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Leticia Delgado-Herrera,1 Kathryn Lasch,2 Ana Popielnicki,3 Akito Nishida,4 Rob Arbuckle,5 Benjamin Banderas,6 Susan Zentner,1 Ingrid Gagainis,1 Bernhardt Zeiher1 1Astellas Pharma Global Development, Northbrook, IL, 2Pharmerit International, Newton, MA, USA; 3TransPerfect, Linguistic Validation Group, Boston, MA, USA; 4Development Project Management, Astellas Pharma Inc, Tokyo, Japan; 5Patient-Centered Outcomes Adelphi Values, Bollington, UK; 6Patient-Centered Outcomes Adelphi Values, Boston, MA, USA Background and objective: Following a 2009 US Food and Drug Administration guidance, a new patient-reported outcome (PRO) instrument was developed to support end points in multinational clinical trials assessing irritable bowel syndrome with diarrhea (IBS-D) symptom severity. Our objective was to assess the translatability of the IBS-D PRO instrument into ten languages, and subsequently perform a cultural adaptation/linguistic validation of the questionnaire into Japanese and US Spanish. Materials and methods: Translatability assessments of the US English version of the IBS-D PRO were performed by experienced PRO translators who were native speakers of each target language and currently residing in target-language countries. Languages were Chinese (People’s Republic of China), Dutch (the Netherlands), French (Belgium), German (Germany), Japanese (Japan), Polish (Poland), Portuguese (Brazil), Russian (Russia), Spanish (Mexico), and Spanish (US). The project team assessed the instrument to identify potential linguistic and/or cultural adaptation issues. After the issues identified were resolved, the instrument was translated into Spanish (US) and Japanese through a process of two forward translations, one reconciled translation, and one backward translation. The project team reviewed the translated versions before the instruments were evaluated by cognitive debriefing interviews with samples of five Spanish (US) and five Japanese IBS-D patients. Results: Linguistic and cultural adaptation concerns identified during the translatability assessment required minor revisions, mainly the presentation of dates/times and word structure. During the cognitive debriefing interviews, two of five Spanish respondents misunderstood the term “bowel movement” to mean only diarrhea in the Spanish version. Consequently, the term was changed from “movimiento intestinal” to “evacuaciones”. None of the Japanese respondents identified issues with the Japanese version. Conclusion: The translatability of the IBS-D PRO instrument into ten target languages was confirmed, with only minor changes made to the translations of the instrument. The translation and linguistic validation into Spanish (US) and Japanese provide evidence that this instrument can be used in multinational trials and clinical settings. Keywords: stool consistency, stool-form scale, translatability, IBS-D PRO instrument

Xinyi Ng,1 Chizoba Nwankwo,2 Jean Marie Arduino,2 Shelby Corman,1 Kathryn Eilene Lasch,1 Jacqueline Mary Lustrino,1 Sushma Patel,2 Heather Loryn Platt,2 Jingjun Qiu,2 Jan Sperl3 1Pharmerit International, LP, Bethesda, MD, USA; 2Merck & Co. Inc., Kenilworth, NJ, USA; 3Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic Purpose: People chronically infected with hepatitis C virus (HCV) have diminished patient-reported outcomes (PROs). This study aimed to compare the impact of elbasvir/grazoprevir (EBR/GZR) treatment versus sofosbuvir with pegylated interferon and ribavirin (SOF/PR) on changes in PROs: 1) during the treatment period and 2) at posttreatment follow-up. Patients and methods: PRO data collected during the Phase III C-EDGE Head-2-Head (H2H) open-label study was analyzed. In this trial, patients infected with HCV were randomized 1:1 to receive either EBR/GZR or SOF/PR for 12 weeks. Patients self-administered the Short Form-36 version 2 (SF-36v2®) Health Survey Acute (1-week recall) Form and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale at baseline, during treatment, and posttreatment. Between-group differences in mean change of PRO scores from baseline were estimated during the treatment period and also at the posttreatment follow-up. Effect sizes were calculated to evaluate if the detected change in mean PRO scores is clinically meaningful between groups. Results: There were 255 patients (99.2% White, 54.1% female, 74.9% treatment naïve) included in the analysis. During the treatment period, significant declines in SF-36v2 scores were observed across all domains for the SOF/PR group. Compared to the SOF/PR group, the EBR/GZR group reported more improvement in scores across all SF-36v2 domain scores at the end of the treatment period. At treatment week 12, the between-group differences for 6 out of the 8 domain scores for these patients reflected at least moderate effects (effect sizes >0.5). No significant between-group differences in change in SF-36v2 scores from baseline were detected posttreatment. The decline in SF-36v2 scores observed during the treatment period for the SOF/PR group returned to near baseline scores or above posttreatment. Treatment with EBR/GZR did not impact fatigue scores, but treatment with SOF/PR led to increased fatigue scores during treatment which resolved by posttreatment follow-up week 12. Conclusion: This study demonstrated that HCV treatment with EBR/GZR resulted in a significantly better PRO profile as compared to SOF/PR. PROs are an important consideration as worsening PROs experienced during treatment may negatively influence adherence and ultimately contribute to an unfavorable clinical outcome. Clinical trials.gov Identifier: NCT02358044 Keywords: hepatitis, direct-acting antivirals, health-related quality of life, fatigue, patient-reported outcomes

Abstract Background Although many symptoms of Major Depressive Disorder (MDD) are assessed through patient-report, there are currently no patient-reported outcome (PRO) instruments that incorporate documented evidence of patient input in PRO instrument development. A review of existing PROs used in MDD suggested the need to conduct qualitative research with patients with MDD to better understand their experience of MDD and develop an evaluative instrument with content validity. The aim of this study was to develop a disease-specific questionnaire to assess symptoms important and relevant to adult MDD patients. Methods The questionnaire development involved qualitative interviews for concept elicitation, instrument development, and cognitive interviews to support content validity. For concept elicitation, ten MDD severity-specific focus group interviews with thirty-eight patients having clinician-confirmed diagnoses of MDD were conducted in January 2009. A semi-structured discussion guide was used to elicit patients' spontaneous descriptions of MDD symptoms. Verbatim transcripts of focus groups were coded and analyzed to develop a conceptual framework to describe MDD. A PRO instrument was developed by operationalizing concepts elicited in the conceptual framework. Cognitive interviews were carried out in patients (n = 20) to refine and test the content validity of the instrument in terms of item relevance and comprehension, instructions, recall period, and response categories. Results Concept elicitation focus groups identified thirty-five unique concepts falling into several domains: i) emotional, ii) cognitive, iii) motivation, iv) work, v) sleep, vi) appetite, vii) social, viii) activities of daily living, ix) tired/fatigue, x) body pain, and xi) suicidality. Concept saturation, the point at which no new relevant information emerges in later interviews, was achieved for each of the concepts. Based on the qualitative findings, the PRO instrument developed had 15 daily and 20 weekly items. The cognitive interviews confirmed that the instructions, item content, and response scales were understood by the patients. Conclusions Rigorous qualitative research resulted in the development of a PRO measure for MDD with supported content validity. The MDD PRO can assist in understanding and assessing MDD symptoms from patients' perspectives as well as evaluating treatment benefit of new targeted therapies.

The activity of unsupported ternary PtRuMeOx (Me=W, Mo, V) high surface area catalysts towards methanol oxidation under fuel cell relevant conditions, at constant potential and elevated temperature of 60 °C, was investigated by the thin-film electrode method. CO-stripping experiments for actual surface area detection, using differential electrochemical mass spectrometry (DEMS) to evaluate the amount of adsorbed CO, show that the electrochemically active area of the particle surface is significantly smaller than the total particle surface area determined by N2 BET measurements, indicating that part of their surface consists of MeOx. The specific surface activity of the catalysts towards methanol oxidation at 60 °C, normalized to the current density per square centimeter of electrochemically active noble metal surface, decreases in the order PtRuVOx>PtRuMoOx>PtRu>PtRuWOx=PtRu (E-TEK). Apparently, the surface oxide leads to an acceleration of the methanol oxidation reaction, which is, however, partly compensated by a decrease in active surface area. [Copyright &y& Elsevier]

Background: Vedolizumab, an anti-α 4 β 7 integrin approved for intravenous (IV) treatment of moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD), was evaluated as a subcutaneous (SC) formulation in maintenance therapy for UC and CD in phase 3 VISIBLE 1, 2, and open-label extension studies, and recently approved in Europe, Australia, and Canada. Our aim was to evaluate efficacy and safety of IV and SC vedolizumab in clinically relevant UC and CD scenarios., Methods: Post hoc data analyses from VISIBLE trials examined: (1) whether baseline characteristics predict clinical response to 2 vs 3 IV vedolizumab induction doses; (2) efficacy and safety of switching during maintenance vedolizumab IV to SC in patients with UC; (3) vedolizumab SC after treatment interruption of 1-46 weeks; (4) increasing dose frequency of vedolizumab SC from every 2 weeks (Q2W) to every week (QW) after disease worsening., Results: No baseline characteristics were identified as strong predictors of response to 2 vs 3 vedolizumab infusions. Most patients achieved clinical response after 2 or 3 doses of IV vedolizumab maintained with SC treatment. Clinical remission and response rates were maintained in patients transitioned from maintenance vedolizumab IV to SC treatment. Of patients with UC, ≥75% achieved response following resumption after dose interruption. Escalation to QW dosing resulted in ≥45% of patients regaining response after loss while receiving vedolizumab Q2W., Conclusions: Clinical real-world scenarios with vedolizumab SC were reviewed using VISIBLE studies data. Vedolizumab SC provides an additional dosing option for patients with UC and CD., Competing Interests: E.V.L. has received consulting fees from AbbVie, Alvotech, Amgen, Arena Pharmaceuticals, Avalo Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, CALIBR, Celgene, Celltrion, Eli Lilly and Company, Fresenius Kabi, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Iota Biosciences, Iterative Scopes, Janssen, KSL Diagnostics, Morphic, Ono Pharma, Pfizer, Protagonist, Scipher Medicine, Sun Pharma, Surrozen, Takeda, and UCB; and research support from AbbVie, Alimentiv Inc., Bristol Myers Squibb, Celgene, Genentech, Gilead Sciences, Gossamer Bio, Janssen, Pfizer, Receptos, Takeda, Theravance Biopharma, and UCB. GD has served as an advisor for AbbVie, Ablynx, Alimentiv Inc., Allergan, Alphabiomics, Amakem, Amgen, AM Pharma, Applied Molecular Therapeutics, Arena Pharmaceuticals, AstraZeneca, Avaxia, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Celgene/Receptos, Celltrion, Cosmo Pharmaceuticals, DSM Pharma, Echo Pharmaceuticals, Eli Lilly and Company, Engene, Exeliom Biosciences, Ferring, Dr FALK Pharma, Galapagos, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Hospira/Pfizer, Immunic, Johnson & Johnson, Kintai Therapeutics, Lycera, Medimetrics, Millennium/Takeda, Medtronics, Mitsubishi Pharma, Merck Sharp & Dohme, Mundipharma, Nextbiotics, Novo Nordisk, Otsuka, Photopill, ProciseDx, Prodigest, Prometheus Laboratories/Nestle, Progenity, Protagonist Therapeutics, RedHill Biopharma, Salix, Samsung Bioepis, Sandoz, Seres/Nestle, SetPoint Medical, Shire, Teva, TiGenix, Tillotts Pharma, Topivert, Versant, and Vifor. D.C.W. has received research support and consulting fees from AbbVie, Arena, Bristol Myers Squibb, Genentech, Janssen, Lilly, and Takeda. WJS reports research grants from AbbVie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Eli Lilly and Company, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, and Theravance Biopharma; consulting fees from AbbVie, Abivax, Admirx, Alfasigma, Alimentiv (previously Robarts Clinical Trials, owned by Alimentiv Health Trust), Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Bausch Health (Salix), Beigene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celgene, Celltrion, Cellularity, Cosmo Pharmaceuticals, Escalier Biosciences, Equillium, Forbion, Genentech/ Roche, Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyverna Therapeutics, Landos Biopharma, Eli Lilly and Company, Oppilan Pharma, Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tillotts Pharma, UCB, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, and Zealand Pharma; stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences, Prometheus Laboratories Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, and Vivreon Biosciences; and is an employee at Shoreline Biosciences. S.D. reports research support, fees, or other support from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals, Gilead Sciences, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB Inc., and Vifor. J.C., S.M.U., N.C., and K.K. are employees of Takeda Pharmaceuticals U.S.A., Inc., and have stock or stock options in that company. KL was employed by Takeda during analysis and manuscript development and has stock or stock options in that company., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.)

Background & Aims: We evaluated the value of post-induction fecal calprotectin (FCP) concentration as a biomarker in patients with ulcerative colitis (UC) treated with a biologic., Methods: This post hoc analysis of the GEMINI 1/GEMINI LTS (N = 620) and VARSITY (N = 771) trials evaluated the cross-sectional accuracy of post-induction FCP in identifying endoscopic activity and histologic inflammation, and the prognostic performance of FCP in identifying patients most likely to achieve endoscopic and histologic remission or require colectomy and UC-related hospitalization., Results: The cross-sectional accuracy of FCP in identifying endoscopic activity and histologic inflammation was modest (63%-79%). However, a post-induction FCP concentration of ≤250 μg/g vs >250 μg/g was associated with a substantially higher probability of achieving clinical remission (odds ratio [OR], 4.03; 95% confidence interval [CI], 2.78-5.85), endoscopic remission (OR, 4.26; 95% CI, 2.83-6.40), and histologic remission (Robarts Histopathology Index: OR, 5.54; 95% CI, 3.77-8.14; Geboes grade: OR, 6.42; 95% CI, 4.02-10.26) at week 52 and a lower probability of colectomy over 7 years (hazard ratio, 0.296; 95% CI, 0.130-0.677) and UC-related hospitalization (hazard ratio, 0.583; 95% CI, 0.389-0.874). The association with colectomy was significant even among patients in symptomatic remission or with endoscopic improvement post-induction, and among patients with elevated FCP at baseline., Conclusions: Although FCP had only modest cross-sectional accuracy in identifying disease activity, an FCP concentration of ≤250 μg/g vs >250 μg/g was associated with increased probability of achieving long-term clinical, endoscopic, and histologic remission, and reduced probability of colectomy and UC-related hospitalization (ClinicalTrials.gov: NCT00783718, NCT00790933, NCT02497469)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Determining the relative cost-effectiveness between advanced therapeutic options for ulcerative colitis (UC) may optimize resource utilization. We evaluated total cost per response, cost per remission, and cost of safety events for patients with moderately-to-severely active UC after 52 weeks of treatment with advanced therapies at standard dosing., Methods: An analytic model was developed to estimate costs from the US healthcare system perspective associated with achieving efficacy outcomes and managing safety outcomes for advanced therapies approved for the treatment of UC. Numbers needed to treat (NNT) for response and remission, and numbers needed to harm (NNH) for serious adverse events (SAEs) and serious infections (SIs) were derived from a network meta-analysis of pivotal trials. NNT for induction and maintenance were combined with drug regimen costs to calculate cost per clinical remission. Cost of managing AEs was calculated using NNH for safety outcomes and published costs of treating respective AEs., Results: Costs per remission were $205,240, $249,417, $267,463, $365,050, $579,622, $750,200, and $787,998 for tofacitinib 10 mg, tofacitinib 5 mg, infliximab, vedolizumab, golimumab, adalimumab, and ustekinumab, respectively. Incremental costs of SAEs and SIs collectively were $136,390, $90,333, $31,888, $31,061, $20,049, $12,059, and $0 for tofacitinib 5 mg, golimumab, adalimumab, tofacitinib 10 mg, infliximab, ustekinumab, and vedolizumab (reference), respectively., Conclusions: Tofacitinib was associated with the lowest cost per response and cost per remission, while vedolizumab had the lowest costs related to SAEs and SIs. Balancing efficacy versus safety is important when evaluating the costs associated with treatment of moderate-to-severe UC., (© 2022. The Author(s).)

Background & Aims: Fistulizing Crohn's disease (CD) is challenging to treat. We report results from ENTERPRISE, a randomized, double-blind, phase 4 trial evaluating 2 vedolizumab intravenous dosing regimens in patients with fistulizing CD., Methods: Patients with moderately to severely active CD and 1-3 active perianal fistulae (identified on magnetic resonance imaging [MRI]) received vedolizumab 300 mg intravenously at weeks 0, 2, 6, 14, and 22 (VDZ) or the same regimen plus an additional vedolizumab dose at week 10 (VDZ + wk10). Reduction from baseline in draining perianal fistulae and disease activity, MRI assessments, health-related quality of life (HRQoL), and safety were evaluated. Enrollment was stopped prematurely because of recruitment challenges; analyses are descriptive., Results: Of 32 patients with ≥1 active fistulae at baseline per MRI and postbaseline fistulae healing assessment, 28 (14 per dosing regimen) had ≥1 draining fistulae at baseline (assessed by gentle finger compression during clinical exam). Rapid and sustained fistula closure was observed; 53.6% (VDZ, 64.3%; VDZ + wk10, 42.9%) and 42.9% (VDZ, 50.0%; VDZ + wk10, 35.7%) of patients achieved ≥50% decrease in draining fistulae and 100% fistulae closure, respectively, at week 30. Mean (standard deviation) CD and Perianal Disease Activity Index scores decreased by 51.1 (78.3) and 4.1 (3.3), respectively, at week 30. HRQoL improved throughout the study. No new safety signals were observed., Conclusions: Sustained improvements in fistulizing CD were seen with both vedolizumab regimens. An additional dose at week 10 does not appear to alter treatment outcomes. Safety profile was consistent with other vedolizumab studies., Clinicaltrials: gov no: NCT02630966; EudraCT: 2015-000852-12., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: We aimed to compare safety and effectiveness of vedolizumab to tumor necrosis factor (TNF)-antagonist therapy in ulcerative colitis in routine practice., Methods: A multicenter, retrospective, observational cohort study (May 2014 to December 2017) of ulcerative colitis patients treated with vedolizumab or TNF-antagonist therapy. Propensity score weighted comparisons for development of serious adverse events and achievement of clinical remission, steroid-free clinical remission, and steroid-free deep remission. A priori determined subgroup comparisons in TNF-antagonist-naïve and -exposed patients, and for vedolizumab against infliximab and subcutaneous TNF-antagonists separately., Results: A total of 722 (454 vedolizumab, 268 TNF antagonist) patients were included. Vedolizumab-treated patients were more likely to achieve clinical remission (hazard ratio [HR], 1.651; 95% confidence interval [CI], 1.229-2.217), steroid-free clinical remission (HR, 1.828; 95% CI, 1.135-2.944), and steroid-free deep remission (HR, 2.819; 95% CI, 1.496-5.310) than those treated with TNF antagonists. Results were consistent across subgroup analyses in TNF-antagonist-naïve and -exposed patients, and for vedolizumab vs infliximab and vs subcutaneous TNF-antagonist agents separately. Overall, there were no statistically significant differences in the risk of serious adverse events (HR, 0.899; 95% CI, 0.502-1.612) or serious infections (HR, 1.235; 95% CI, 0.608-2.511) between vedolizumab-treated and TNF-antagonist-treated patients. However, in TNF-antagonist-naïve patients, vedolizumab was less likely to be associated with serious adverse events than TNF antagonists (HR, 0.192; 95% CI, 0.049-0.754)., Conclusions: Treatment of ulcerative colitis with vedolizumab is associated with higher rates of remission than treatment with TNF-antagonist therapy in routine practice, and lower rates of serious adverse events in TNF-antagonist-naïve patients., (Copyright © 2022. Published by Elsevier Inc.)

Background: Patients with Crohn's disease (CD) are at risk of complications. Performance characteristics of a decision support tool assessing the risk of CD complications were evaluated., Methods: CDPATH (formerly called the Personalized Risk and Outcome Prediction Tool [PROSPECT]) was calibrated and validated in 2 cohorts. Tool prediction of disease characteristics was assessed using Cox regression and Harrell's C -statistic., Results: All associations of CD complications and CDPATH components were significant except perianal location. There was a significant association between individualized risk assessment scores and CD complications in both cohorts., Conclusion: CDPATH is validated as a clinical decision support tool for assessing the risk of CD complications., (© The Author(s) 2021. Published by Oxford University Press on behalf of Crohn\'s & Colitis Foundation.)

Background & Aims: We created and validated a clinical decision support tool (CDST) to predict outcomes of vedolizumab therapy for ulcerative colitis (UC)., Methods: We performed logistic regression analyses of data from the GEMINI 1 trial, from 620 patients with UC who received vedolizumab induction and maintenance therapy (derivation cohort), to identify factors associated with corticosteroid-free remission (full Mayo score of 2 or less, no subscore above 1). We used these factors to develop a model to predict outcomes of treatment, which we called the vedolizumab CDST. We evaluated the correlation between exposure and efficacy. We validated the CDST in using data from 199 patients treated with vedolizumab in routine practice in the United States from May 2014 through December 2017., Results: Absence of exposure to a tumor necrosis factor (TNF) antagonist (+3 points), disease duration of 2 y or more (+3 points), baseline endoscopic activity (moderate vs severe) (+2 points), and baseline albumin concentration (+0.65 points per 1 g/L) were independently associated with corticosteroid-free remission during vedolizumab therapy. Patients in the derivation and validation cohorts were assigned to groups of low (CDST score, 26 points or less), intermediate (CDST score, 27-32 points), or high (CDST score, 33 points or more) probability of vedolizumab response. We observed a statistically significant linear relationship between probability group and efficacy (area under the receiver operating characteristic curve, 0.65), as well as drug exposure (P < .001) in the derivation cohort. In the validation cohort, a cutoff value of 26 points identified patients who did not respond to vedolizumab with high sensitivity (93%); only the low and intermediate probability groups benefited from reducing intervals of vedolizumab administration due to lack of response (P = .02). The vedolizumab CDST did not identify patients with corticosteroid-free remission during TNF antagonist therapy., Conclusions: We used data from a trial of patients with UC to develop a scoring system, called the CDST, which identified patients most likely to enter corticosteroid-free remission during vedolizumab therapy, but not anti-TNF therapy. We validated the vedolizumab CDST in a separate cohort of patients in clinical practice. The CDST identified patients most likely to benefited from reducing intervals of vedolizumab administration due to lack of initial response. ClinicalTrials.gov no: NCT00783718., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Direct comparisons are lacking between vedolizumab and tumour necrosis factor (TNF)-antagonist therapy in Crohn's disease (CD)., Aim: To compare safety and effectiveness of vedolizumab and TNF-antagonist therapy in adult CD patients., Methods: Retrospective observational cohort (May 2014-December 2017) propensity score-weighted comparison of vedolizumab vs TNF-antagonist therapy (infliximab, adalimumab, certolizumab) in CD. Propensity scores were weighted for age, prior treatments, disease complications, extent and severity, steroid dependence, and concomitant immunosuppressive drug use. The primary outcome was comparative risk for infections or non-infectious serious adverse events (requiring antibiotics, antivirals, antifungals, hospitalisation, or treatment discontinuation, or resulting in death). Secondary comparative effectiveness outcomes were clinical remission (resolution of CD-related symptoms), steroid-free clinical remission and endoscopic remission (absence of ulcers/erosions)., Results: We included 1266 patients (n = 659 vedolizumab). Rates of non-infectious serious adverse events (odds ratio [OR] 0.072, 95% confidence interval [CI] 0.012-0.242), but not serious infections (OR 1.183, 95% CI 0.786-1.795), were significantly lower with vedolizumab vs TNF-antagonist therapy. Safety comparisons for non-infectious serious adverse events remained significant after adjusting for differences in duration of exposure. No significant difference was observed between vedolizumab and TNF-antagonist therapy for clinical remission (hazard ratio [HR] 0.932, 95% CI 0.707-1.228), steroid-free clinical remission (HR 1.250, 95% CI 0.677-2.310) or endoscopic remission (HR 0.827, 95% CI 0.595-1.151). TNF-antagonist therapy was associated with higher treatment persistence compared with vedolizumab., Conclusions: There was a lower risk of non-infectious serious adverse events, but not serious infections, with vedolizumab vs TNF-antagonist therapy, with no significant difference for achieving disease remission., (© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: A clinical decision support tool (CDST) has been validated for predicting treatment effectiveness of vedolizumab (VDZ) in Crohn's disease., Aim: To assess the utility of this CDST for predicting exposure-efficacy and disease outcomes., Methods: Using data from three independent datasets (GEMINI, GETAID and VICTORY), we assessed clinical remission rates and measured VDZ exposure, rapidity of onset of action, response to dose optimisation and progression to surgery by CDST-defined response groups (low, intermediate and high)., Results: A linear relationship existed between CDST-defined groups, measured VDZ exposure, rapidity of onset of action and efficacy in GEMINI through week 52 (P < 0.001 at all time points across three CDST-defined groups). In GETAID, CDST predicted differences in clinical remission at week 14 (AUC = 0.68) and rapidity of onset of action (P = 0.04) between probability groups. The high-probability patients did not benefit from shortening of infusion intervals, and differences in onset of action between the high-intermediate and low-probability groups within GETAID were no longer significant when including low-probability patients who received a week 10 infusion. CDST predicted a twofold increase in surgery risk over 12 months of VDZ therapy among low- to intermediate-probability vs high-probability patients (adjusted HR 2.06, 95% CI 1.33-3.21)., Conclusions: We further extended the clinical utility of a previously validated VDZ CDST, which accurately predicts at baseline exposure-efficacy relationships and rapidity of onset of action and could be used to help identify patients who would most benefit from interval shortening and those most likely to require surgery while on active therapy., (© 2019 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: Patients with Crohn's disease (CD), but not ulcerative colitis (UC), of shorter duration have higher rates of response to tumor necrosis factor (TNF) antagonists than patients with longer disease duration. Little is known about the association between disease duration and response to other biologic agents. We aimed to evaluate response of patients with CD or UC to vedolizumab, stratified by disease duration., Methods: We analyzed data from a retrospective, multicenter, consortium of patients with CD (n = 650) or UC (n = 437) treated with vedolizumab from May 2014 through December 2016. Using time to event analyses, we compared rates of clinical remission, corticosteroid-free remission (CSFR), and endoscopic remission between patients with early-stage (≤2 years duration) and later-stage (>2 years) CD or UC. We used Cox proportional hazards models to identify factors associated with outcomes., Results: Within 6 months initiation of treatment with vedolizumab, significantly higher proportions of patients with early-stage CD, vs later-stage CD, achieved clinical remission (38% vs 23%), CSFR (43% vs 14%), and endoscopic remission (29% vs 13%) (P < .05 for all comparisons). After adjusting for disease-related factors including previous exposure to TNF antagonists, patients with early-stage CD were significantly more likely than patients with later-stage CD to achieve clinical remission (adjusted hazard ratio [aHR], 1.59; 95% CI, 1.02-2.49), CSFR (aHR, 3.39; 95% CI, 1.66-6.92), and endoscopic remission (aHR, 1.90; 95% CI, 1.06-3.39). In contrast, disease duration was not a significant predictor of response among patients with UC., Conclusions: Patients with CD for 2 years or less are significantly more likely to achieve a complete response, CSFR, or endoscopic response to vedolizumab than patients with longer disease duration. Disease duration does not associate with response vedolizumab in patients with UC., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Patients with inflammatory bowel diseases frequently require surgery, but immunotherapies used in disease management may increase the risk of post-operative complications. We investigated frequencies of post-operative complications in patients who received vedolizumab-a gut-selective antibody approved for the treatment of moderately to severely active ulcerative colitis and Crohn's disease-in clinical-trial and post-marketing settings., Methods: This post hoc analysis of safety data from GEMINI 1, GEMINI 2, and long-term safety studies included patients who had had colectomy or bowel surgery/resection. Data from the post-marketing Vedolizumab Global Safety Database were also analysed (data cutoff point: 19 May 2016). Adverse events relating to post-operative complications were identified using Medical Dictionary for Regulatory Activities preferred terms., Results: Of 58 total surgeries in patients included in GEMINI 1 and GEMINI 2, post-operative complications were reported for 3/51 vedolizumab-treated patients (5.9%) and 1/7 placebo-treated patients (14.3%). In the long-term safety study, 157/2,243 patients (7%) had colectomy or bowel surgery/resection; of these 157 patients who underwent surgery, 11 (7%) experienced a post-operative complication. Median time between last pre-operative vedolizumab dose and surgery was 23 days in GEMINI 1, 20 days in GEMINI 2, and 39‒40 days in the long-term safety study. In the post-marketing setting, based on data covering approximately 46,978 patient-years of vedolizumab exposure, post-operative complications were reported in 19 patients., Conclusions: In clinical trials, complications of colectomy and bowel surgery/resection appeared infrequent, with minimal difference between vedolizumab and placebo. The frequency of post-operative complications in the post-marketing setting appears low., (© The Author(s) 2019. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Background: Prospectively designed studies assessing the exposure-response profile of vedolizumab are lacking. Observational exposure-response data for vedolizumab are limited and have not been adjusted for potential confounding factors, particularly those that may affect vedolizumab clearance., Aims: To (a) investigate the vedolizumab exposure-response relationship after adjusting for potential confounding variables; (b) propose potential target serum vedolizumab concentrations for future study; (c) ascertain whether early vedolizumab serum concentrations were associated with short- and long-term clinical outcomes in adults with ulcerative colitis in GEMINI 1., Methods: Propensity-score-based case-matching analysis was performed using data from GEMINI 1 and an earlier large population pharmacokinetic study, with vedolizumab clearance or concentration as predictors of clinical remission and response, adjusted for age, weight, anti-tumour necrosis factor alpha therapy history, serum albumin and faecal calprotectin concentrations. Potential vedolizumab concentration targets at weeks 6, 14 and steady state were proposed. Association between early vedolizumab concentrations at weeks 2, 4 and 6 and clinical remission at weeks 14 and 52 was evaluated., Results: Among 693 patients with pharmacokinetic data at week 6, potential target vedolizumab concentrations at weeks 6, 14 and steady state were 37.1, 18.4 and 12.7 µg/mL respectively. Week 6 was identified as the earliest time at which vedolizumab concentrations were consistently associated with clinical remission at weeks 14 and 52., Conclusions: In this comprehensively adjusted analysis, vedolizumab concentrations at week 6 were associated with short- and long-term remission. Potential induction and maintenance target concentrations were proposed for further study., (© 2019 John Wiley & Sons Ltd.)

Background & Aims: Vedolizumab, a humanized monoclonal antibody against α4β7 integrin, is used to treat adults with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). We investigated the time course of clinical response to vedolizumab in patients who were and were not previously treated with tumor necrosis factor (TNF) antagonists., Methods: We performed a post-hoc analysis of data from phase 3, randomized, controlled trials of vedolizumab vs placebo in adult patients with UC (N = 374) or CD (N = 784). We collected data on patient-reported symptoms (rectal bleeding and stool frequency for patients with UC, abdominal pain and loose stool frequency for patients with CD) reported at weeks 2, 4, and 6 of treatment. We reported mean percentage score changes from baseline and proportions of patients who achieved predefined scores. We performed multivariate logistic regression analysis to identify factors associated with an early response (at week 2)., Results: In patients with UC (overall or naive to TNF antagonist therapy), a significantly greater percentage of patients given vedolizumab achieved the predefined composite symptom score at weeks 2, 4, and 6 compared to those given placebo. In patients with CD who were naive to TNF antagonists, a significantly greater percentage of patients given vedolizumab achieved the predefined score at weeks 2 and 4 compared to those given placebo. Among patients with UC given vedolizumab, 19.1% (overall) and 22.3% (TNF antagonist naive) achieved a composite score of rectal bleeding of 0 and stool frequency ≤1 at week 2 compared to 10% (overall) and 6.6% (TNF antagonist naive) of those receiving placebo. Among TNF antagonist-naive patients with CD, 15.0% of those given vedolizumab achieved an average daily composite score of abdominal pain ≤1 and loose stool frequency ≤3 at week 2 (compared to 7.9% given placebo), and 23.8% of those given vedolizumab achieved these by week 4 (compared to 10.3% given placebo)., Conclusions: In a post-hoc analysis of data from phase 3 clinical trials, vedolizumab significantly improved patient-reported symptoms of UC and CD as early as week 2 of treatment, continuing through the first 6 weeks-especially when given as first-line biologic therapy. ClinicalTrials.gov no: NCT00783718, NCT00783692, NCT01224171., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: As more treatment options for inflammatory bowel diseases become available, it is important to identify patients most likely to respond to different therapies. We created and validated a scoring system to identify patients with Crohn's disease (CD) who respond to vedolizumab., Methods: We collected data from the GEMINI 2 phase 3 trial of patients with active CD treated with vedolizumab for 26 weeks (n = 814) and performed logistic regression analysis to identify factors associated with clinical, steroid-free, and durable remission (derivation set). We used these data to develop a clinical decision support tool, which we validated using data from 366 participants in a separate clinical practice observational cohort of patients with active CD treated with vedolizumab for 26 weeks (the VICTORY cohort). We evaluated the ability of this tool to identify patients in clinical remission or corticosteroid-free remission, or those with mucosal healing (MH), clinical remission with MH, or corticosteroid-free remission with MH after vedolizumab therapy using receiver operating characteristic area under the curve (AUC) analyses. The primary outcome was to develop and validate a list of factors associated with achieving remission by vedolizumab in patients with active CD., Results: In the derivation analysis, we identified absence of previous treatment with a tumor necrosis factor antagonist (+3 points), absence of prior bowel surgery (+2 points), absence of prior fistulizing disease (+2 points), baseline level of albumin (+0.4 points per g/L), and baseline concentration of C-reactive protein (reduction of 0.5 points for values between 3.0 and 10.0 mg/L and 3.0 points for values >10.0 mg/L) as factors associated with remission. In the validation set, our model identified patients in clinical remission with an AUC of 0.67, patients in corticosteroid-free remission with an AUC of 0.66, patients with MH with an AUC of 0.72, patients in clinical remission with MH with an AUC of 0.73, and patients in corticosteroid-free clinical remission with MH with an AUC of 0.75. A cutoff value of 13 points identified patients in clinical remission after vedolizumab therapy with 92% sensitivity, patients in corticosteroid-free remission with 94% sensitivity, patients with MH with 98% sensitivity, patients with clinical remission and MH with 100% sensitivity, and patients with corticosteroid-free clinical remission with MH with 100% sensitivity., Conclusions: We developed and validated a scoring system to identify patients with CD most likely to respond to 26 weeks of vedolizumab therapy. Further studies are needed to optimize its accuracy in select populations and determine its cost-effectiveness., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Using patient global impression of change (PGIC) as an anchor, an approximately 30% reduction on an 11-point numeric pain intensity rating scale (PI-NRS) is considered a clinically important difference (CID) in pain. Our objective was to define the CID for another pain measure, the worst pain severity (WPS) item of the modified Brief Pain Inventory (m-BPI)., Methods: In this post hoc analysis of a double-blind, placebo-controlled, phase 2 study, 452 randomized patients with diabetic peripheral neuropathic pain (DPNP) were followed over 5 weeks, with m-BPI data collected weekly and PGIC at treatment conclusion. Receiver operating characteristic (ROC) curves (via logistic regression) were used to determine the changes in the m-BPI-WPS score that best predicted ordinal clinical improvement thresholds (i.e., "minimally improved" or better) on the PGIC., Results: Similar to the PI-NRS, a change of -3 (raw) or -33.3% from the baseline on the m-BPI-WPS optimized prediction for the "much improved" or better PGIC threshold and represents a CID. There was a high correspondence between observed and predicted PGIC categories at each PGIC threshold (ROC AUCs were 0.78-0.82)., Conclusions: Worst pain on the m-BPI may be used to assess clinically important improvements in DPNP studies. Findings require validation in larger studies.

Background: To evaluate the psychometric properties of the newly developed seven-item Irritable Bowel Syndrome - Diarrhea predominant (IBS-D) Daily Symptom Diary and four-item Event Log using phase II clinical trial safety and efficacy data in patients with IBS-D. This instrument measures diarrhea (stool frequency and stool consistency), abdominal pain related to IBS-D (stomach pain, abdominal pain, abdominal cramps), immediate need to have a bowel movement (immediate need and accident occurrence), bloating, pressure, gas, and incomplete evacuation., Methods: Psychometric properties and responsiveness of the instrument were evaluated in a clinical trial population [ClinicalTrials.gov identifier: NCT01494233]., Results: A total of 434 patients were included in the analyses. Significant differences were found among severity groups ( p < 0.01) defined by IBS Patient Global Impression of Severity (PGI-S) and IBS Patient Global Impression of Change (PGI-C). Severity scores for each Diary and Event Log item score and five-item, four-item, and three-item summary scores were calculated. Between-group differences in changes over time were significant for all summary scores in groups stratified by changes in PGI-S ( p < 0.05), two of six Diary items, and three of four Event Log items; a one-grade change in PGI-S was considered a meaningful difference with mean change scores on all Diary items -0.13 to -0.86 [standard deviation (SD) 0.79-1.39]. Similarly, for patients who reported being 'slightly improved' (considered a clinically meaningful difference) on the PGI-C, mean change scores on Diary items ranged from -0.45 to -1.55 (SD 0.69-1.39). All estimates of clinically important change for each item and all summary scores were small and should be considered preliminary. These results are aligned with the previous standalone psychometric study regarding reliability and validity tests., Conclusions: These analyses provide evidence of the psychometric properties of the IBS-D Daily Symptom Diary and Event Log in a clinical trial population., Competing Interests: Conflict of interest statement: L. Delgado-Herrera and C. Lademacher and B. Zeiher are employees of Astellas. K. Lasch is an employee of Pharmerit International. A. Lembo has received consultancy fees from AstraZeneca, Ironwood/Forest, Prometheus, and Salix outside the submitted work. D.A. Drossman has received consultancy fees from Shire and Salix. R. Arbuckle, B. Banderas, and K. Rosa are employees of Adelphi Values (formerly Mapi Values), which was under contract by Astellas for this work; K Rosa has a patent pending.

Background: Compliance, palatability, gastrointestinal (GI) symptom, and treatment satisfaction patient- and observer-reported outcome (PRO, ObsRO) measures were developed/modified for patients with transfusion-dependent anemias or myelodysplastic syndrome (MDS) requiring iron chelation therapy (ICT)., Methods: This qualitative cross-sectional observational study used grounded theory data collection and analysis methods and followed PRO/ObsRO development industry guidance. Patients and caregivers of patients with transfusion-dependent anemias or MDS were individually interviewed face-to-face to cognitively debrief the Compliance, Palatability, GI Symptom Diary, and Modified Satisfaction with Iron Chelation Therapy (SICT) instruments presented electronically. Interviews were conducted in sets. Interviews began open-endedly to spontaneously elicit ICT experiences. Item modifications were debriefed during the later interviews. Interviews were audio recorded, transcribed, and coded. Data was analyzed using ATLAS.ti qualitative research software., Results: Twenty-one interviews were completed (Set 1: 5 patients, 6 caregivers; Set 2: 6 patients, 4 caregivers) in 6 US cities. Mean age was 43 years for patients and 9 years for children of caregivers. Conditions requiring ICT use across groups included transfusion-dependent anemias (85.7%) and MDS (14.3%). Concepts spontaneously reported were consistent with instruments debriefed. Interview analysis resulted in PRO and ObsRO versions of each instrument: Compliance (2 items), Palatability (4 items), GI Symptom Diary (6 items), and Modified SICT (PRO = 13, ObsRO = 17 items)., Conclusion: Qualitative research data from cognitive interviews supports the content validity and relevance of the instruments developed/modified. Quantitative validation of these PRO and ObsRO measures is needed testing for validity, reliability, and responsiveness for future research use with new formulations of oral ICT.