bluuebunny/crossref_metadata_2025_split huggingface dataset:
715 Corticosteroid Sparing Effects of Ustekinumab Therapy in UC Patients: Results From the UNIFI Program
Authors: Danese Silvio , Sands Bruce E. , Peyrin-Biroulet Laurent , Marano Colleen , O'Brien Christopher , Zhang Hongyan , Oortwijn Alessandra , Rowbotham David , Leong Rupert W.L. , Arasaradnam Ramesh P. , Van Assche Gert , Sandborn William J. , Panaccione Remo 
Published: October 2019

INTRODUCTION:
Ustekinumab (UST), an IL12/23 blocker approved for Crohn's disease, was effective in Phase 3 induction and maintenance studies of patients with moderate-severe ulcerative colitis (UC). Since discontinuation of corticosteroids (CS) is an important goal of therapy in UC, this analysis aims to further describe the CS sparing effects of ustekinumab treatment through Week 44 of the UNIFI trial.

METHODS:
Responders to UST IV induction entered maintenance and were randomized to UST 90 mg SC (q12wks or q8wks), or PBO. During the induction and maintenance studies, oral CS were not to be initiated or increased beyond baseline. At Week 0 of the maintenance study, a scheduled taper was recommended for all patients receiving CS. CS-free Clinical Response (CSR) and remission (CSRem) rates (at Week 44, and for >90 days prior to Week 44) were calculated for the overall population and for the subset of patients on CS at maintenance baseline. Among the subset of patients on CS at maintenance baseline, the mean prednisone-equivalent (P.Eq) CS dose (mg/day) through Week 44 were calculated as were the rates of subjects who were CS-free at Week 44 and for >90 days prior to Week 44.

RESULTS:
Overall 50.6% (265/523) of patients in the primary analysis population were receiving CS at maintenance baseline. The proportions of patients who were receiving concomitant CS at maintenance baseline were 52.3%, 47.7%, and 52.3% in the UST q8w, UST q12w and PBO groups, respectively. As detailed in Table 1, in the overall population, CSR and CSRem rates were significantly higher for patients who continued on UST therapy during maintenance compared with placebo. Among the patients who achieved CSR or CSRem at Week 44, the majority achieved these endpoints and eliminated CS use at or up to 90 days prior to Week 44. Similar results were observed in the subset of patients on concomitant CS at maintenance BL. In this group, the mean daily P.Eq CS dose at maintenance BL was approximately 15.0 mg/day for all treatment groups. Mean decrease in average daily P.Eq dose at Wk 44 was more pronounced and the proportion of patients who were CS-free was greater in the UST maintenance arms.

CONCLUSION:
UST maintenance therapy, with both q8w and q12w dosing regimens, is effective in reducing and eliminating the use of CS in patients with UC; the majority of patients (>90%) who achieved clinical response or clinical remission were able to eliminate corticosteroids.
716 Early Clinical Response and Remission With Vedolizumab Versus Adalimumab in Ulcerative Colitis: Results From VARSITY
Authors: Danese Silvio , Loftus Edward V. , Colombel Jean-Frédéric , Peyrin-Biroulet Laurent , Abhyankar Brihad , Chen Jingjing , Rogers Raquel , Lirio Richard A. , Bornstein Jeffrey D. , Schreiber Stefan , Sands Bruce E. 
Published: October 2019

INTRODUCTION:
VARSITY is the first head-to-head trial comparing the efficacy and safety of 2 biologic therapies, vedolizumab (VDZ) and adalimumab (ADA), in patients with moderately to severely active ulcerative colitis (UC). We previously reported significantly higher rates of clinical remission (31.3% vs 22.5%; P = 0.0061) and endoscopic improvement (39.7% vs 27.7%; P = 0.0005) at Week (Wk) 52 with VDZ vs ADA.
1

METHODS:
VARSITY was a phase 3b, randomized, double-blind, double-dummy, active-controlled study (NCT02497469; EudraCT 2015-000939-33). Here we report the predefined, exploratory endpoints of early clinical response and clinical remission (defined in the Table 1) within the first 14 wks, as well as durable clinical remission (patients in clinical remission at Wk 14 and Wk 52).

RESULTS:
A total of 769 patients received ≥1 dose of VDZ (n = 383) or ADA (n = 386). Baseline characteristics were comparable between the 2 groups. A trend for separation in clinical response started to emerge at Wk 6 favoring VDZ vs ADA. Clinical response at Wk 14 favored VDZ vs ADA (257 [67.1%] vs 177 [45.9%]; treatment difference 21.2%). More patients achieved clinical remission at Wk 14 on VDZ vs ADA (102 [26.6%] vs 82 [21.2%]; treatment difference 5.3%). Patients on VDZ achieved higher rates of durable clinical remission (70 [18.3%] vs 46 [11.9%]); laboratory results correlated with these findings. Post hoc analyses showed a larger mean (standard deviation) change of C-reactive protein (CRP) from baseline to Wk 14 (−32.88 [155.77] nmol/L VDZ vs −3.35 [260.81] nmol/L ADA) and to Wk 52 (−50.87 [174.76] nmol/L VDZ vs −37.21 [169.17] nmol/L ADA) in favor of VDZ. Greater mean declines in fecal calprotectin (FCP) levels were seen in patients on VDZ compared with ADA (Wk 14: −1,551.3 [6,236.70] mg/kg VDZ vs −1,167.6 [4,647.67] mg/kg ADA; Wk 52: −2,187.3 [7,440.42] mg/kg VDZ vs −1,846.6 [4,560.55] mg/kg ADA).

CONCLUSION:
Patients on VDZ had numerically higher rates of both clinical response and clinical remission by Wk 14 compared with ADA. Patients on VDZ also achieved higher rates of durable clinical remission compared with ADA. CRP and FCP results correlated with these findings. These data on early clinical response and clinical remission, as well as durable remission, further support the use of VDZ over ADA in patients with moderately to severely active UC.
717 The Vedolizumab Pregnancy Exposure Registry: An OTIS Pregnancy Study Update
Authors: Chambers Christina , Adams Jane , Johnson Diana , Xu Ronghui , Luo Yunjun , Lyons-Jones Kenneth 
Published: October 2019

INTRODUCTION:
Vedolizumab is a gut-selective immunoglobulin (Ig) G1 monoclonal antibody that binds to α4β7 integrin; it is approved for the treatment of moderately to severely active Crohn's disease (CD) and ulcerative colitis (UC) in the U.S. and elsewhere. Published studies on the effect of vedolizumab during human pregnancy are limited. Data from the ongoing Vedolizumab Pregnancy Exposure Registry (NCT02678052) in the U.S. and Canada have been collected by the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS). This prospective observational cohort study intends to enroll and analyze the outcomes of 100 vedolizumab-exposed participants compared to 100 disease-matched (DM) comparison and 100 healthy comparison (HC) participants. This abstract describes progress of the study through March 1, 2019.

METHODS:
Pregnant women treated with vedolizumab for UC or CD for at least some part of the first trimester were enrolled in the vedolizumab-exposed group. Pregnant women with no exposure to vedolizumab were enrolled in a DM comparison group. Pregnant women with no exposure to any biologic during pregnancy and not diagnosed with an autoimmune disease or any other disease as defined by the OTIS Research Center were enrolled in a HC group. Pregnancy exposure and outcome data were collected from telephone interviews and medical records. The Short Quality of Life in Inflammatory Bowel Disease Questionnaire (SIBDQ) was administered to women with CD or UC at enrollment and 32 weeks' gestation. Follow-up of live born children included a dysmorphological exam, pediatric records review and developmental screening at one year of age.

RESULTS:
Between December 2015 and March 2019, outcomes were collected for 223 women, 53 in the vedolizumab group, 88 in the DM group, and 82 in the HC group. Preliminary descriptive data are shown in Table 1. No major structural birth defects were reported in the vedolizumab group, compared to 5 (5.7%) in the DM group, and 4 (5.3%) in the HC group. There was no evidence of a pattern of minor structural defects in the vedolizumab group.

CONCLUSION:
Updated data indicate pregnant women treated with vedolizumab in at least the 1st trimester have similar birth outcomes to disease-matched and healthy comparison women. The Vedolizumab Pregnancy Exposure Registry is ongoing with formal statistical analysis to be performed when the study is completed.
720 Does Undetectable Absolute Eosinophil Count at Initial Clostridioides difficile Infection Predict Future Disease in Inflammatory Bowel Disease Patients?
Authors: Dickson Zachary , Baray Merwise , Hunold Thomas , Hays R. Ann 
Published: October 2019

INTRODUCTION:
According to a 2018 study, an undetectable absolute eosinophil count at the time of admission for Clostridioides difficile infection (CDI) is associated with an increased risk for vasopressor requirement, emergency colectomy, and mortality during the index hospitalization. Patients with inflammatory bowel disease (IBD) are at greater risk for development of CDI than the general population. We aim to investigate whether an undetectable absolute eosinophil count at the time of an initial CDI can be used to predict recurrence versus reinfection of CDI in IBD patients.

METHODS:
A retrospective cohort of patients age 18-75 with a history of IBD and a diagnosis of CDI from January 2012–December 2016. The absolute eosinophil count at the time of initial CDI for patients with a history of single CDI and multiple CDIs was recorded. Absolute eosinophil counts were grouped as either detectable (>0.0 cells/mL) or undetectable (0.0 cells/mL). Recurrence was defined as CDI diagnosis within 3 months of the initial CDI. Reinfection was defined as a second episode of CDI between 3 months to 3 years of the initial CDI. Data was analyzed with chi square tests.

RESULTS:
62 of 121 IBD subjects with CDI had a documented absolute eosinophil count at the time of their initial CDI. Absolute eosinophil count was undetectable in 15 of 62 patients (24.2%). Of these, 67% (n = 10) experienced multiple CDIs. 4 patients had recurrent CDI and 6 patients had CDI reinfections. 27 (43.5%) patients had history of a single CDI and 35 (56.5%) patients had a history of multiple CDI. An undetectable eosinophil count was observed in 18.5% (n = 5) of patients with a single CDI and 28.5% (n = 10) of patients with a history of multiple CDI. Of the 47 patients with a detectable eosinophil count, 22 patients experienced a single CDI vs 25 patients with multiple CDI.

CONCLUSION:
In patients with a peripheral eosinopenia, insufficient IL-25 mediated immunity can predispose patients to development of CDI. Although the absolute eosinophil count at the time of CDI may have implications for inpatient morbidity and mortality in the general population, our study suggests that an undetectable absolute eosinophil count at the time of initial CDI does not reliably predict future acquisition of CDI in IBD patients. However, based on the observation that patients with an initial undetectable eosinophil count more frequently experienced multiple CDIs, it is possible that a significant relationship could manifest with a larger study population.
728 Second-Line Biologic Therapy After Vedolizumab
Authors: Ritter Timothy E. , Fourment Chris , Kuten Samantha A. , Hardin Thomas C. , Van Anglen Lucinda J. 
Published: October 2019

INTRODUCTION:
Vedolizumab (VDZ), an anti-integrin monoclonal antibody approved for the treatment of Crohn's disease (CD) and ulcerative colitis (UC), is increasingly being utilized as first-line biologic therapy in bio-naïve inflammatory bowel disease (IBD) patients (pts) with moderate-to-severe disease. While prior studies have described the efficacy of VDZ after anti-TNF failure, there is little guidance on the use of alternative biologics following initial VDZ therapy. This study describes the clinical response of IBD pts treated with a second (2nd) biologic following VDZ discontinuation.

METHODS:
We performed a retrospective review of all bio-naïve IBD pts started on VDZ as first-line therapy at a large multicenter gastroenterology private practice since drug approval in 2014. Pts were identified who failed initial VDZ treatment and were switched to a 2nd biologic agent. Data collection included demographics, diagnosis, therapy, and disease activity scores using the partial Mayo score (pMayo) for UC pts and the Harvey-Bradshaw Index (HBI) for CD pts. Clinical remission was assessed for those pts with ≥6 months of data and defined as pMayo less than 2 or HBI less than 5.

RESULTS:
A total of 135 IBD pts receiving VDZ as first-line biologic therapy were identified, of which VDZ was discontinued in 30 (22%). Our study cohort included 25 pts who received a 2nd line biologic following VDZ failure (11 primary non-response, 14 secondary non-response). Second-line biologic agents included 19 infliximab, 3 adalimumab, 2 ustekinumab, and 1 tofacitinib. Baseline demographics of the 25 pts were as follows: mean age 47 ± 18 years, male gender 13 (52%), UC 19 (76%), CD 6 (24%), time to 2nd biologic 8.2 ± 4.5 weeks. Disease severity scores prior to and following initiation of the 2nd line biologic are depicted in Figure 1. Clinical remission assessment was available for 18 of 25 patients. Remission was achieved in 11 of 18 pts (61%), driven by UC pts treated with infliximab [Figure 2]. Overall, pts treated with anti-TNF agents following VDZ had higher rates of remission compared to those treated with other biologics.

CONCLUSION:
Biologic-naïve IBD pts treated initially with VDZ have high treatment persistence. In addition, rates of remission with 2nd-line biologic therapy are significantly greater than expected when first-line failure is VDZ. Further studies are warranted to determine the optimal order in which advanced therapies should be initiated.
739 Development and Validation of an Administrative Codes Algorithm to Identify Abdominal Surgery and Bowel Obstruction in Patients With Inflammatory Bowel Disease
Authors: Gandle Cassandra , Scott Frank , Waljee Akbar , Hou Jason 
Published: October 2019

INTRODUCTION:
International Classification of Diseases (ICD) codes are utilized in reporting patient diagnoses while current procedural terminology (CPT) codes identify medical, surgical, and diagnostic procedures. Use of administrative codes may be used to efficiently identify patients with inflammatory bowel disease and related outcomes, but require validation due to variability of coding patterns. The aim of this study was to determine the accuracy of ICD and CPT codes for surgery and post-operative obstructive complications in a cohort of IBD patients at the VA.

METHODS:
We performed a retrospective study of patients with IBD at the Michael E. DeBakey VA Medical Center in Houston, Texas between February 1, 2000 and August 30, 2015. IBD patients with with administrative codes for abdominal surgery and post-operative complications were reviewed by manual chart review to confirm type and date of surgery and type and date of post-operative complication. A total of 710 abdominal surgery ICD-9 and CPT codes and 3 post-operative obstruction related ICD-codes (560.81, 560.89, and 560.9) were evaluated. Analyses were performed on a per encounter basis. Codes were considered accurate if the procedure or complication occurred within 3 months of the coded date. Sensitivity analyses were performed, broadening the time window to 6 months. Positive predictive values (PPV) and negative predictive value (NPV) were calculated for each code and overall.

RESULTS:
A total of 77 IBD patients had at least one encounter with ICD-9 or CPT codes for abdominal surgery. The PPV for abdominal surgery codes overall was 96.4%, which remained unchanged on sensitivity analyses extending time window to 6 months. Evaluating the accuracy of post-operative obstructive-type complications, 39 patients were identified utilizing 3 ICD-9 codes for obstructive complications in 67 individual encounters. The PPV of any obstruction-type ICD-9 code for confirmed bowel obstruction was 80.5%. The NPV for obstructive complications in patient encounters without a corresponding obstruction-related code was 96%. On sensitivity analyses extending window to 6 months prior to date of code, the PPV for obstructive ICD-9 codes increased to 82.1%.

CONCLUSION:
ICD-9 and CPT codes for abdominal surgery and post-operative obstructive-type complications can be accurately utilized in IBD patients at the VA.
747 Pilot Study of Gut Dysbiosis and Bile Acid Dysmetabolism in Active Ulcerative Colitis
Authors: Gaidos Jill , Kang Jason D. , Kakiyama Genta , Pandak William M. , Hylemon Phillip B. 
Published: October 2019

INTRODUCTION:
Ulcerative colitis (UC) is a chronic relapsing inflammatory disease of the colon associated with an increased risk for Clostridioides difficile infection (CDI). C. difficile is a spore-forming organism that colonizes the GI tract and is potentially pathogenic. Under healthy conditions, homeostasis of the gut microbiome plays a role in preventing germination of C. difficile spores while bile acids are vital to the germination process. Primary bile acids can stimulate germination of C. difficile spores while secondary bile acids inhibit growth of the vegetative form. The aim of this study is to assess for changes in the gut microbiome and bile acid profile with active UC as compared to remission that may explain the increased CDI risk.

METHODS:
After obtaining IRB approval, we performed a single center, prospective, cohort study of Veteran's with active UC at the McGuire VA Medical Center. After obtaining consent, subjects with active UC, based on markers of inflammation and elevated Simple Clinical Colitis Activity Index score (≥5), provided a stool sample for analysis of the gut microbiome (using fingerprinting of the 16S rRNA), bile acid profile (using high performance liquid chromatography) and for the presence of Clostridioides species (using 7α-dehydroxylating bacteria analysis). Subjects were treated for their active UC and a second stool sample was collected in the setting of clinical remission for repeat analyses.

RESULTS:
Four males with active UC enrolled, median age 61 yrs, however subject 2 was excluded due to suboptimal sample size. The total bile acids were relatively unchanged in both samples however there were less secondary bile acids (deoxycholic acid and lithocholic acid) in the remission samples in 2 of 3 subjects (Table 1). With active UC, study subjects had a higher concentration of C. scindens (Figure 1). Inversely, subjects had higher concentrations of the C. difficile toxin B gene during clinical remission (Figure 2). The results of the microbiome analysis are pending.

CONCLUSION:
In this limited pilot study, we found that patients with UC have a decreased luminal concentration of both total and secondary bile acids compared to healthy controls. Active UC seems to lead to a decrease in secondary bile acids, including C. scindens, with a subsequent increase in the presence of C. difficile toxin. This change in bile acid profile could be contributing to the increased prevalence of CDI in IBD patients.
751 Safety, Tolerability, and Pharmacokinetics of PTG-200, an Oral GI-Restricted Peptide Antagonist of IL-23 Receptor, in Normal Healthy Volunteers
Authors: Cheng Xiaoli , Lee Tien-Yi , Ledet Grace , Zemade Genet , Tovera James , Campbell Robert , Purro Nobert , Annamalai Thamil , Masjedizadeh Mohammad , Liu David , Nawabi Roya , Kanwar Bittoo 
Published: October 2019

INTRODUCTION:
PTG-200 (JNJ-67864238) is an oral peptide that acts locally in intestinal tissues to block IL-23 signaling by selectively binding the IL-23 receptor (IL-23R). The gastrointestinal (GI)-restriction of PTG-200 is demonstrated in vivo by marked drug concentrations in GI tissues and feces and limited systemic blood exposure. PTG-200 therapeutic potential was established in a rat model of TNBS-induced colitis, where its threshold concentration in colonic tissue and luminal feces associated with efficacy was determined to inform the human efficacious dose.
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The objectives of this Phase 1 study were to assess safety, tolerability, and pharmacokinetics (PK) of PTG-200.

METHODS:
This first-in-human (FIH) Phase 1 study was a single-center, randomized, double-blind, placebo-controlled trial comprising single and 14-day multiple ascending dose (SAD and MAD) arms in 82 healthy male volunteers. Oral doses ranged from 150 mg to 900 mg once daily (QD, fasted or fed) or twice daily (BID, fed). Subjects were monitored for safety and tolerability. PK in plasma, urine and feces was evaluated.

RESULTS:
Oral administration of PTG-200 was well-tolerated. There were no serious adverse events, dose-limiting toxicities, or clinically significant adverse events. PTG-200 plasma exposure was low (Table 1), below that expected to result in systemic biological activity. Following single-dose oral administration under fasted conditions, plasma PTG-200 concentrations exhibited dose-related increases with a median time to maximal concentration (Tmax) at 2 h. Administration of a high-fat meal prolonged the median Tmax to 4 h and had a modest effect on peak concentration (Cmax) and estimated overall exposure. Repeat dosing led to dose-related increases in plasma exposure. Consistent with a terminal half-life of ∼1.5 h in plasma, PTG-200 showed no evidence of accumulation except for the 900 mg BID group. Fecal concentrations in several cohorts met or exceeded the targeted threshold concentration associated with efficacy as established using the preclinical colitis model.

CONCLUSION:
Orally administered PTG-200 was well-tolerated in this FIH study. Systemic PK was consistent with the GI-restricted design of PTG-200. These safety and PK characteristics, combined with fulfillment of fecal drug threshold concentrations, support further clinical development of PTG-200 for the treatment of IBD. A Phase 2 study in patients with moderate-to-severe Crohn's disease is planned.