Comparison of a Novel, Flavor-optimized, Polyethylene Glycol and Sulfate Bowel Preparation With Oral Sulfate Solution in Adults Undergoing Colonoscopy.

INTRODUCTION: A new bowel preparation for colonoscopy has been developed containing poorly absorbed sulfate salts and polyethylene glycol 3350, which retain water within the intestinal lumen resulting in copious diarrhea, thereby cleansing the bowel. The product was formulated to be safe and effective with a sports drink-like flavor. This study evaluated the new flavored polyethylene glycol and sulfate solution (FPSS) compared with a Food and Drug Administration-approved bowel preparation containing sulfate salts only [oral sulfate solution (OSS)]. METHODS: Five hundred adults were enrolled in this multicenter, noninferiority study. Subjects were assigned FPSS or OSS administered in split-dose regimens (PM/AM). FPSS subjects took 2 L of the flavored osmotic solution (1 L at night and 1 L in the morning). OSS was taken according to its approved labeling. Colonoscopies were graded globally and segmentally by blinded local investigators using a 4-point scale (excellent, good, fair, and poor), with "good" and "excellent" considered successful. Safety was assessed by adverse events (AEs) and laboratory testing. RESULTS: A high rate of cleansing success was seen with FPSS (94%), which was noninferior to OSS (94%). This conclusion was confirmed by blinded central readers. Segmental success rates were >90% for both preparations, including the right colon. Questionnaire ratings indicated the FPSS experience was preferred over OSS with 87% of FPSS subjects noting their preparation was "tolerable" to "very easy" to consume versus 74% for OSS. The majority of FPSS subjects agreed their preparation tasted like a sports drink. Gastrointestinal symptoms were the most common AEs. There was no difference between preparations for any AE and no clinically significant differences in laboratory parameters. CONCLUSIONS: The new sports drink-like flavored preparation achieved a high level of cleansing in the study, demonstrating noninferiority to OSS. FPSS was well-tolerated with low rates of expected gastrointestinal symptoms. The optimized flavor of FPSS resulted in significantly better acceptance ratings.

Validating the Simplified Endoscopic Mucosal Assessment for Crohn's Disease: A Novel Method for Assessing Disease Activity.

BACKGROUND: To demonstrate treatment efficacy in Crohn's disease (CD), regulatory authorities require that trials include an endoscopic remission/response end point; however, standardized endoscopic assessment of disease activity, such as the Simple Endoscopic Score for Crohn's Disease (SES-CD), is not typically recorded by clinicians in practice or outside of clinical trials. The novel Simplified Endoscopic Mucosal Assessment for Crohn's Disease (SEMA-CD) was developed to be easy to use in routine clinical practice and as a trial end point. We conducted a study to assess and validate the reliability and feasibility of SEMA-CD as a measure of endoscopic disease activity. METHODS: Pre- and post-treatment ileocolonoscopy videos of pediatric (n = 36) and adult (n = 74) CD patients from 2 ustekinumab clinical trials were each scored with SEMA-CD by 2 to 3 professional central readers, blinded to clinical history and other video scorings; the correlation between SEMA-CD and SES-CD previously completed during the trials was assessed. Sensitivity to change, inter- and intrarater reliability, and comparative ease of scoring were also assessed. RESULTS: The SEMA-CD strongly correlated with SES-CD (Spearman ρ = 0.89; 95% confidence interval, 0.86-0.92). Pre- to post-treatment changes in SEMA-CD vs in SES-CD were strongly correlated, and the correlation remained strong between the scores when compared by study population (pediatric, adult), disease severity, and video quality. Intra- and inter-rater reliability were good, and SEMA-CD was rated easier than SES-CD to score 63.0% of the time, although slightly more difficult than SES-CD to score <1.0% of the time. CONCLUSIONS: The SEMA-CD is reliable, reproducible, sensitive to change, and easy to use in both pediatric and adult patients with CD.

Etrolizumab versus adalimumab or placebo as induction therapy for moderately to severely active ulcerative colitis (HIBISCUS): two phase 3 randomised, controlled trials.

BACKGROUND: Etrolizumab is a gut-targeted anti-ß7 integrin monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission relative to placebo in patients with moderately to severely active ulcerative colitis. The HIBISCUS studies aimed to compare the efficacy and safety of etrolizumab to adalimumab and placebo for induction of remission in patients with moderately to severely active ulcerative colitis. METHODS: HIBISCUS I and HIBISCUS II were identically designed, multicentre, phase 3, randomised, double-blind, placebo-controlled and active-controlled studies of etrolizumab, adalimumab, and placebo in adult (18-80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. All patients had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In both studies, patients were randomly assigned (2:2:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks; subcutaneous adalimumab 160 mg on day 1, 80 mg at week 2, and 40 mg at weeks 4, 6, and 8; or placebo. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All patients and study site personnel were masked to treatment assignment. The primary endpoint was induction of remission at week 10 (defined as MCS of 2 or lower, with individual subscores of 1 or lower, and rectal bleeding subscore of 0) with etrolizumab compared with placebo. Pooled analyses of both studies comparing etrolizumab and adalimumab were examined for several clinical and endoscopic endpoints. Efficacy was analysed using a modified intent-to-treat population, defined as all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT02163759 (HIBISCUS I), NCT02171429 (HIBISCUS II). FINDINGS: Between Nov 4, 2014, and May 25, 2020, each study screened 652 patients (HIBISCUS I) and 613 patients (HIBISCUS II). Each study enrolled and randomly assigned 358 patients (HIBISCUS I etrolizumab n=144, adalimumab n=142, placebo n=72; HIBISCUS II etrolizumab n=143; adalimumab n=143; placebo n=72). In HIBISCUS I, 28 (19·4%) of 144 patients in the etrolizumab group and five (6·9%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 12·3% (95% CI 1·6 to 20·6; p=0·017) in favour of etrolizumab. In HIBISCUS II, 26 (18·2%) of 143 patients in the etrolizumab group and eight (11·1%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 7·2% (95% CI -3·8 to 16·1; p=0·17). In the pooled analysis, etrolizumab was not superior to adalimumab for induction of remission, endoscopic improvement, clinical response, histological remission, or endoscopic remission; however, similar numerical results were observed in both groups. In HIBISCUS I, 50 (35%) of 144 patients in the etrolizumab group reported any adverse event, compared with 61 (43%) of 142 in the adalimumab group and 26 (36%) of 72 in the placebo group. In HIBISCUS II, 63 (44%) of 143 patients in the etrolizumab group reported any adverse event, as did 62 (43%) of 143 in the adalimumab group and 33 (46%) in the placebo group. The most common adverse event in all groups was ulcerative colitis flare. The incidence of serious adverse events in the pooled patient population was similar for etrolizumab (15 [5%] of 287) and placebo (seven [5%] of 144) and lower for adalimumab (six [2%] of 285). Two patients in the etrolizumab group died; neither death was deemed to be treatment related. INTERPRETATION: Etrolizumab was superior to placebo for induction of remission in HIBISCUS I, but not in HIBISCUS II. Etrolizumab was well tolerated in both studies. FUNDING: F Hoffmann-La Roche.

Effect of celiac disease on maternal and neonatal outcomes of pregnancy.

PURPOSE: Celiac disease (CD) is a permanent immune reaction to gluten that is likely related to genetic factors. Some studies have linked CD to adverse maternal and/or neonatal outcomes but the data has been contradictory. The purpose of this study was to evaluate the effect of CD on pregnancy outcomes. MATERIALS AND METHODS: We used data from the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (NIS) of the USA to conduct a population-based retrospective cohort study of women who delivered between 1999 and 2014. Pregnancies were categorized as having CD if corresponding ICD-9 code was present. Unconditional logistic regression models were used to estimate the adjusted effect on maternal and fetal outcomes. RESULTS: There were 14,513,587 births during the study period of which 2755 were to women with CD, for an overall prevalence of 1.9 cases/10,000 births and with rates increasing over the study period. Women with CD tended to be older, Caucasian and to have pre-existing comorbidities, especially other autoimmune diseases. Women with CD were at greater risk of hyperemesis gravidarum, 4.52 (3.68-5.57), Clostridium difficile colitis, 7.56 (3.14-18.20), and venous thromboembolic events, 2.93 (2.07-4.15), as well as, hospital stays >3 d, 2.06 (1.75-2.43). Infants of women with CD were more likely to be growth restricted, 1.80 (1.46-2.21) and have congenital malformations, 3.51 (2.68-4.58). CONCLUSIONS: CD in pregnancy is associated with increased adverse maternal and newborn complications. These pregnancies should be considered high risk and may benefit from increased surveillance.

Triage of General Gastrointestinal Endoscopic Procedures During the COVID-19 Pandemic: Results From a National Delphi Consensus Panel.

BACKGROUND AND AIMS: As the COVID-19 pandemic moves into the postpeak period, the focus has now shifted to resuming endoscopy services to meet the needs of patients who were deferred. By using a modified Delphi process, we sought to develop a structured framework to provide guidance regarding procedure indications and procedure time intervals. METHODS: A national panel of 14 expert gastroenterologists from throughout the US used a modified Delphi process, to achieve consensus regarding: (1) common indications for general endoscopy, (2) critical patient-important outcomes for endoscopy, (3) defining time-sensitive intervals, (4) assigning time-sensitive intervals to procedure indications. Two anonymous rounds of voting were allowed before attempts at consensus were abandoned. RESULTS: Expert panel reached consensus that procedures should be allocated to one of three timing categories: (1) time-sensitive emergent = scheduled within 1 week, (2) time-sensitive urgent = scheduled within 1-8 weeks, (3) nontime sensitive = defer to > 8 weeks and reassess timing then. The panel identified 62 common general endoscopy indications (33 for EGD, 21 for colonoscopy, 5 for sigmoidoscopy). Consensus was reached on patient-important outcomes for each procedure indication, and consensus regarding timing of the procedure indication was achieved for 74% of indications. Panelists also identified adequate personal-protective-equipment, rapid point-of-care testing, and staff training as critical preconditions before endoscopy services could be resumed. CONCLUSION: We used the validated Delphi methodology, while prioritized patient-important outcomes, to provide consensus recommendations regarding triaging a comprehensive list of general endoscopic procedures.

Impact of various central endoscopy reading models on treatment outcome in Crohn's disease using data from the randomized, controlled, exploratory cohort arm of the BERGAMOT trial.

BACKGROUND AND AIMS: Endoscopic assessment of mucosal appearance by independent central reading has become the standard method to assess Crohn's disease activity in clinical trials. The performance characteristics of various endoscopy reading models have yet to be systematically evaluated. METHODS: This substudy included patients with Crohn's disease in the exploratory induction cohort of the BERGAMOT trial (NCT02394028) randomly assigned to etrolizumab or placebo. Endoscopies conducted at baseline and week 14 were independently scored using the Simple Endoscopic Score for Crohn's Disease (SES-CD) by a local reader (LR) and 2 central readers (CRs). Five endoscopy reading models were compared: single LR, single CR, average of 2 CRs, and 2 models incorporating the LR and 1 or 2 CRs depending on alignment between the LR and the CR, defined according to a sliding scale applied to a range of scores. RESULTS: Five hundred thirty-five videos were scored. Models involving 2 readers demonstrated lower placebo rates (3.4%) than the single LR (11.9%) and the single CR (6.8%) models. Treatment effect size based on endoscopic improvement (≥50% reduction in SES-CD from baseline) was highest with the 2 models incorporating the LR and 1 or 2 CRs (Δ = 16.2%). Further, in the etrolizumab arm, models with 2 readers demonstrated the lowest variability for the SES-CD. CONCLUSIONS: Central endoscopy reading models in Crohn's disease have an impact on placebo response rates and effect size. Incorporating the LR appears to be important because models using both CRs and LRs resulted in the greatest treatment effect size for endoscopic improvement with etrolizumab, lower placebo rates, and reduced variability.

Management and outcomes of peptic ulcer disease in pregnancy.

PURPOSE: Given the altered physiology of pregnancy, gastroenterologists are often reluctant to perform endoscopic procedures in pregnant women. The purpose of our study was to compare management practices and outcomes among pregnant and nonpregnant women admitted to the hospital for peptic ulcer disease (PUD). MATERIALS AND METHODS: A retrospective matched cohort study was carried out using the Healthcare Cost and Utilization Project - National Inpatient Sample from 1999 to 2015. A cohort of pregnant women with PUD was generated and compared with an age-matched cohort of nonpregnant women with PUD at a 1:5 ratio. Conditional logistic regression analyses were used to evaluate the adjusted effect of PUD on variables and outcomes of interest, including associated conditions, management and treatment types, and complications. RESULTS: PUD was diagnosed in 2535 pregnant women and 12,675 age-matched nonpregnant women during the 16-year study period. As compared with nonpregnant women, pregnant women with PUD were less likely to undergo diagnostic or therapeutic esophagogastroduodenoscopies (EGD) for this indication. Outcomes including fever, infection, sepsis, shock, and transfusion were less likely to occur in pregnant women as compared to nonpregnant women. Pregnant women also experienced shorter hospital stays. Pregnant women who underwent EGD were more likely to experience a venous thromboembolism than nonpregnant women. CONCLUSIONS: Pregnant women with PUD are less likely to undergo interventional diagnostic and therapeutic procedures than nonpregnant women with PUD. The reluctance to intervene in pregnancy does not appear to result in more adverse PUD-associated outcomes.

A Safety and Efficacy Comparison of a New Sulfate-Based Tablet Bowel Preparation Versus a PEG and Ascorbate Comparator in Adult Subjects Undergoing Colonoscopy.

INTRODUCTION: A new tablet-based bowel prep for colonoscopy has been developed containing poorly absorbed sulfate salts which act to retain water within the intestinal lumen resulting in a copious diarrhea, thereby cleansing the bowel. This study evaluated the safety and efficacy of these oral sulfate tablets (OST) compared with a US FDA-approved bowel prep solution containing PEG3350, electrolytes, and ascorbate (polyethylene glycol and ascorbate [PEG-EA]). METHODS: Five hundred fifteen adult patients (mean 57y) were enrolled in this single-blind, multicenter, noninferiority study. Subjects were assigned either PEG-EA or OST to be administered in a split-dose regimen starting the evening before colonoscopy. PEG-EA was taken according to its approved labeling (1 L of prep solution with 16 oz. of additional water) in the evening and again in the morning. OST patients took a total of 24 tablets. OST patients were administered 12 tablets in the evening, and the following morning. Patients consumed 16 ounces of water with each dose of 12 tablets and drank an additional 32 oz. of water with each dose. Colonoscopies were performed by blinded investigators. Cleansing efficacy was evaluated globally and segmentally using a 4-point scale (Excellent-no more than small bits of feces/fluid which can be suctioned easily; achieves clear visualization of the entire colonic mucosa. Good-feces and fluid requiring washing and suctioning, but still achieves clear visualization of the entire colonic mucosa. Fair-enough feces even after washing and suctioning to prevent clear visualization of the entire colonic mucosa. Poor-large amounts of fecal residue and additional bowel preparation required). Scores of Good or Excellent were considered to be a success. Safety was assessed by spontaneously reported adverse events, solicited ratings of expected prep symptoms, and laboratory testing. RESULTS: A high rate of cleansing success was seen with OST (92%), which was noninferior to PEG-EA (89%). Only a small proportion of subjects rated their expected gastrointestinal symptoms as severe (<5% for both preps). No clinically significant differences were seen between preps for chemistry and hematology parameters. No serious adverse experiences were reported with OST. DISCUSSION: Sulfate tablets achieved a high level of cleansing in the study, comparable with US FDA-approved preps. OST was noninferior to PEG-EA in this study and achieved significantly more Excellent preps overall and in the proximal colon. The OST prep was well-tolerated, with a similar rate of spontaneously reported adverse experiences to PEG-EA and a low rate of severe expected gastrointestinal symptoms.

Pregnancy outcomes among women with peptic ulcer disease.

Background Little is known about the impact of peptic ulcer disease (PUD) on pregnancy. Our objective was to evaluate the effect of PUD on pregnancy and newborn outcomes. Methods A retrospective cohort study was carried out using the Healthcare Cost and Utilization Project (HCUP)-National Inpatient Sample (NIS) from the United States. The cohort consisted of all births that took place from 1999 to 2015. PUD was classified on the basis of the International Classification of Diseases-Ninth Revision (ICD-9) coding. Multivariate logistic regression was used to evaluate the adjusted effect of PUD on maternal and neonatal outcomes. Results Of the 13,792,544 births in this cohort, 1005 were to women with PUD (7/100,000 births). Between 1999 and 2015, prevalence of PUD in pregnancy increased from 4/100,000 to 11/100,000, respectively. Women with PUD were more commonly older and more likely to have comorbid illnesses. Women with PUD were at greater risk of preeclampsia [odds ratio (OR) 2.11, 95% confidence interval (CI) 1.67-2.66], preterm premature rupture of membranes (PPROM; OR 2.16, 95% CI 1.30-3.59), cesarean delivery (OR 1.60, 95% CI 1.40-1.82), venous thromboembolism (OR 3.77, 95% CI 2.08-6.85) and maternal death (OR 24.50, 95% CI 10.12-59.32). Births to women with PUD were at increased risk of intrauterine growth restriction (IUGR; OR 1.54, 95% CI 1.11-2.14), preterm birth (OR 1.84, 95% CI 1.54-2.21), intrauterine fetal death (OR 2.18, 95% CI 1.35-3.52) and congenital anomalies (OR 2.69, 95% CI 1.59-4.56). Conclusion The prevalence of PUD in pregnancy has risen over the last several years. PUD in pregnancy should be considered a high-risk condition associated with important adverse maternal and neonatal outcomes.

Evaluation of management and surgical outcomes in pregnancies complicated by acute cholecystitis.

OBJECTIVE: To evaluate the management of pregnancies complicated by acute cholecystitis (AC) and determine whether pregnant women are more likely to have medical and surgical complications. METHODS: We carried out a population-based matched cohort study using the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample from 2003 to 2011. Pregnant women with AC were age matched to non-pregnant women with AC on a 1:5 ratio. Management and outcomes were compared using descriptive analysis and conditional logistic regression. RESULTS: There were 11,835 pregnant women admitted with AC who were age matched to 59,175 non-pregnant women. As compared to non-pregnant women, women with AC were more commonly managed conservatively, odds ratio (OR) 6.1 (5.8-6.4). As compared to non-pregnant women, pregnant women with AC more commonly developed sepsis [OR 1.4 (1.0-1.9)], developed venous thromboembolism [OR 8.7 (4.3-17.8)] and had bowel obstruction [OR 1.3 (1.1-1.6)]. Among pregnant women with AC, surgical management was associated with a small but significant increased risk of septic shock and bile leak. CONCLUSION: AC, in the context of pregnancy, is associated with an increased risk of adverse outcomes. Although the literature favors early surgical intervention, pregnancies with AC appear to be more commonly managed conservatively with overall comparable outcomes to surgically managed AC. Conservative management may have a role in select pregnant women with AC.

Pregnancy outcomes in liver transplant patients, a population-based study.

OBJECTIVE: To determine the incidence of pregnancy in liver transplant (LT) patients in a large population-based cohort and to determine the maternal and fetal risks associated with these pregnancies. METHODS: We conducted an age-matched cohort study using the US Healthcare and Utilization project-Nationwide Inpatient Sample from 2003-2011. We used unconditional logistic regression, adjusted for baseline characteristics, to estimate the likelihood of common obstetric complications in the LT group compared with age-matched nontransplant patients. RESULTS: There were 7 288 712 deliveries and an estimated incidence of 2.1 LTs/100 000 deliveries over the nine-year study period. LT patients had higher rates of maternal complications including hypertensive disorders (OR 6.5, 95% CI: 4.4-9.5), gestational diabetes (OR 1.9, 95% CI: 1.0-3.5), anemia (OR 3.2, 95% CI: 2.1-4.9), thrombocytopenia (OR 27.5, 95% CI: 12.7-59.8) and genitourinary tract infections (OR 4.2, 95% CI: 1.8-9.8). Deliveries among women with LT had higher risks of cesarean section (OR 2.9, 95% CI: 2.0-4.1), postpartum hemorrhage (OR 3.2, 95% CI: 1.7-6.2) and blood transfusion (OR 18.7, 95% CI: 8.5-41.0). Fetal complications in LT patients included preterm delivery (OR 4.7, 95% CI: 3.2-7.0), intrauterine growth restriction (OR 4.1, 95% CI: 2.1-7.7) and congenital anomalies (OR 6.0, 95% CI: 1.1-32.0). CONCLUSION: Although pregnancies in LT recipients are feasible, they are associated with a high rate of maternal and fetal morbidities. Close antenatal surveillance is recommended.

Central endoscopy reads in inflammatory bowel disease clinical trials: The role of the imaging core lab.

Clinical trials in inflammatory bowel disease (IBD) are evolving at a rapid pace by employing central reading for endoscopic mucosal assessment in a field that was, historically, largely based on assessments by local physicians. This transition from local to central reading carries with it numerous technical, operational, and scientific challenges, many of which can be resolved by imaging core laboratories (ICLs), a concept that has a longer history in clinical trials in a number of diseases outside the realm of gastroenterology. For IBD trials, ICLs have the dual goals of providing objective, consistent assessments of endoscopic findings using central-reading paradigms whilst providing important expertise with regard to operational issues and regulatory expectations. This review focuses on current approaches to using ICLs for central endoscopic reading in IBD trials.

Stratifying the risks of oral anticoagulation in patients with liver disease.

BACKGROUND: Chronic liver disease presents a relative contraindication to warfarin therapy, but some patients with liver disease nevertheless require long-term anticoagulation. The goal is to identify which patients with liver disease might safely receive warfarin. METHODS AND RESULTS: Among 102 134 patients who received warfarin from the Veterans Affairs from 2007 to 2008, International Classification of Diseases-Ninth Revision codes identified 1763 patients with chronic liver disease. Specific diagnoses and laboratory values (albumin, aspartate aminotransferase, alanine aminotransferase, creatinine, and cholesterol) were examined to identify risk of adverse outcomes, while controlling for available bleeding risk factors. Outcomes included percent time in therapeutic range, a measure of anticoagulation control, and major hemorrhagic events, by International Classification of Diseases-Ninth Revision codes. Patients with liver disease had lower mean time in therapeutic range (53.5%) when compared with patients without (61.7%; P<0.001) and more hemorrhages (hazard ratio, 2.02; P<0.001). Among patients with liver disease, serum albumin and creatinine levels were the strongest predictors of both outcomes. We created a 4-point score system: patients received 1 point each for albumin (2.5-3.49 g/dL) or creatinine (1.01-1.99 mg/dL), and 2 points each for albumin (<2.5 g/dL) or creatinine (≥2 mg/dL). This score predicted both anticoagulation control and hemorrhage. When compared with patients without liver disease, those with a score of zero had modestly lower time in therapeutic range (56.7%) and no increase in hemorrhages (hazard ratio, 1.16; P=0.59), whereas those with the worst score (4) had poor control (29.4%) and high hazard of hemorrhage (hazard ratio, 8.53; P<0.001). CONCLUSIONS: Patients with liver disease receiving warfarin have poorer anticoagulation control and more hemorrhages. A simple 4-point scoring system using albumin and creatinine identifies those at risk for poor outcomes.