Systematic Review: Non-medical Switching of Infliximab to CT-P13 in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Biosimilar approval, such as Inflectra™ (CT-P13) for treating ulcerative colitis (UC) and Crohn's disease (CD), has reduced direct drug costs. Though clinicians are comfortable with biosimilar use in treatment-naïve patients, there are concerns in some jurisdictions that there are insufficient data from well-controlled trials to support non-medical switching. A systematic review, along with a critical assessment of the study design, was conducted to assess the potential impact of switching stable CD/UC patients from infliximab to CT-P13. METHODS: A literature search using PubMed and abstracts/posters from 3 major gastroenterology conferences from 2014 to 2018 was completed. Two individual reviewers extracted data from each relevant report and compiled it into evidence tables to facilitate descriptive analyses. Key randomized trial and observational study designs were critically assessed to contextualize data relevance. RESULTS: A total of 49 reports (3 randomized controlled trials, 40 observational trials, and 1 case series) were included. Most studies revealed no efficacy, safety, or immunogenicity concerns with non-medical switch. Limitations of supporting data include a small number of randomized controlled trials; predominance of observational studies with varying outcome assessments and lack of appropriate controls; and scarcity of research on biosimilar switch long-term effects. CONCLUSIONS: The majority of studies suggested non-medical switch is safe. However, clinicians and regulatory bodies should be aware of differences and limitations in study designs when making inferences about the risks and benefits of switching stable IBD patients to biosimilars.

Early Initiation of Tumor Necrosis Factor Antagonist-Based Therapy for Patients With Crohn's Disease Reduces Costs Compared With Late Initiation.

BACKGROUND & AIMS: Antagonists of tumor necrosis factor (TNF) are effective for induction and maintenance of remission of Crohn's disease (CD) and are generally prescribed when patients do not respond to conventional, less-costly medical therapies. Early initiation of anti-TNF therapy reduced rates of surgery and dose escalation due to loss of response. However, these drugs are expensive, so studies are needed on the cost effectiveness of early initiation. We aimed to determine the cost effectiveness of initiating treatment early in the disease course (within 2 years of CD diagnosis) vs later in the disease course (more than 2 years after diagnosis). METHODS: We constructed a Markov model of a hypothetical cohort of patients with CD in Canada to simulate disease progression after initiation of infliximab or adalimumab therapy. We used published loss-of-response rates to compare the lifetime cost effectiveness of early vs late initiation of anti-TNF therapies. Transition probabilities and utilities were obtained through a literature search, and costs were obtained from the Alberta Ministry of Health. Sensitivity analysis was used to characterize uncertainty. RESULTS: Early initiation of infliximab yielded an additional 0.72 quality-adjusted life-years (QALYs) and saved $50,418 compared with late initiation. Early initiation of adalimumab yielded an additional 0.54 QALYs and saved $43,969. At a willingness-to-pay threshold of $50,000, early initiations of infliximab or adalimumab therapy had a 74% chance of being cost effective compared with late initiation. CONCLUSIONS: In a Markov model analysis, we found initiation of either infliximab or adalimumab within 2 years of CD diagnosis to provide significant cost savings and QALYs compared with later initiation (more than 2 years after diagnosis).

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

Heterogeneity in Definitions of Efficacy and Safety Endpoints for Clinical Trials of Crohn's Disease: A Systematic Review.

BACKGROUND & AIMS: Endpoints in randomized controlled trials (RCTs) of Crohn's disease (CD) are changing. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled RCTs of patients with CD. METHODS: We searched the MEDLINE, EMBASE, and the Cochrane Library through March 1, 2017 for placebo-controlled RCTs of adult patients with CD treated with aminosalicylates, immunomodulators, corticosteroids, biologics, and oral small molecules. Efficacy and safety outcomes, definitions, and measurement tools were collected and stratified by decade of publication. RESULTS: Our final analysis included 116 RCTs (81 induction, 44 maintenance, 7 postoperative prevention trials, comprising 27,263 patients). Clinical efficacy endpoints were reported in all trials; the most common endpoint was CD activity index score. We identified 38 unique definitions of clinical response or remission and 32 definitions of loss of response. Definitions of endoscopic response, remission, and endoscopic healing were also heterogeneous, evaluated using the CD endoscopic index of severity, the simple endoscopic score for CD, ulcer resolution, and Rutgeerts' Score for postoperative endoscopic appearance. Histologic outcomes were reported in 11.1% of induction trials, 2.3% of maintenance trials, and 14.3% of postoperative prevention trials. Biomarker outcomes were reported in 81.5% induction trials, 68.2% of maintenance trials, and 42.9% of postoperative prevention trials. Safety outcomes were reported in 93.8% of induction trials, 97.7% of maintenance trials, and 85.7% of postoperative prevention trials. CONCLUSIONS: In this systematic review, we demonstrate heterogeneity in definitions of response and remission, and changes in outcomes reported in RCTs of CD. It is a priority to select a core set of outcomes to standardize efficacy and safety evaluation in trials of patients with CD.

Heterogeneity in Definitions of Endpoints for Clinical Trials of Ulcerative Colitis: A Systematic Review for Development of a Core Outcome Set.

BACKGROUND & AIMS: Advances in development of therapeutic agents for ulcerative colitis (UC) have been paralleled by innovations in trial design. It would be useful to identify a core outcome set, to standardize outcome definitions for efficacy and safety in clinical trials. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled randomized controlled trials of patients with UC. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library from inception through March 1, 2017, for placebo-controlled randomized controlled trials of adult patients with UC treated with aminosalicylates, immunosuppressants, corticosteroids, biologics, and oral small molecules. We collected information on efficacy and safety outcomes, definitions, and measurement tools, stratified by decade of publication. RESULTS: We analyzed data from 83 randomized controlled trials (68 induction and 15 maintenance) comprising 17,737 patients. Clinical or composite-clinical efficacy outcomes were reported in all trials; the UC Disease Activity Index and Mayo Clinic Score were frequently used to determine clinical response or remission. We found substantial variation in definitions of clinical or composite-clinical endpoints, with more than 50 definitions of response or remission. Endoscopic factors, histologic features, and fecal or serum biomarkers were used to determine outcomes in 83.1% (69 of 83), 24.1% (20 of 83), and 24.1% (20 of 83) of trials, respectively. A greater proportion of trials published after 2007 reported objective outcomes (96.5% endoscopic, 26.3% histologic, and 36.8% biomarker outcomes), but no standardized definitions of histologic or biomarker endpoints were found. Patient-reported efficacy and quality-of-life outcomes were described in 25 trials (30.1%) and safety outcomes were reported in 77 trials (92.8%). CONCLUSION: In a systematic review, we found that despite recent advances in clinical trials methods, there is a great deal of variation in definitions of endpoints, including response and remission, in randomized controlled trials of patients with UC. Researchers should identify a core set of outcomes to standardize efficacy and safety reporting in UC clinical trials.

Within-Stool and Within-Day Sample Variability of Fecal Calprotectin in Patients With Inflammatory Bowel Disease: A Prospective Observational Study.

BACKGROUND AND GOALS: The use of fecal calprotectin (FC) as a stool biomarker for differentiating inflammatory bowel disease (IBD) from IBS has been well validated, and there is a strong correlation between FC and the presence of endoscopic inflammatory lesions. However, recent studies have demonstrated intraindividual sample variability in patients with IBD, possibly limiting the reliability of using a single sample for monitoring disease activity. Our aim was to assess the within-stool and within-day sample variability of FC concentrations in patients with IBD. STUDY: We examined a cross-sectional cohort of 50 adult IBD patients. Eligible patients were instructed to collect 3 samples from different parts of the stool from their first bowel movement of the day and 3 samples from each of up to 2 additional bowel movements within 24 hours. FC concentrations were measured by a rapid, quantitative point-of-care test using lateral flow technology (Quantum Blue). Descriptive statistics were used to assess FC variability within a single bowel movement and between different movements at different FC positivity cutoffs. RESULTS: Within a single bowel movement, there was clinically significant sample variability ranging from 8% to 23% depending on the time of the day or on the FC positivity cutoff value. Between bowel movements, there was clinically significant sample variability ranging from 13% to 26% depending on the FC positivity cutoff. CONCLUSIONS: Considering a single FC sample, the first sample of the day with an FC positivity cutoff of 250 µg/g provided the most reliable indication of disease activity.

Oral versus intravenous iron replacement therapy distinctly alters the gut microbiota and metabolome in patients with IBD.

OBJECTIVE: Iron deficiency is a common complication in patients with IBD and oral iron therapy is suggested to exacerbate IBD symptoms. We performed an open-labelled clinical trial to compare the effects of per oral (PO) versus intravenous (IV) iron replacement therapy (IRT). DESIGN: The study population included patients with Crohn's disease (CD; N=31), UC (N=22) and control subjects with iron deficiency (non-inflamed, NI=19). After randomisation, participants received iron sulfate (PO) or iron sucrose (IV) over 3 months. Clinical parameters, faecal bacterial communities and metabolomes were assessed before and after intervention. RESULTS: Both PO and IV treatments ameliorated iron deficiency, but higher ferritin levels were observed with IV. Changes in disease activity were independent of iron treatment types. Faecal samples in IBD were characterised by marked interindividual differences, lower phylotype richness and proportions of Clostridiales. Metabolite analysis also showed separation of both UC and CD from control anaemic participants. Major shifts in bacterial diversity occurred in approximately half of all participants after IRT, but patients with CD were most susceptible. Despite individual-specific changes in phylotypes due to IRT, PO treatment was associated with decreased abundances of operational taxonomic units assigned to the species Faecalibacterium prausnitzii, Ruminococcus bromii, Dorea sp. and Collinsella aerofaciens. Clear IV-specific and PO-specific fingerprints were evident at the level of metabolomes, with changes affecting cholesterol-derived host substrates. CONCLUSIONS: Shifts in gut bacterial diversity and composition associated with iron treatment are pronounced in IBD participants. Despite similar clinical outcome, oral administration differentially affects bacterial phylotypes and faecal metabolites compared with IV therapy. TRIAL REGISTRATION NUMBER: clinicaltrial.gov (NCT01067547).

The Oral ß-Lactamase SYN-004 (Ribaxamase) Degrades Ceftriaxone Excreted into the Intestine in Phase 2a Clinical Studies.

SYN-004 (ribaxamase) is a ß-lactamase designed to be orally administered concurrently with intravenous ß-lactam antibiotics, including most penicillins and cephalosporins. Ribaxamase's anticipated mechanism of action is to degrade excess ß-lactam antibiotic that is excreted into the small intestine. This enzymatic inactivation of excreted antibiotic is expected to protect the gut microbiome from disruption and thus prevent undesirable side effects, including secondary infections such as Clostridium difficile infections, as well as other antibiotic-associated diarrheas. In phase 1 clinical studies, ribaxamase was well tolerated compared to a placebo group and displayed negligible systemic absorption. The two phase 2a clinical studies described here were performed to confirm the mechanism of action of ribaxamase, degradation of ß-lactam antibiotics in the human intestine, and were therefore conducted in subjects with functioning ileostomies to allow serial sampling of their intestinal chyme. Ribaxamase fully degraded ceftriaxone to below the level of quantitation in the intestines of all subjects in both studies. Coadministration of oral ribaxamase with intravenous ceftriaxone was also well tolerated, and the plasma pharmacokinetics of ceftriaxone were unchanged by ribaxamase administration. Since ribaxamase is formulated as a pH-dependent, delayed-release formulation, the activity of ribaxamase in the presence of the proton pump inhibitor esomeprazole was examined in the second study; coadministration of these drugs did not adversely affect ribaxamase's ability to degrade ceftriaxone excreted into the intestine. These studies have confirmed the in vivo mechanism of action of ribaxamase, degradation of ß-lactam antibiotics in the human intestine (registered at ClinicalTrials.gov under NCT02419001 and NCT02473640).

Clinical validation of a novel urine-based metabolomic test for the detection of colonic polyps on Chinese population.

PURPOSE: Colorectal cancer is the fifth leading cause of cancer-related deaths in China. When detected early, with the removal of adenomatous polyps, precursors of colorectal cancer, it is preventable. The aim of this study was to evaluate a novel urine-based metabolomic diagnostic test for the detection of adenomatous polyps, PolypDx™, that was originally developed and validated using 1000 samples from Canadian Cohort, on Chinese population. METHODS: Prospective urine samples were collected from 1000 participants undergoing colonoscopy examination, from March 2013 to July 2014 at Minhang District, Shanghai Centre for Disease Control and Prevention. One-dimensional nuclear magnetic resonance spectra of urine metabolites were analyzed to determine the concentrations of three key metabolites used in PolypDx™. The predicted results were then compared to the gold standard for colorectal cancer diagnostic, colonoscopy. Area under curve (AUC) was calculated specifically for the Chinese population and compared with the Canadian dataset. Sensitivity and specificity of this urine-based metabolomic diagnostic test were also compared with three commercially available fecal-based tests. RESULTS: An AUC of 0.717 for PolypDx™ was calculated on Chinese dataset which is slightly lower than the AUC on the Canadian dataset. A sensitivity of 82.6% and a specificity of 42.4% were achieved on Chinese dataset. CONCLUSIONS: Here, we validated a novel urine-based metabolomic diagnostic test for the detection of adenomatous polyps, PolypDx™, on Chinese population through a sample size of 1000 participants with a greater level of sensitivity than fecal-based tests.

The Economic Contribution of Industry-Sponsored Pharmaceutical Clinical Trials.

PURPOSE: In pharmaceutical clinical trials, industrial sponsors pay for study drugs and related healthcare services. We conducted a study to determine industry's economic contribution of these trials to the Alberta healthcare system.  Methods: We used data from two trial centers for cancer and non-cancer trials at the University of Alberta. For each trial (cancer, non-cancer), we calculated the cost of drugs provided by the sponsors using the market price, the cost of clinical services, and the cost of administrative services that they paid. We extrapolated these results to all trials in Alberta based on information obtained from the registration website ClinicalTrials.gov.  Results: Our sample consisted of 40 non-cancer and 39 cancer drug trials which were initiated in 2012. The monetary value of the industry sponsors' contribution was $799,055 per non-cancer and $630,243 per cancer drug trial. Drugs (in-trial and post-trial) accounted for 84% of the total contribution of the non-cancer drug trials whereas it represented 93% of all trial-related contributions in the cancer category. The total province-wide contribution of industry-sponsored drug trials which were initiated in 2012 was estimated to be $101 million, including open-label drugs in the non-cancer category.  Conclusions: Industry-sponsored pharmaceutical trials represent a major economic contributor to clinical research within the province.

Vedolizumab as induction and maintenance therapy for Crohn's disease.

BACKGROUND: The efficacy of vedolizumab, an α4ß7 integrin antibody, in Crohn's disease is unknown. METHODS: In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS: At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%). CONCLUSIONS: Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).

Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial.

BACKGROUND & AIMS: Celiac disease (CeD) is a prevalent autoimmune condition. Recurrent signs and symptoms are common despite treatment with a gluten-free diet (GFD), yet no approved or proven nondietary treatment is available. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study, we assessed larazotide acetate 0.5, 1, or 2 mg 3 times daily to relieve ongoing symptoms in 342 adults with CeD who had been on a GFD for 12 months or longer and maintained their current GFD during the study. The study included a 4-week placebo run-in, 12 weeks of treatment, and a 4-week placebo run-out phase. The primary end point was the difference in average on-treatment Celiac Disease Gastrointestinal Symptom Rating Scale score. RESULTS: The primary end point was met with the 0.5-mg dose of larazotide acetate, with fewer symptoms compared with placebo by modified intention to treat (n = 340) (analysis of covariance, P = .022; mixed model for repeated measures, P = .005). The 0.5-mg dose showed an effect on exploratory end points including a 26% decrease in celiac disease patient-reported outcome symptomatic days (P = .017), a 31% increase in improved symptom days (P = .034), a 50% or more reduction from baseline of the weekly average abdominal pain score for 6 or more of 12 weeks of treatment (P = .022), and a decrease in the nongastrointestinal symptoms of headache and tiredness (P = .010). The 1- and 2-mg doses were no different than placebo for any end point. Safety was comparable with placebo. CONCLUSIONS: Larazotide acetate 0.5 mg reduced signs and symptoms in CeD patients on a GFD better than a GFD alone. Although results were mixed, this study was a successful trial of a novel therapeutic agent targeting tight junction regulation in patients with CeD who are symptomatic despite a GFD. Clinicaltrials.gov: NCT01396213.

Ulcerative Colitis Patients With Clostridium difficile are at Increased Risk of Death, Colectomy, and Postoperative Complications: A Population-Based Inception Cohort Study.

OBJECTIVES: Clostridium difficile (C. difficile) may worsen the prognosis of ulcerative colitis (UC). The objectives of this study were to: (i) validate the International Classification of Diseases-10 (ICD-10) code for C. difficile; (ii) determine the risk of C. difficile infection after diagnosis of UC; (iii) evaluate the effect of C. difficile infection on the risk of colectomy; and (iv) assess the association between C. difficile and postoperative complications. METHODS: The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated by comparing ICD-10 codes for C. difficile with stool toxin tests. A population-based surveillance cohort of newly diagnosed UC patients living in Alberta, Canada were identified from 2003 to 2009 (n=1,754). The effect of a C. difficile infection on colectomy was modeled using competing risk survival regression after adjusting for covariates. The effect of a C. difficile infection on postoperative complications was assessed using a mixed effects logistic regression model. RESULTS: The sensitivity, specificity, PPV, and NPV of the ICD-10 code for C. difficile were 82.1%, 99.4%, 88.4%, and 99.1%, respectively. The risk of C. difficile infection within 5 years of diagnosis with UC was 3.4% (95% confidence interval (CI): 2.5-4.6%). The risk of colectomy was higher among UC patients diagnosed with C. difficile (sub-hazard ratio (sHR)=2.36; 95% CI: 1.47-3.80). C. difficile increased the risk of postoperative complications (odds ratio=4.84; 95% CI: 1.28-18.35). C. difficile was associated with mortality (sHR=2.56 times; 95% CI: 1.28-5.10). CONCLUSIONS: C. difficile diagnosis worsens the prognosis of newly diagnosed patients with UC by increasing the risk of colectomy, postoperative complications, and death.

Practical Considerations and the Intestinal Microbiome in Disease: Antibiotics for IBD Therapy.

The inflammatory bowel diseases, Crohn's and ulcerative colitis, have been treated with a range of antibiotics for inducing and maintaining remission, as well as the prevention of post-operative symptoms. To date, many studies have been performed assessing the efficacy of antibiotics when used alone, in combination with other antibiotics, or as an adjunctive therapy to other pharmaceutical treatments. Literature evidence supporting the use of antibiotics in IBD can be ambiguous, especially when considering the potential role of dysbiosis in the gastrointestinal tract. The review considers the systemic effect of antibiotics and the evidence base for their efficacy in the treatment of IBD.

Epithelial Cell Extrusion Zones Observed on Confocal Laser Endomicroscopy Correlates with Immunohistochemical Staining of Mucosal Biopsy Samples.

BACKGROUND AND AIMS: The density of epithelial cell extrusion zones in the intestinal lining, also known as gap density (number of gaps/1000 epithelial cells counted), can be quantitated using probe-based confocal laser endomicroscopy (pCLE). Gap density has been reported to be higher than normal in both inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) patients. Epithelial cells destined for extrusion from the intestinal surface would stain positive for either activated caspase-1 or caspase-3 on mucosal biopsy samples. The aim of this study was to determine whether epithelial gap density on pCLE correlates with quantitative analysis of activated caspase staining of mucosal biopsy samples from patients. METHODS: We obtained pCLE images and biopsy samples of the terminal ileum during colonoscopies of healthy controls and patients with either IBD or IBS. The pCLE images and biopsy samples were blindly analyzed for gap density and for cells staining positive for activated caspases, respectively. The degree of correlation was determined using nonparametric statistical tests. RESULTS: The median results were 10 gaps/1000 cells counted for controls versus 33 gaps/1000 cells counted for chronic intestinal disorder patients (p = 0.02). Activated caspase staining showed 13 positive cells/1000 epithelial cells counted versus 26 positive cells/1000 epithelial cells counted, respectively (p = 0.02), thus showing a strong correlation with a Spearman's coefficient ρ of 0.61 (strong correlation for ρ = 0.4-0.75, p = 0.01). CONCLUSIONS: Intestinal epithelial gap density via pCLE correlated strongly with quantitative analysis of immunohistochemical staining of mucosal biopsy samples.

The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: GS-9620 is an oral agonist of toll-like receptor 7, a pattern-recognition receptor whose activation results in innate and adaptive immune stimulation. We evaluated the safety, pharmacokinetics, and pharmacodynamics of GS-9620 in patients with chronic hepatitis B. METHODS: In two double-blind, phase 1b trials of identical design, 49 treatment-naïve and 51 virologically suppressed patients were randomized 5:1 to receive GS-9620 (at doses of 0.3mg, 1mg, 2mg, 4mg) or placebo as a single dose or as two doses seven days apart. Pharmacodynamic assessment included evaluation of peripheral mRNA expression of interferon-stimulated gene 15 (ISG15), serum interferon gamma-induced protein 10 and serum interferon (IFN)-alpha. RESULTS: Overall, 74% of patients were male and 75% were HBeAg negative at baseline. No subject discontinued treatment due to adverse events. Fifty-eight percent experienced ⩾1 adverse event, all of which were mild to moderate in severity. The most common adverse event was headache. No clinically significant changes in HBsAg or HBV DNA levels were observed. Overall, a transient dose-dependent induction of peripheral ISG15 gene expression was observed peaking within 48 hours of dosing followed by return to baseline levels within seven days. Higher GS-9620 dose, HBeAg positive status, and low HBsAg level at baseline were independently associated with greater probability of ISG15 response. Most patients (88%) did not show detectable levels of serum IFN-alpha at any time point. CONCLUSIONS: Oral GS-9620 was safe, well tolerated, and associated with induction of peripheral ISG15 production in the absence of significant systemic IFN-alpha levels or related symptoms.

Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease.

BACKGROUND & AIMS: Methotrexate and infliximab are effective therapies for Crohn's disease (CD). In the combination of maintenance methotrexate-infliximab trial, we evaluated the potential superiority of combination therapy over infliximab alone. METHODS: In a 50-week, double-blind, placebo-controlled trial, we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy (15-40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. Prednisone was tapered, beginning at week 1, and discontinued no later than week 14. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50. RESULTS: Patients' baseline characteristics were similar between groups. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group (P = .63; hazard ratio, 1.16; 95% confidence interval, 0.62-2.17). Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. Combination therapy was well tolerated. CONCLUSIONS: The combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone. ClincialTrials.gov number, NCT00132899.

The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn's disease.

BACKGROUND & AIMS: Probiotic formulations of single species of bacteria have not been effective in preventing the recurrence of Crohn's disease after surgery. We investigated the ability of VSL#3, a mixture of 8 different bacterial probiotic species, to prevent Crohn's disease recurrence after surgery in a multicenter, randomized, double-blind, placebo-controlled trial. METHODS: Within 30 days of ileocolonic resection and re-anastomosis, patients with Crohn's disease were randomly assigned to groups given 1 sachet of VSL#3 (900 billion viable bacteria, comprising 4 strains of Lactobacillus, 3 strains of Bifidobacterium, and 1 strain of Streptococcus salivarius subspecies thermophilus) (n = 59) or matching placebo (n = 60). Colonoscopy was performed at days 90 and 365 to evaluate the neoterminal ileum for disease recurrence and obtain mucosal biopsies for cytokine analysis. Patients from both groups with either no or mild endoscopic recurrence at day 90 received VSL#3 until day 365. The primary outcome was the proportion of patients with severe endoscopic recurrence at day 90. RESULTS: At day 90, the proportion of patients with severe endoscopic lesions did not differ significantly between VSL#3 (9.3%) and placebo (15.7%, P = .19). The proportions of patients with non-severe lesions at day 90 who had severe endoscopic recurrence at day 365 were 10.0% in the early VSL#3 group (given VSL#3 for the entire 365 days) and 26.7% in the late VSL#3 group (given VSL#3 from days 90 through 365) (P = .09). Aggregate rates of severe recurrence (on days 90 and 365) were not statistically different, 20.5% of subjects in the early VSL#3 group and 42.1% in the late VSL#3 group. Patients receiving VSL#3 had reduced mucosal inflammatory cytokine levels compared with placebo at day 90 (P < .05). Crohn's disease activity index and inflammatory bowel disease quality of life scores were similar in the 2 groups. CONCLUSIONS: There were no statistical differences in endoscopic recurrence rates at day 90 between patients who received VSL#3 and patients who received placebo. Lower mucosal levels of inflammatory cytokines and a lower rate of recurrence among patients who received early VSL#3 (for the entire 365 days) indicate that this probiotic should be further investigated for prevention of Crohn's disease recurrence. Clinical trials.gov number: NCT00175292.

Outpatient Ulcerative Colitis Primary Anti-TNF Responders Receiving Adalimumab or Infliximab Maintenance Therapy Have Similar Rates of Secondary Loss of Response.

GOALS: To compare the proportion of secondary loss of response to adalimumab and infliximab during maintenance treatment of ulcerative colitis (UC) after primary response to induction therapy. BACKGROUND: The efficacy of anti-tumor necrosis factor-α (TNF-α) therapy used to maintain response in patients with UC after primary response to induction therapy wanes with time, resulting in secondary loss of response. METHODS: A retrospective cohort study evaluating anti-TNF-naive UC outpatients who were primary responders to adalimumab and infliximab induction therapy and who advanced onto a maintenance regimen with the respective anti-TNF agent from 2003 to 2013 was conducted. The primary outcome was the proportion of patients in each treatment group that had secondary loss of response. The secondary outcome was time to secondary loss of response, analyzed by the Kaplan-Meier method analysis. RESULTS: A total of 102 UC primary anti-TNF responders met inclusion criteria. Thirty-six patients (35.3%) were treated with adalimumab and 66 patients (64.7%) with infliximab. Mean follow-up was 139.0 weeks for adalimumab and 158.8 weeks for infliximab. A total of 21/36 (58.3%) adalimumab-treated patients and 39/66 (59.1%) infliximab-treated patients experienced a secondary loss of response during maintenance therapy. Mean time to secondary loss of response was similar for adalimumab (55.8 wk) and infliximab (59.4 wk) (P=0.82). Sex, extent of colitis, previous or concomitant azathioprine, and concurrent corticosteroids with anti-TNF induction were not associated with increased risk of secondary loss of response. CONCLUSIONS: In this real-life cohort of anti-TNF-naive primary responders with UC, the proportion of secondary loss of response and the time to secondary loss of response are similar for adalimumab and infliximab.

Real-life treatment paradigms show infliximab is cost-effective for management of ulcerative colitis.

BACKGROUND & AIMS: Infliximab is effective for induction and maintenance of response in patients with moderate to moderately severe ulcerative colitis. Previous cost analyses of infliximab treatment for ulcerative colitis used models of colectomy vs infliximab and response rates derived from early clinical trials. In real life, therapeutic options are more complex; patients frequently choose to remain in an unwell state rather than undergo colectomy, and rates of response to infliximab are generally higher than those reported from clinical trials. We evaluate the real-life cost-effectiveness of infliximab for treatment of ulcerative colitis where infliximab was readily available compared with not available, causing patients to remain in unwell states. METHODS: We constructed a Markov model to simulate disease progression of patients with moderate or moderately severe ulcerative colitis who depended on corticosteroids and/or did not respond to thiopurine therapy. Utility scores and transition probabilities between health states were determined by using data from randomized controlled trials and real-life rates published by expert inflammatory bowel disease centers. Health care costs were obtained from the Ontario Case Costing Initiative and the Alberta Health Schedule of Medical Benefits documents. RESULTS: The incremental cost-effectiveness ratios for infliximab treatment of ulcerative colitis were $79,000 and $64,000 per quality-adjusted life year, compared with ongoing medical therapy, at 5-year and 10-year treatment time horizons, respectively. CONCLUSIONS: By using real-life response rates and patients' preference to avoid colectomy, infliximab therapy is a cost-effective strategy at a willingness-to-pay threshold of $80,000 for treatment of ulcerative colitis.