate ulcerative colitis in clinical trials: A systematic literature review.

We performed a systematic review to investigate the definition of mild to moderate active ulcerative colitis (UC), and to describe predictors of good response to treatment in clinical trials assessing 5‐ASA and/or budesonide. Thirty‐nine randomized controlled trials were included. The UC Disease Activity Index (UCDAI) was the most frequent score used for defining mild to moderate active UC (16 studies, 41%), followed by Clinical Activity Index in 11 studies (28.2%). Four different cut‐offs were used to define mild to moderate active UC using the UCDAI. The most frequently reported predictors of good response to treatment was a mild and moderate disease activity. There is heterogeneity in the definition of mild to moderate active UC in randomized clinical trials. A standardized definition of mild to moderate active UC used for inclusion of patients in clinical trials is needed.

Ustekinumab Exposure in Pregnant Women From Inflammatory Bowel Disease Clinical Trials: Pregnancy Outcomes Through Up To 5 Years in Crohn's Disease and 2 Years in Ulcerative Colitis.

While no adverse developmental outcomes were observed in preclinical animal studies, limited data exist regarding effects of ustekinumab on human pregnancies. Previously, no data have been reported for women treated with ustekinumab in inflammatory bowel disease (IBD) clinical trials and corresponding pregnancy outcomes. Here, we present pregnancy outcomes from IBD clinical trials, incorporating 5 years of treatment in Crohn's disease (CD) and 2 in ulcerative colitis (UC). All patients in the clinical trials agreed to use adequate birth control and were discontinued from treatment upon pregnancy confirmation. Nonetheless, 39 pregnancies occurred with maternal ustekinumab exposure from 4 CD and 1 UC study. Maternal and neonatal outcomes and data are presented with summary statistics, where available. Of 1289 women who received ≥1 dose of ustekinumab, 39 maternal pregnancies with outcomes were reported (pregnancy cohort). Median maternal age was 28.0 years and median duration of ustekinumab treatment before pregnancy was 63.7 weeks with the last dose of ustekinumab administered prior to or during the first trimester (terminal half-life of ~3 weeks). Outcomes for the 39 pregnancies were: 26 live births (all normal newborns), 8 spontaneous abortions, and 5 elective abortions. No congenital anomalies were reported among normal newborns and no safety signals emerged with neonatal outcomes. Based on this series of 39 pregnancies with outcomes from IBD clinical trials, mothers treated with ustekinumab (limited to up to the first trimester) did not demonstrate a risk of negative outcomes. More data are needed to characterize the safety profile of ustekinumab use during pregnancy.

Comparative efficacy trials in inflammatory bowel disease: current and future implications for practice.

Over the last decade, there has been rapid expansion of the therapeutic armamentarium, and evolution of treatment strategies, for the management of inflammatory bowel diseases (IBDs). Consequently, there is an increasing need for head-to-head or comparative efficacy trials to inform optimal positioning of therapies, and pragmatic trials comparing treatment strategies to inform treatment approach. In this review, we will discuss the current status and future of comparative efficacy clinical trials in IBD. Pivotal phase IIIB superiority clinical trials have demonstrated superiority of vedolizumab over adalimumab for achieving clinical remission in patients with moderate-to-severe ulcerative colitis (VARSITY) and failed to demonstrate superiority of ustekinumab over adalimumab in patients with moderate-to-severe Crohn's disease (SEAVUE). Noninferiority clinical trials of biosimilars have confirmed absence of meaningful differences in safety and efficacy of biosimilar infliximab over originator infliximab, as initial therapy or switching stable patients during maintenance. Network meta-analyses, indirect treatment comparison using patient-level data from placebo-controlled trials and real-world observational studies have inform comparative effectiveness and safety of different therapies for management of IBD. Head-to-head clinical trials are critically important to advance the field of IBD. Comparative efficacy trials are slow and expensive to conduct, may not be broadly generalizable, and are not powered for safety events or other relevant outcomes. Alternative approaches to comparative effectiveness such as network meta-analysis and well designed real-world observational studies are able to bridge gaps in clinical practice.

Korean clinical practice guidelines on biologics and small molecules for moderate-to-severe ulcerative colitis.

Ulcerative colitis (UC), a relapsing-remitting chronic inflammatory bowel disease (IBD), has a variable natural course but potentially severe disease course. Since the development of anti-tumor necrosis factor (TNF) agents has changed the natural disease course of moderate-to-severe UC, therapeutic options for patients who failed conventional treatments are expanding rapidly. IBD clinical trials have demonstrated the potential efficacy and safety of novel biologics such as anti-integrin α4β7 and anti-interleukin-12/23 monoclonal antibodies and small molecules such as a Janus kinase inhibitor. Anti-TNF biosimilars also have been approved and are widely used in IBD patients. Wise drug choices should be made considering evidence-based efficacy and safety. However, the best position of these drugs remains several questions, with limited data from direct comparative trials. In addition, there are still concerns to be elucidated on the effect of therapeutic drug monitoring and combination therapy with immunomodulators. The appropriate treatment regimens in acute severe UC and the risk of perioperative use of biologics are unclear. As novel biologics and small molecules have been approved in Korea, we present the Korean guidelines for medical management of adult outpatients with moderate-to-severe UC and adult hospitalized patients with acute severe UC, focusing on biologics and small molecules.

Severe acute respiratory syndrome coronavirus 2 infection: Role of interleukin-6 and the inflammatory cascade.

Since December 2019, a novel coronavirus that represents a serious threat to human lives has emerged. There is still no definite treatment for severe cases of the disease caused by this virus, named coronavirus disease 2019 (COVID-19). One of the most considered treatment strategies targets the exaggerated immune regulator, and interleukin (IL)-6 is a crucial pro-inflammatory mediator. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases show an elevated level of IL-6 related to disease severity. IL-6 activity can be inhibited by the following: IL-6 itself, IL-6 signaling pathways such as Janus kinase and signal transducer and activator of transcription (JAK-STAT), gp130, IL-6R, and downstream activated ILs, such as IL-17 and IL-6 cytokine. Currently, according to these studies and their results, IL-6 blockade with anti-IL-6 or its receptor antibodies such as tocilizumab in COVID-19 is beneficial in severe cases and may reduce the mortality rate. JAK-STAT inhibitors block the cytokine storm by inhibiting several crucial pro-inflammatory mediators such as TNF-α and IL-6 and have shown various results in clinical trials. IL-6 induces IL-17 secretion, and IL-17 is involved in the pathogenesis of inflammatory processes. Clinical trials of anti-IL-17 drugs are currently recruiting, and anti-gp130 antibody is preclinical. However, this agent has shown positive effects in inflammatory bowel disease clinical trials and could be tested for SARS-CoV-2. This study aimed to review the role of IL-6 in the cytokine storm and studies regarding IL-6 and blockade of its inflammatory pathways in COVID-19 to determine if any of these agents are beneficial for COVID-19 patients.

Disparities Persist in Inclusion of Female, Pregnant, Lactating, and Older Individuals in Inflammatory Bowel Disease Clinical Trials

There is an intensified focus in the United States regarding the inclusion of under-represented groups in medical research, particularly clinical trials. Editorial boards of medical journals have released statements on diversity and inclusion in their publications as well as calls for clarity in sex-, gender-, racial-, and ethnic-related nomenclature.1,2 Despite formal recommendations from the National Institutes of Health (NIH) to increase inclusion of women, older adults, and people who identify as members of racial or ethnic minority groups,3 recent studies using the largest database in the world, clinicaltrials.gov, have demonstrated disparities in inclusion.

Precision Medicine in Inflammatory Bowel Diseases: Challenges and Considerations for the Path Forward

Precision Medicine in Inflammatory Bowel Diseases: Challenges and Considerations for the Path Forward

Review article: randomised controlled trials in inflammatory bowel disease-common challenges and potential solutions.

Recruitment rates for Crohn's disease and ulcerative colitis clinical trials continue to decrease annually. The inability to reach recruitment targets and complete trials has serious implications for stakeholders in the inflammatory bowel disease (IBD) community. Action is required to ensure patients with an unmet medical need have access to new therapies to improve the management of their IBD. Identify challenges contributing to recruitment decline in IBD clinical trials and propose potential solutions. PubMed and Google were used to identify literature, regulatory guidelines and conference proceedings related to IBD clinical trials and related concepts. Data on IBD clinical trials conducted between 1989 and 2020 were extracted from the Trialtrove database. Key aspects that may improve recruitment rates were identified. An increasingly patient-centric approach should be taken to study design including improvements to the readability of key trial documentation and inclusion of patient representatives in trial planning. Placebo is unappealing to patients; approaches including platform trials should be explored to minimise placebo exposure. Non-invasive imaging, biomarkers and novel digital endpoints should continue to be examined to reduce the burden on patients. Reducing the administrative burden associated with trials via the use of electronic signatures, for example, may benefit study sites and investigators. Changes implemented to IBD trials during the COVID-19 pandemic provided examples of how trial conduct can be rapidly and constructively adapted. To improve recruitment in Crohn's disease and ulcerative colitis trials, the IBD community should address a broad range of issues related to clinical trial conduct.

S903 Assessment of the Inclusion of Female, Racial/ethnic Minority and Older Individuals in Inflammatory Bowel Disease Clinical Trials

S903 Assessment of the Inclusion of Female, Racial/ethnic Minority and Older Individuals in Inflammatory Bowel Disease Clinical Trials

Inflammatory Bowel Disease Patients' Perspectives of Clinical Trials: A Global Quantitative and Qualitative Analysis.

Despite recent progress, inflammatory bowel disease (IBD) therapies with pronounced long-term efficacy and improved safety are needed. IBD clinical trials face challenges with patient recruitment because of study designs, competitive or overlapping trials, and limited numbers of eligible patients. We aimed to better understand patients' awareness of, attitudes toward, and experience with IBD clinical trials. This multinational, cross-sectional cohort study of adults with IBD recruited online consisted of 2 components: a quantitative 15-minute online survey completed by all participants and a qualitative 30-minute telephone interview completed by a subset of patients from the United States. Quantitative survey respondents (N = 226) included patients with ulcerative colitis (52%) and Crohn's disease (48%) from the United States (n = 100, 21 of whom were interviewed), Brazil (n = 26), Canada (n = 25), France (n = 25), Germany (n = 25), and Spain (n = 25); 96% of respondents reported at least a basic understanding of clinical trials. Patients rated conversations with health care providers most helpful for researching trials, but during interviews patients discussed their desire for increased patient-physician communication about trials. Major barriers to participation included invasive screening/monitoring (35% of quantitative responses) and concern over receiving placebo (35%) or suboptimal treatment (33%). Most respondents (68%) reported that clinical trial participants are "guinea pigs" for an experimental treatment. Opportunities to improve participation in IBD trials include improved communication with health care providers, further patient education, and alternative trial designs. Ultimately, a better understanding of the patient perspective will be important for more informed patients and more successful recruitment and enrollment.

Oral Delivery of Encapsulated All-Trans Retinoic Acid Ameliorates Disease in Rodent Models of Colitis.

All-trans retinoic acid (ATRA) is a biologically active isomer of retinoic acid (RA). Topical ATRA (retin-a, retin-a micro, atralin, renova, and avita) is the active pharmaceutical ingredient for FDA-approved treatments for acne and skin wrinkles. Oral formulations (Vesanoid) treat acute promyelocytic leukemia, but oral dosing can induce severe side effects. Despite benefits in various rodent models of inflammatory bowel disease (IBD), toxicity and controversial clinical observations have diminished enthusiasm for ATRA IBD clinical trials. To circumvent these issues and to use ATRA's key role in maintaining gut tolerance, we developed a poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) encapsulated ATRA formulation aimed at directing ATRA delivery to immune structures of the gut, limiting systemic exposure. Initially, ATRA MS was developed as a component of a combinatorial product (TreXTAM) that also contained encapsulated transforming growth factor (TGF)-β and ATRA in a 1:2 w/w ratio. Although the combination was optimal, benefit was also observed when ATRA MS was given alone in the CD4+ CD25-T-cell adoptive transfer (ACT) colitis model. We used the ACT and DSS-induced murine models of colitis to expand on the dose-dependent effects of oral ATRA MS when given alone. The DSS model was also used to compare the efficacy of ATRA MS and soluble ATRA, while healthy animals were used to compare the pharmacokinetics of the two drugs. In both the ACT and DSS-induced murine models of colitis, ATRA MS was observed to be effective in ameliorating disease. ATRA MS was also observed to be more effective than soluble ATRA in these models and displayed more favorable pharmacokinetics. We suggest ATRA MS, as a standalone product, may attenuate IBD and perhaps limit fibrosis, while limiting systemic side effects.