Endoscopy and central reading in inflammatory bowel disease clinical trials: achievements, challenges and future developments

Central reading, that is, independent, off-site, blinded review or reading of imaging endpoints, has been identified as a crucial component in the conduct and analysis of inflammatory bowel disease clinical trials. Central reading is the final step in a workflow that has many parts, all of which can be improved. Furthermore, the best reading algorithm and the most intensive central reader training cannot make up for deficiencies in the acquisition stage (clinical trial endoscopy) or improve on the limitations of the underlying score (outcome instrument). In this review, academic and industry experts review scoring systems, and propose a theoretical framework for central reading that predicts when improvements in statistical power, affecting trial size and chances of success, can be expected: Multireader models can be conceptualised as statistical or non-statistical (social). Important organisational and operational factors, such as training and retraining of readers, optimal bowel preparation for colonoscopy, video quality, optimal or at least acceptable read duration times and other quality control matters, are addressed as well. The theory and practice of central reading and the conduct of endoscopy in clinical trials are interdisciplinary topics that should be of interest to many, regulators, clinical trial experts, gastroenterology societies and those in the academic community who endeavour to develop new scoring systems using traditional and machine learning approaches.

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Preferences of Adult Patients With Inflammatory Bowel Disease for Attributes of Clinical Trials: Evidence From a Choice-Based Conjoint Analysis

Crohn's & Colitis 360 ◽

10.1093/crocol/otz048 ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Dallas Wood ◽

Katherine Kosa ◽

Derek Brown ◽

Orna G Ehrlich ◽

Peter D R Higgins ◽

...

Keyword(s):

Clinical Trial ◽

Inflammatory Bowel Disease ◽

Clinical Trials ◽

Bowel Disease ◽

Latent Class ◽

Open Label ◽

Monetary Compensation ◽

Open Label Extension ◽

Inflammatory Bowel ◽

New Treatments

Abstract Background Clinical trial recruitment is the rate-limiting step in developing new treatments. To understand inflammatory bowel disease (IBD) patient recruitment, we investigated two questions: Do changes in clinical trial attributes, like monetary compensation, influence recruitment rates, and does this influence differ across subgroups? Methods We answered these questions through a conjoint survey of 949 adult IBD patients. Results Recruitment rates are influenced by trial attributes: small but significant increases are predicted with lower placebo rates, reduced number of endoscopies, less time commitment, open label extension, and increased involvement of participant’s primary GI physician. A much stronger effect was found with increased monetary compensation. Latent class analysis indicated three patient subgroups: some patients quite willing to participate in IBD trials, some quite reluctant, and others who can be persuaded. The persuadable group is quite sensitive to monetary compensation, and payments up to US$2,000 for a 1-year study could significantly increase recruitment rates for IBD clinical trials. Conclusions This innovative study provides researchers with a framework for predicting recruitment rates for different IBD clinical trials.

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Reinventing Inflammatory Bowel Disease (IBD) Clinical Trial Recruitment Using Novel Digital Medicine Tools (Preprint)

10.2196/preprints.11815 ◽

2018 ◽

Author(s):

Emamuzo Otobo ◽

Christopher Park ◽

Jason Rogers ◽

Farah Fasihuddin ◽

Shashank Garg ◽

...

Keyword(s):

Clinical Trial ◽

Inflammatory Bowel Disease ◽

Clinical Trials ◽

Bowel Disease ◽

Rapid Development ◽

The United States ◽

Population Characteristics ◽

Patient Recruitment ◽

Digital Medicine ◽

Inflammatory Bowel

BACKGROUND Issues with patient recruitment and enrollment are the primary barriers for missed clinical trial timelines; 8 out of 10 clinical trials are delayed or unable to be completed because of lack of timely patient recruitment. Current patient recruitment efforts are inefficient and time-consuming, since they are typically dependent on manually screening patients during face-to-face visits to the clinic or hospital. With the rapid development of digital communication platforms within health care and the broad consumer adoption of smartphones, there are increasing opportunities to overcome some of these barriers. These platforms have particularly great potential for research and clinical care of chronic conditions, such as inflammatory bowel disease (IBD), an often debilitating disease which currently affects over three million adults in the United States. OBJECTIVE To integrate and utilize a digital medicine platform to improve patient recruitment and enrollment processes in clinical trials. METHODS Patients enrolled in the Mount Sinai Crohn’s and Colitis Registry (MSCCR) were remotely approached about enrolling in a mindfulness study for IBD patients. A text-based clinical rules engine was used to inform registry patients about the trial and to allow patients to indicate interest in participating via text message. Eligible IBD patients were bulk “prescribed” a notification through RxHealth’s digital medicine platform, RxUniverse. Characteristics of the enrolled population, characteristics of patients who responded, and timeliness of responses were analyzed. RESULTS Of the 1364 patients in the MSCCR with available phone numbers, 270 patients affirmatively replied they wanted to participate in to the study. Patients who opted into receiving more information about the study were more likely to have inadequate control of their IBD (25.64% vs 18.97%; P<.05) and more likely to have a recent history of depression based on a validated patient health questionnaire (15.38% vs 8.4%; P<.05) than those who opted out. Furthermore, patients who opted in tended to be younger, were more likely to be female, and less likely to have ulcerative colitis, though these trends did not reach statistical significance. Patient race did not significantly differ between those who opted in and opted out. In terms of timeliness of response among those enrolled, the majority of patients responded within 2 hours of notification. CONCLUSIONS Digital medicine software platforms can facilitate large-scale, lower-effort recruitment of eligible patients for clinical trials. Future research should be done to explore their expanded use for recruitment, patient education, and study data collection. Additional technologies such as patient-powered networks, social media, e-recruiting bots, and other remote engagement platforms can aid clinical trials by saving time and reducing costs of patient recruitment.

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Are We Ready to Include Prognostic Factors in Inflammatory Bowel Disease Trials?

Current Pharmaceutical Design ◽

10.2174/1381612825666190312113935 ◽

2019 ◽

Vol 25 (1) ◽

pp. 64-68 ◽

Cited By ~ 2

Author(s):

Christopher R. Lindholm ◽

Corey A. Siegel

Keyword(s):

Inflammatory Bowel Disease ◽

Clinical Trials ◽

Bowel Disease ◽

Clinical Decision Making ◽

Scoring Systems ◽

Clinical Decision ◽

Chronic Inflammatory Disease ◽

Response To Therapy ◽

Clinical Activity ◽

Inflammatory Bowel

Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by periodic episodes of flares and remission. Treatment is aimed at healing the bowel, to ultimately decrease hospitalization rates, need for surgeries and overall disability. In more recent years, treatment has transitioned from a reactive approach to a more proactive approach focusing on treating disease earlier and preventing complications. The challenge lies in identifying patients who need more intensive treatment early and trying to determine who will respond to which medications. Biomarkers and clinical activity scoring systems can be used to help guide treatment decisions. However, IBDs are very heterogeneous and the significance of these biomarkers can be difficult to discern on an individual basis. Recently, prognostic tools have been developed to aid in determining a patient’s prognosis as well as their likelihood to respond to different therapies. Despite this progress, clinical trials have not routinely adopted this approach in their study design. Tools for stratification of disease severity and to personalize treatment choices have the potential to improve our studies both by enriching the patient population and further guiding clinical decision making in practice. This review aims to discuss biomarkers, current prognosticating tools, tools that determine response to therapy and how incorporating these into clinical trials will be beneficial.

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Designing fecal microbiota transplant trials that account for differences in donor stool efficacy

Statistical Methods in Medical Research ◽

10.1177/0962280216688502 ◽

2017 ◽

Vol 27 (10) ◽

pp. 2906-2917 ◽

Cited By ~ 10

Author(s):

Scott W Olesen ◽

Thomas Gurry ◽

Eric J Alm

Keyword(s):

Inflammatory Bowel Disease ◽

Clinical Trials ◽

Bowel Disease ◽

Statistical Power ◽

Fecal Microbiota Transplantation ◽

Optimal Strategies ◽

Fecal Microbiota ◽

Fecal Microbiota Transplant ◽

Number Of Patients ◽

Inflammatory Bowel

Fecal microbiota transplantation is a highly effective intervention for patients suffering from recurrent Clostridium difficile, a common hospital-acquired infection. Fecal microbiota transplantation’s success as a therapy for C. difficile has inspired interest in performing clinical trials that experiment with fecal microbiota transplantation as a therapy for other conditions like inflammatory bowel disease, obesity, diabetes, and Parkinson’s disease. Results from clinical trials that use fecal microbiota transplantation to treat inflammatory bowel disease suggest that, for at least one condition beyond C. difficile, most fecal microbiota transplantation donors produce stool that is not efficacious. The optimal strategies for identifying and using efficacious donors have not been investigated. We therefore examined the optimal Bayesian response-adaptive strategy for allocating patients to donors and formulated a computationally tractable myopic heuristic. This heuristic computes the probability that a donor is efficacious by updating prior expectations about the efficacy of fecal microbiota transplantation, the placebo rate, and the fraction of donors that produce efficacious stool. In simulations designed to mimic a recent fecal microbiota transplantation clinical trial, for which traditional power calculations predict [Formula: see text] statistical power, we found that accounting for differences in donor stool efficacy reduced the predicted statistical power to [Formula: see text]. For these simulations, using the heuristic Bayesian allocation strategy more than quadrupled the statistical power to [Formula: see text]. We use the results of similar simulations to make recommendations about the number of patients, the number of donors, and the choice of clinical endpoint that clinical trials should use to optimize their ability to detect if fecal microbiota transplantation is effective for treating a condition.

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Designing fecal microbiota transplant trials that account for differences in donor stool efficacy

10.1101/065383 ◽

2016 ◽

Author(s):

Scott W. Olesen ◽

Thomas Gurry ◽

Eric J. Alm

Keyword(s):

Inflammatory Bowel Disease ◽

Clinical Trials ◽

Bowel Disease ◽

Statistical Power ◽

Fecal Microbiota Transplantation ◽

Optimal Strategies ◽

Fecal Microbiota ◽

Fecal Microbiota Transplant ◽

Number Of Patients ◽

Inflammatory Bowel

1AbstractFecal microbiota transplantation (FMT) is a highly effective intervention for patients suffering from recurrent Clostridium difficile, a common hospital-acquired infection. FMT’s success as a therapy for C. difficile has inspired interest in performing clinical trials that experiment with FMT as a therapy for other conditions like inflammatory bowel disease, obesity, diabetes, and Parkinson’s disease. Results from clinical trials that use FMT to treat inflammatory bowel disease suggest that, for at least one condition beyond C. difficile, most FMT donors produce stool that is not efficacious. The optimal strategies for identifying and using efficacious donors have not been investigated. We therefore examined the optimal Bayesian response-adaptive strategy for allocating patients to donors and formulated a computationally-tractable myopic heuristic. This heuristic computes the probability that a donor is efficacious by updating prior expectations about the efficacy of FMT, the placebo rate, and the fraction of donors that produce efficacious stool. In simulations designed to mimic a recent FMT clinical trial, for which traditional power calculations predict ~100% statistical power, we found that accounting for differences in donor stool efficacy reduced the predicted statistical power to ~9%. For these simulations, using the heuristic Bayesian allocation strategy more than quadrupled the statistical power to ~39%. We use the results of similar simulations to make recommendations about the number of patients, number of donors, and choice of clinical endpoint that clinical trials should use to optimize their ability to detect if FMT is effective for treating a condition.

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REINVENTING INFLAMMATORY BOWEL DISEASE (IBD) CLINICAL TRIAL RECRUITMENT USING NOVEL DIGITAL MEDICINE TOOLS

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa347.017 ◽

2021 ◽

Vol 27 (Supplement_1) ◽

pp. S7-S7

Author(s):

Farah Fasihuddin ◽

Nicole Wedel ◽

Ashish Atreja ◽

Divya Madisetty ◽

Charu Madhwani Jain ◽

...

Keyword(s):

Clinical Trial ◽

Inflammatory Bowel Disease ◽

Clinical Trials ◽

Bowel Disease ◽

Rapid Development ◽

The United States ◽

Population Characteristics ◽

Patient Recruitment ◽

Digital Medicine ◽

Inflammatory Bowel

Abstract Background Issues with patient recruitment and enrolment are the primary barriers for missed clinical trial timelines; 8 out of 10 clinical trials are delayed or unable to be completed because of the lack of timely patient recruitment. Current patient recruitment efforts are inefficient as they are typically dependent on the manual screening of patients during face-to-face visits. With the rapid development of digital communication platforms within healthcare and the broad consumer adoption of smartphones, there are increasing opportunities to overcome some of these barriers. Digital platforms have great potential for research and clinical care of chronic conditions, such as inflammatory bowel disease (IBD), an often debilitating disease that currently affects over three million adults in the United States. In this paper, we utilized a digital medicine platform (Trialengage, Rx.Health, New York, NY) to improve patient recruitment for an ongoing mindfulness trial which had limited success in face-face enrolment (16 patients over 6 months). Methods Patients enrolled in the Mount Sinai Crohn’s and Colitis Registry (MSCCR) were remotely outreached about enrolling in a mindfulness study for IBD patients. A text-based clinical rules engine was used to inform registry patients about the trial and to allow patients to indicate interest in participating via text message. Eligible IBD patients were bulk “prescribed” a notification through RxHealth’s digital medicine platform, RxUniverse. Characteristics of the enrolled population, characteristics of patients who responded, and timeliness of responses were analyzed. Results Of the 1364 patients in the MSCCR with available phone numbers, 270 patients affirmatively replied they wanted to participate in the study. Patients who opted-in to receiving more information about the study were more likely to have inadequate control of their IBD (25.64% vs 18.97%; P<.05) and more likely to have a recent history of depression based on a validated patient health questionnaire (15.38% vs 8.4%; P<.05) than those who opted-out. There were no significant differences in terms of race, gender, and age between the two groups. In terms of timeliness of response among those enrolled, the majority of patients responded within 2 hours of notification. Conclusion Digital medicine software platforms can facilitate large-scale, lower-effort recruitment of eligible patients for clinical trials. Future research should be done to explore their expanded use for recruitment, patient education, and study data collection. Additional technologies such as patient-powered networks, social media, e-recruiting bots, and other remote engagement platforms can aid clinical trials by saving time and reducing costs of patient recruitment.

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Prebiotics and Probiotics in Inflammatory Bowel Disease: Where are we now and where are we going?

Current Clinical Pharmacology ◽

10.2174/1574884715666200312100237 ◽

2020 ◽

Vol 15 (3) ◽

pp. 216-233 ◽

Cited By ~ 1

Author(s):

Maliha Naseer ◽

Shiva Poola ◽

Syed Ali ◽

Sami Samiullah ◽

Veysel Tahan

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Clinical Trials ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Adverse Effects ◽

Bowel Disease ◽

Relapse Prevention ◽

Remission Induction ◽

Inflammatory Bowel

The incidence, prevalence, and cost of care associated with diagnosis and management of inflammatory bowel disease are on the rise. The role of gut microbiota in the causation of Crohn's disease and ulcerative colitis has not been established yet. Nevertheless, several animal models and human studies point towards the association. Targeting intestinal dysbiosis for remission induction, maintenance, and relapse prevention is an attractive treatment approach with minimal adverse effects. However, the data is still conflicting. The purpose of this article is to provide the most comprehensive and updated review on the utility of prebiotics and probiotics in the management of active Crohn’s disease and ulcerative colitis/pouchitis and their role in the remission induction, maintenance, and relapse prevention. A thorough literature review was performed on PubMed, Ovid Medline, and EMBASE using the terms “prebiotics AND ulcerative colitis”, “probiotics AND ulcerative colitis”, “prebiotics AND Crohn's disease”, “probiotics AND Crohn's disease”, “probiotics AND acute pouchitis”, “probiotics AND chronic pouchitis” and “prebiotics AND pouchitis”. Observational studies and clinical trials conducted on humans and published in the English language were included. A total of 71 clinical trials evaluating the utility of prebiotics and probiotics in the management of inflammatory bowel disease were reviewed and the findings were summarized. Most of these studies on probiotics evaluated lactobacillus, De Simone Formulation or Escherichia coli Nissle 1917 and there is some evidence supporting these agents for induction and maintenance of remission in ulcerative colitis and prevention of pouchitis relapse with minimal adverse effects. The efficacy of prebiotics such as fructooligosaccharides and Plantago ovata seeds in ulcerative colitis are inconclusive and the data regarding the utility of prebiotics in pouchitis is limited. The results of the clinical trials for remission induction and maintenance in active Crohn's disease or post-operative relapse with probiotics and prebiotics are inadequate and not very convincing. Prebiotics and probiotics are safe, effective and have great therapeutic potential. However, better designed clinical trials in the multicenter setting with a large sample and long duration of intervention are needed to identify the specific strain or combination of probiotics and prebiotics which will be more beneficial and effective in patients with inflammatory bowel disease.

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