Inflammatory Bowel Disease Trials Research Articles

Nuclear Receptors Regulate Intestinal Inflammation in the Context of IBD.

Gastrointestinal (GI) homeostasis is strongly dependent on nuclear receptor (NR) functions. They play a variety of roles ranging from nutrient uptake, sensing of microbial metabolites, regulation of epithelial intestinal cell integrity to shaping of the intestinal immune cell repertoire. Several NRs are associated with GI pathologies; therefore, systematic analysis of NR biology, the underlying molecular mechanisms, and regulation of target genes can be expected to help greatly in uncovering the course of GI diseases. Recently, an increasing number of NRs has been validated as potential drug targets for therapeutic intervention in patients with inflammatory bowel disease (IBD). Besides the classical glucocorticoids, especially PPARγ, VDR, or PXR-selective ligands are currently being tested with promising results in clinical IBD trials. Also, several pre-clinical animal studies are being performed with NRs. This review focuses on the complex biology of NRs and their context-dependent anti- or pro-inflammatory activities in the regulation of gastrointestinal barrier with special attention to NRs already pharmacologically targeted in clinic and pre-clinical IBD treatment regimens.

Fecal microbiota transplantation: great potential with many challenges.

In January of 2019, Samuel P. Costello and colleagues published a wonderfully executed, double blind placebo-controlled trial on fecal microbiota transplantation (FMT) versus autologous stool as placebo in mild to moderately active adult ulcerative colitis [UC: one type of inflammatory bowel disease (IBD)] patients. This review-commentary examines the current state of knowledge on human gut microbiome (live microbiota + their products and surrounding environment, i.e., fecal matter) and microbial therapeutics from a gastrointestinal (GI) clinician's standpoint. The varied forms of dysbiosis as the target of FMT, recipient donor and placebo considerations are also discussed in respect to randomized control trials in IBD [and the lack thereof in Crohn's disease (CD)] with this unconventional treatment modality.

Designing clinical trials in paediatric inflammatory bowel diseases: a PIBDnet commentary

IntroductionThe optimal trial design for assessing novel therapies in paediatric IBD (PIBD) is a subject of intense ongoing global discussions and debate among the different stakeholders. However, there is a...

Spinal Instability in Rats Counteracted by Pentadecapeptide BPC 157

To induce spinal instability, we focused on bilateral facetectomy in rats and possible therapeutic benefit with the stable gastric pentadecapeptide BPC 157 given in the drinking water. Recently, using a well‐designed rat model (L2‐L3 compression), we demonstrated that the stable gastric pentadecapeptide BPC 157 improved the spinal cord injury (FASEB J 2015, 29, 617.5), concluding that under the conditions of one single application, given soon after spinal cord injury, motor function was markedly recovered, axonal and neuronal necrosis was counteracted, as was demyelination and cyst formation. Previously shown to counteract the consequence of peripheral (sciatic) nerve transection/anastomosis, improve nerve healing (Regul Pept. 2010 Feb 25;160(1–3):33–41.), brain trauma (Regul Pept. 2010;160(1–3):26–32.), and various encephalopathies (Curr Pharm Des. 2018;24(18):1990–2001), BPC 157 (LD1 not achieved) was implemented as an anti‐ulcer peptide in inflammatory bowel disease trials and now in a multiple sclerosis trial(Curr Pharm Des. 2018;24(18):1990–2001). In this study, the bilateral paravertebral muscles attached to the L3–L4 segment were peeled from the lumbar spine to expose the posterior bony elements. The rats then underwent complete resection of bilateral L3–L4 facet joints without neural tissue injuries. The medication was given in drinking water (BPC 157 10 ng/kg, 0.16 ng/mL, 12 ml/rat/day) through next 8 weeks, while controls received drinking water only. Radiological assesment of rat spines acquired at 1 week or 8 weeks was conducted (Figure 1). At 1 week, controls and BPC 157 animals exhibited no gross deformity observed in any plane, disk spaces seem unaffected, neural foramen at operated level is slightly widened, though BPC 157 drinking animals had higher bone density overall. At 8 weeks, both groups exhibited no gross deformity observed in any plane, unaffected disk spaces, widened neural foramen at the operated level is slightly widened, though there was an additional discrepancy in bone density overall between groups (BPC 157 having markedly more sclerotic and better defined bones). Also worth noting is the lack of abundant callus formation in the BPC 157 rats whereas the controls have visible callus formation in seemingly random patterns near the affected level. In addition, a significant motor disability which appears in controls immediately upon injury induction, was completely counteracted in BPC 157 drinking rats.Support or Funding InformationThis work was supported by the Ministry of Science, Education and Sports, Republic of Croatia [grant number 108‐1083570‐3635].This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Publisher Correction: Death by inflammation: drug makers chase the master controller.

In the version of this article initially published, a GlaxoSmithKline compound referred to as GSK298559 was listed in Table 1 as a RIPK1 inhibitor in phase 1 trials for inflammatory bowel disease. The correct designation is GSK2983559; however, this compound is a RIPK2 inhibitor and thus should not have been included in the table in question. The table row has been deleted. The error has been corrected in the HTML and PDF versions of the article.

Effect of TELEmedicine for Inflammatory Bowel Disease on Patient Activation and Self-Efficacy.

Limitations in inflammatory bowel disease (IBD) care necessitate greater patient activation and self-efficacy, measures associated with positive health outcomes. We assessed change in patient activation and general self-efficacy from baseline to 12months through our TELEmedicine for IBD trial, a multicenter, randomized controlled trial consisting of a web-based monitoring system that interacts with participants via text messaging. A total of 222 adults with IBD who had experienced an IBD flare within 2years prior to the trial were randomized into either a control arm that received standard care (SC) or an intervention arm that completed self-testing through the TELE-IBD system every other week (EOW) or weekly (W). Changes in self-efficacy scores were not significantly different between control and experimental groups. Patient activation scores were significantly different between standard care and the TELE-IBD EOW group only (p = 0.03). Use of remote monitoring did not improve self-efficacy or patient activation compared to routine care.

Evolution of Clinical Trials in Inflammatory Bowel Diseases.

Since the first clinical trial of cortisone in ulcerative colitis in 1955, remarkable progress has been made in the design and conduct of clinical trials in inflammatory bowel diseases (IBD). In this review article, we will discuss evolution of clinical trials in IBD over the last 3-5years. Recognizing limitations intrinsic to clinical disease activity indices in IBD, regulatory authorities have recommended evaluating co-primary endpoints of patient-reported outcomes and endoscopic disease activity in clinical trials. Biomarker-enriched trial enrolment and central endoscopy reading have emerged as critical events in trial recruitment and outcome assessment and have driven placebo response rates down. While trials of novel biologic therapies and advanced small molecules continue at an accelerated pace, pragmatic comparative efficacy trials of treatment strategy aimed at optimizing current therapies (such as early combined immunosuppression [REACT], tight disease control [CALM], therapeutic drug monitoring [TAXIT, TAILORIX]) have directly informed clinical practice. With emphasis on value-based care and population health management, multi-pronged remote monitoring, self-management, and telemedicine approaches in the era of smartphones have re-emerged with promise. Non-conventional therapies such as fecal microbiota transplantation, though still experimental, have provided insight into disease pathogenesis and offered hope for microbial manipulation strategies for treating these complex diseases. Clinical trials have rapidly evolved over the last 5years not only focusing on novel therapies but also optimizing existing treatment approaches and population health management. Over the next decade, these trials will continue to advance the field, and be readily translatable into clinical practice.

Oligonucleotide-Based Therapies for Inflammatory Bowel Disease.

The growing understanding of the immunopathogenesis of inflammatory bowel diseases (IBDs) has contributed to the identification of new targets whose expression/activity can be modulated for therapeutic purposes. Several approaches have been employed to develop selective pharmaceutical compounds; among these, antisense oligonucleotides (ASOs) or synthetic oligonucleotides represent a valid option for inhibiting or enhancing, respectively, the expression/function of molecules that have been implicated in the control of IBD-related inflammation. In this context, data have been accumulated for the following compounds: alicaforsen, an ASO targeting intercellular adhesion molecule-1, a transmembrane glycoprotein that regulates rolling and adhesion of leukocytes to inflamed intestine; DIMS0150 and BL-7040, two oligonucleotides that enhance Toll-like receptor-9 activity; Mongersen, an ASO that inhibits Smad7, thereby restoring transforming growth factor-β1/Smad-associated signaling; STNM01, a double-stranded RNA oligonucleotide silencing carbohydrate sulfotransferase, an enzyme involved in fibrogenic processes, and hgd40, a specific DNAzyme inhibiting expression of the transcription factor GATA3. In this article, we review the rationale and the available data relative to the use of these agents in IBD. Although pre-clinical and phase II trials in IBD support the use of oligonucleotide-based therapies for treating the pathogenic process occurring in the gut of patients with these disorders, further work is needed to establish whether and which patients can benefit from specific ASOs and identify biomarkers that could help optimize treatment.

Sphingosine-1-Phosphate Signaling and Metabolism Gene Signature in Pediatric Inflammatory Bowel Disease: A Matched-case Control Pilot Study.

The aim of this study was to investigate gene expression levels of proteins involved in sphingosine-1-phosphate (S1P) metabolism and signaling in a pediatric inflammatory bowel disease (IBD) patient population. IBD is a debilitating disease affecting 0.4% of the US population. The incidence of IBD in childhood is rising. Identifying effective targeted therapies that can be used safely in young patients and developing tools for selecting specific candidates for targeted therapies are important goals. Clinical IBD trials now underway target S1PR1, a receptor for the pro-inflammatory sphingolipid S1P. However, circulating and tissue sphingolipid levels and S1P-related gene expression have not been characterized in pediatric IBD. Pediatric IBD patients and controls were recruited in a four-site study. Patients received a clinical score using PUCAI or PCDAI evaluation. Colon biopsies were collected during endoscopy. Gene expression was measured by qRT-PCR. Plasma and gut tissue sphingolipids were measured by LC-MS/MS. Genes of S1P synthesis (SPHK1, SPHK2), degradation (SGPL1), and signaling (S1PR1, S1PR2, and S1PR4) were significantly upregulated in colon biopsies of IBD patients with moderate/severe symptoms compared with controls or patients in remission. Tissue ceramide, dihydroceramide, and ceramide-1-phosphate (C1P) levels were significantly elevated in IBD patients compared with controls. A signature of elevated S1P-related gene expression in colon tissues of pediatric IBD patients correlates with active disease and normalizes in remission. Biopsied gut tissue from symptomatic IBD patients contains high levels of pro-apoptotic and pro-inflammatory sphingolipids. A combined analysis of gut tissue sphingolipid profiles with this S1P-related gene signature may be useful for monitoring response to conventional therapy.

Sa1774 - Incidence of Venous Thromboembolic Complications in Controlled Trials of Inflammatory Bowel Disease

Sa1774 - Incidence of Venous Thromboembolic Complications in Controlled Trials of Inflammatory Bowel Disease

The Effect of BPC 157 on Tracheocutaneous Fistula Healing in Rat

IntroductionOne of the common late complications of a tracheotomy is tracheocutaneous fistula. The surgical procedure is needed to close such fistulas. BPC 157, anti‐ulcer peptide (GEPPPGKPADDAGLV, M.W. 1419) successful in trials for inflammatory bowel disease, wound treatment, effective alone without a carrier. BPC 157 interferes with NO‐system in vitro/in vivo on different models and different animal species. The impact of BPC 157 and NO‐system on gastrocutaneous, colocutaneous and oesophagocutaneous fistulas healing process indicates potential effect of BPC 157 in tracheocutaneous fistula healing process, which has not yet been investigated.MethodsAlbino Wistar male rats were used in this experiment, 220–280 g. Tracheocutaneous fistula, 4 mm trachea and skin defect, was surgically made under anaesthesia. Animals were treated according to the experiment protocol: a) drinking water p.o., b) BPC 157 (10 μg/kg, 12 ml/rat/day) p.o., c) BPC 157 (10 ng/kg, 12 ml/rat/day) p.o., d) saline 5ml/kg/day i.p., e) BPC 157 (10μg/kg, 5ml/kg/day) i.p., f) BPC 157 (10 ng/kg, 5 ml/kg/day) i.p., g) L‐NAME (5 mg/kg/day) i.p., h) L‐arginine (100 mg/kg/day) i.p., i) L‐NAME L‐arginine i.p., j) L‐NAME BPC 157 (μg) i.p., k) L‐arginine BPC 157 (μg) i.p., l) L‐NAME L‐arginine BPC 157 (μg) i.p., m) L‐NAME BPC 157 (ng) i.p., n) L‐arginine BPC 157 (ng) i.p., o) L‐NAME L‐arginine BPC 157 (ng) i.p.. Third, fifth and seventh postoperative day animals were euthanized. Fistula specimens were harvested and macroscopic and histological analysis was made.ResultsA consistent counteracting beneficial effect was shown in all animals treated with BPC 157, alone and with (L‐NAME) and/or L‐arginine in a 7‐day interval. BPC 157 accelerated healing of tracheocutaneous fistulas and showed macroscopic and histological healing improvements. Tracheocutaneous fistulas healing was improved speedily (BPC 157 completely counteracted L‐NAME effects (L‐NAME+BPC 157 and L‐NAME+L‐arginine+BPC 157 groups), or with delay and to less extent (L‐arginine) or aggravated, rapidly and prominently (L‐NAME). L‐arginine reduces aggravation by NOS‐blockade (L‐NAME) to the control levels. Also, BPC 157 more than nullifies the effect of L‐NAME.ConclusionBPC 157 improved healing of both tracheal and skin defects and mediated fistula closing. This effect was shared by L‐arginine, with an opposite effect seen by L‐NAME, thereby portraying NO‐system involvement in the healing of tracheocutaneous fistula.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Physicians' perspective on the clinical meaningfulness of inflammatory bowel disease trial results: an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) survey.

Several novel compounds are being developed for inflammatory bowel diseases (IBD). In addition, biosimilar drugs are being approved. An increasing number of head-to-head, superiority and non-inferiority trials in patients with IBD are expected in the future. The clinical relevance of the magnitude of the effect size is often debated. To better understand physicians' perspectives on the clinical meaningfulness of IBD trial results. We conducted an online survey among all IOIBD (International Organization for the Study of Inflammatory Bowel Diseases) members, asking their opinion on the clinical relevance of the results of IBD trials. Forty-six IOIBD members responded to the survey (52.3%). In biologic-naïve ulcerative colitis (UC) and Crohn's disease (CD) patients, most of the participants considered a 15% difference with placebo for clinical remission and endoscopic remission to be clinically relevant. In head-to-head trials, most of participants considerer a 10% difference between groups for clinical remission and endoscopic remission to be clinically relevant. Half of respondents considered 10% to be an adequate margin in non-inferiority trials. In bioequivalence studies, most of the participants considered adequate a ± 5% difference between a biosimilar and the originator for pharmacokinetic parameters, efficacy, safety and immunogenicity. Regarding safety, the difference between two drugs considered clinically relevant varied from 1% to 5%, depending on the type of adverse event. This is the first survey exploring how physicians perceive IBD trial results, providing an estimation of the magnitude of the difference between treatment arms that may directly influence clinical practice.

P735 Incidence of venous thromboembolic complications in controlled trials of inflammatory bowel disease

P735 Incidence of venous thromboembolic complications in controlled trials of inflammatory bowel disease

Development of a core outcome set for clinical trials in inflammatory bowel disease: study protocol for a systematic review of the literature and identification of a core outcome set using a Delphi survey

IntroductionCrohn’s disease (CD) and ulcerative colitis (UC), the main forms of inflammatory bowel disease (IBD), are chronic, progressive and disabling disorders of the gastrointestinal tract. Although data from randomised controlled...

The Importance and Challenges of Dietary Intervention Trials for Inflammatory Bowel Disease.

Inflammatory bowel disease is believed to be caused by a combination of genetic and environmental stimuli such as our diet. Diets high in meat and fats and low in fruits and vegetables have been associated with new-onset inflammatory bowel disease. This has triggered interest in using dietary modification as a treatment. The 3 principle models of dietary intervention are supplementation with selected dietary components, exclusion of selected dietary components, or use of dietary formulas in place of a normal diet. Despite the high level of interest in dietary interventions as a treatment for inflammatory bowel disease, few well-designed clinical trials have been conducted to firmly establish the optimal diet to induce or maintain remission. This may be in part related to the challenges of conducting dietary intervention trials. This review examines these challenges and potential approaches to be used in dietary intervention trials.

Brain-gut Axis and Pentadecapeptide BPC 157: Theoretical and Practical Implications.

BackgroundBrain-gut interaction involves, among others, peptidergic growth factors which are native in GI tract and have strong antiulcer potency and thus could from periphery beneficially affect CNS-disorders. We focused on the stable gastric pentadecapeptide BPC 157, an antiulcer peptidergic agent, safe in inflammatory bowel disease trials and now in multiple sclerosis trial, native and stable in human gastric juice.MethodsReview of our research on BPC 157 in terms of brain-gut axis.ResultsBPC 157 may serve as a novel mediator of Robert’s cytoprotection, involved in maintaining of GI mucosa integrity, with no toxic effect. BPC 157 was successful in the therapy of GI tract, periodontitis, liver and pancreas lesions, and in the healing of various tissues and wounds. Stimulated Egr-1 gene, NAB2, FAK-paxillin and JAK-2 pathways are hitherto implicated. Initially corresponding beneficial central influence was seen when BPC 157 was given peripherally and a serotonin release in particular brain areas, mostly nigrostriatal, was changed. BPC 157 modulates serotonergic and dopaminergic systems, beneficially affects various behavioral disturbances that otherwise appeared due to specifically (over)stimulated/damaged neurotransmitters systems. Besides, BPC 157 has neuroprotective effects: protects somatosensory neurons; peripheral nerve regeneration appearent after transection; after traumatic brain injury counteracts the otherwise progressing course, in rat spinal cord compression with tail paralysis, axonal and neuronal necrosis, demyelination, cyst formation and rescues tail function in both short-terms and long-terms; after NSAIDs or insulin overdose or cuprizone encephalopathies were attenuated along with GI, liver and vascular injuries.ConclusionBPC 157, a gastric peptide, may serve as remedy in various CNS-disorders.

Development of an Electronic Application for Landmark Trials in Inflammatory Bowel Disease

Development of an Electronic Application for Landmark Trials in Inflammatory Bowel Disease

Standardisation of Study Protocols - Pros and Cons.

Designing clinical trials in inflammatory bowel diseases is challenging. Composite scores that have been used for drug approval until recently such as the Crohn's disease activity index (CDAI) and the Mayo score for ulcerative colitis have been criticized by regulatory bodies for its lack of validation, poor correlation with objective mucosal disease and absence of 'patient reported outcomes'.Most drug development programs use the 'classic 'separation' between an induction and a maintenance phase. Challenging issues are the 'ideal timing' of the primary endpoint for induction and maintenance studies, strategies to reduce placebo response rates and rules for corticosteroids withdrawal. Discussion about which patients to re-randomize after induction into the maintenance phase of the study is critical.Presently, new instruments for disease assessment in IBD are being developed and validated. Central (independent) review of endoscopic recordings at screening and at the end of the intervention will probably become standard. Finally, the most optimal trial design for every individual intervention is likely to depend on the mechanism of action of the medication under study.

Are We Ready to Abandon Placebo in Randomised Clinical Trials for Inflammatory Bowel Disease? Pros and Cons.

The role of placebo in clinical trials for drug development in inflammatory bowel disease [IBD] was the topic of a panel discussion held during the 10th Congress of the European Crohn's and Colitis Organisation [ECCO], in Barcelona, Spain, in 2015. Panellists discussed a number of issues around placebo-controlled trials in IBD, noting issues such as difficulties with recruitment, leading to less then representative patient populations in clinical studies. It was noted that, whereas the easiest answer may be to drop placebo, it is much more complicated than that. The relevance of placebo is affected by a number of factors, including the phase of the trial, as well as the nature of the drug. In most cases where placebo has been left out in drug development, it has been for trials involving a new formulation, a new dosing schedule, or a biosimilar, for example. The panel agreed that placebo-controlled trials are of particular importance early in the development programme, perhaps not so much in phase III, although placebo is important for monitoring safety. The current trial paradigm, in which patients remain on a plethora of, likely ineffective and toxic, background medication, was also questioned. The applicability of placebo in the paediatric population was also discussed. The overall consensus from this panel discussion was that placebo is still necessary in clinical trials in inflammatory bowel disease, but there remain questions as to how and when placebo should be used.

NIHR statistics group imaging studies section: a network for statisticians and researchers using imaging in healthcare research

Incorporating imaging modalities into clinical trials and healthcare research presents particular challenges: What should be measured, and how? What summary statistic should be used? How can we best handle large amounts of multiple testing? How can reliability and misdiagnosis be assessed, and what are their implications? The NIHR Statistics group (http://www.statistics-group.nihr.ac.uk/) aims to promote statistical methodology, provide educational opportunities, share best practice and develop a community of statisticians funded by NIHR research units or grants. The NIHR Statistics group imaging Studies Section of the group provides a forum to address statistical issues in the design and analysis of imaging studies. The group aims to facilitate networking among statisticians, data analysts and other methodologists working in this area. The Imaging Studies Section organises meetings every six months, with presentations on statistical challenges in imaging studies, small group discussions to share design ideas and expertise, and networking. A working group has been formed to organise meetings and facilitate related activities. Our first meeting took place on the 22nd October 2014 in Oxford, attended by 25 members. This was followed by a second meeting on 27th April 2015 in Warwick, which focussed on inter-rater agreement and reproducibility of endpoint assessment within the context of clinical trials in Inflammatory Bowel Disease. This poster will outline the key statistical issues that need to be addressed when designing and analysing studies that use medical imaging, and will also summarise the current and future plans of the Imaging Studies Section.