bluuebunny/crossref_metadata_2025_split huggingface dataset:
P427 A hybrid approach of handling missing data in inflammatory bowel disease (IBD) trials: results from VISIBLE 1 and VARSITY
Authors: Chen J , Hunter S , Kisfalvi K , Lirio R A 
Published: January 2020

Abstract

Background
Missing data is common in IBD trials. Depending on the volume and nature of missing data, it can reduce statistical power for detecting treatment difference, introduce potential bias and invalidate conclusions. Non-responder imputation (NRI), where patients (patients) with missing data are considered treatment failures, is widely used to handle missing data for dichotomous efficacy endpoints in IBD trials. However, it does not consider the mechanisms leading to missing data and can potentially underestimate the treatment effect. We proposed a hybrid (HI) approach combining NRI and multiple imputation (MI) as an alternative to NRI in the analyses of two phase 3 trials of vedolizumab (VDZ) in patients with moderate-to-severe UC – VISIBLE 11 and VARSITY2.

Methods
VISIBLE 1 and VARSITY assessed efficacy using dichotomous endpoints based on complete Mayo score. Full methodologies reported previously.1,2 Our proposed HI approach is aimed at imputing missing Mayo scores, instead of imputing the missing dichotomous efficacy endpoint. To assess the impact of dropouts for different missing data mechanisms (categorised as ‘missing not at random [MNAR]’ and ‘missing at random [MAR]’, HI was implemented as a potential sensitivity analysis, where dropouts owing to safety or lack of efficacy were imputed using NRI (assuming MNAR) and other missing data were imputed using MI (assuming MAR). For MI, each component of the Mayo score was imputed via a multivariate stepwise approach using a fully conditional specification ordinal logistic method. Missing baseline scores were imputed using baseline characteristics data. Missing scores from each subsequent visit were imputed using all previous visits in a stepwise fashion. Fifty imputation datasets were computed for each component of Mayo score. The complete Mayo score and relevant efficacy endpoints were derived subsequently. The analysis was performed within each imputed dataset to determine treatment difference, 95% CI and p-value, which were then combined via Rubin’s rules3.

Results
Tables 1 and 2 show a comparison of efficacy in the two studies using the primary NRI analysis vs. the alternative HI approach for handling missing data.

Conclusion
HI and NRI approaches can provide consistent efficacy analyses in IBD trials. The HI approach can serve as a useful sensitivity analysis to assess the impact of dropouts under different missing data mechanisms and evaluate the robustness of efficacy conclusions.

Reference
P446 Transcriptional and microbial biomarkers of response to anti-TL1A therapy in ulcerative colitis: the Phase 2a TUSCANY study
Authors: Hassan-Zahraee M , Ye Z , Xi L , Baniecki M L , Li X , Farin W , Tibaldi L , Allegretti J R , Romatowski J , Scherl E J , Klopocka M , Hyde C , Danese S , Longman R , Hung K E 
Published: January 2020

Abstract

Background
Tumour necrosis factor α-like ligand 1A (TL1A) acts as a synergistic cytokine that amplifies pro-inflammatory signals to increase T-cell, natural killer (NK) cell, and innate lymphoid cell production of cytokines, which are thought to be key drivers of inflammatory bowel disease (IBD) and intestinal fibrosis. The recent Phase 2a TUSCANY study demonstrated the efficacy of PF-06480605, a fully human immunoglobulin G1 monoclonal antibody targeting TL1A, in the treatment of participants with moderate to severe active Ulcerative Colitis (UC). Here, we present transcriptomic analysis of intestinal tissue biopsies and metagenomic analysis of the faecal microbiome to further evaluate the treatment effect of PF-06480605.

Methods
The Phase 2a, open-label, multicentre, single-arm TUSCANY study (NCT02840721) evaluated the safety, tolerability and efficacy of PF-06480605 in participants with moderate to severe UC. Participants received 500 mg intravenous (IV) PF-06480605 every 2 weeks (Q2W) for a total of 7 doses, with a 14-week follow-up period. We performed RNA sequencing of colonic biopsies and metagenomic sequencing (&gt;40 million reads per sample) of faecal samples taken prior to and after 12 weeks of therapy. Differential expression and cell subset deconvolution by CytoReason were used to identify genes and immune cells involved in response to therapy. Differential abundance analyses based on taxonomic profiling was performed using the GOTTCHA metagenome mapping algorithm to discover whether microbial taxa changed in response to treatment.

Results
Tissue transcriptomic analysis identified a robust inhibition of adaptive (Th1, Th2 and Th17) and innate (macrophage) inflammatory pathways known to be associated with UC pathogenesis and a significant reduction in fibrosis-associated pathways (MMP3, MMP7 and MMP10). Transcriptomic responses were most pronounced in participants achieving endoscopic improvement (Mayo endoscopic subscore of ≤1). A candidate baseline gene signature was predictive of endoscopic improvement (area under the curve [AUC] 0.75; p-value = 0.03). Metagenomic analysis revealed a significant reduction in inflammatory pathobiont species (S. salivarius, S. parasanguinis, and H. parainfluenzae) following treatment.

Conclusion
These results provide insight into the molecular and microbial mechanisms underlying the efficacy of anti-TL1A therapy for UC. We defined a baseline transcriptomic signature to predict response and a pathobiont treatment signature. These findings may enable the development of precision medicine strategies for anti-TL1A therapy in the treatment of intestinal inflammation.
P450 Thioguanine and low dose thiopurines and allopurinol are both safe options after failure of conventional thiopurines: a comparative analysis of two multicentre cohorts
Authors: Biemans Drs V , Savelkoul E , Dijkstra G , Simsek M , Gabriels R , Pierik M , West R , de Boer N , Hoentjen F 
Published: January 2020

Abstract

Background
Both thioguanine (TG) and low dose thiopurines and allopurinol (LDTA) can be considered for the treatment of inflammatory bowel disease (IBD) when conventional thiopurines fail due to intolerance or adverse events (AE). However, head-to-head trials are currently not available. The aim of this study was to compare the safety of TG and LDTA in IBD patients.

Methods
Adult IBD patients who failed conventional thiopurines and initiated LDTA in standard care were identified in the observational prospective multicentre ICC Registry. IBD patients who failed conventional thiopurines and initiated TG were retrospectively enrolled in three university hospitals. Patients with concomitant treatment with biologicals were excluded. The primary outcome was discontinuation of therapy due to AE. Secondary outcomes included: medication-related AE, infections (moderate: oral medication, severe: intravenously administrated medication), hospitalisations, and biological- and corticosteroid-free clinical remission (i.e. physician global assessment = 0) after 104 weeks of treatment. To adjust for confounding and selection bias, both multiple logistic regression and propensity score matching (PSM) were used to correct for baseline characteristics associated with disease severity or therapy refractoriness.

Results
In total, 182 IBD patients treated with TG (n = 94) or LDTA (n = 88) were included with a median follow-up of 104 weeks (IQR 91–104). The median dose of TG was 0.27 mg/kg (IQR 0.22–0.32), for LDTA: 100 mg allopurinol with either 0.67 mg/kg (IQR 0.54–0.75) azathioprine (n = 45) or 0.35 mg/kg (IQR 0.28–0.38) mercaptopurine (n = 41) (n = 2 unknown). By PSM, 64 TG patients were strictly matched with 64 LDTA patients with comparable baseline characteristics. In total, 19% (TG: 20%, LDTA: 18%) of patients discontinued therapy due AE. After adjusting for confounders, there were no significant differences in terms of discontinuation rate due to AE (TG: n = 19, LDTA = 16, OR 0.50 95% CI 0.15–1.68 p = 0.26), other AE (TG: n = 46, LDTA: n = 44, OR 0.89 95% CI 0.44–1.81 p = 0.75) (no cases of nodular regenerative hyperplasia of the liver were reported), infections (TG: n = 13, LDTA: n = 18, OR 1.05 95% CI 0.40–2.73 p = 0.93), hospitalisations (TG: n = 5, LDTA: n = 9, OR 2.00, 95% CI 0.64–6.23 p = 0.23), or biological- and corticosteroid-free clinical remission (OR 0.74 95% CI 0.33–1.68 p = 0.48). Escalation to biological treatment was comparable (TG 21% vs. LDTA 24% p = 0.68). All these results were in line with the PSM cohort.

Conclusion
A relative low percentage of patients with prior failure to conventional thiopurines discontinued therapy with TG or LDTA due to AE. Both maintenance therapies may be considered after failure of conventional thiopurines before escalating to biological therapy.
P467 Can induction and maintenance serum vedolizumab levels predict long-term clinical outcome in inflammatory bowel disease (IBD)?
Authors: Miller C , Morgan H , Steel A , Wahed M 
Published: January 2020

Abstract

Background
Vedolizumab (VDZ) is an established IBD therapy, however, the role of therapeutic drug levels (TDM) is not fully established.1 Our aim was to assess whether week 6 and maintenance serum trough VDZ levels predict the clinical outcome at week 52.

Methods
A retrospective review of patients with Crohn’s disease (CD) or ulcerative colitis (UC) on VDZ was performed. Twenty-one IBD patients with serum VDZ trough level monitoring between January 2016 and December 2017 were identified. All patients received VDZ induction and maintenance as per standard protocol. Patients were excluded if complete dataset of VDZ levels was not available. Clinical remission was defined as a partial Mayo score &lt; 2 for patients with UC or a Harvey–Bradshaw index (HBI) score &lt; 4 for those with CD. A trough VDZ level ≥ 27 μg/ml cut-off was used to evaluate remission outcomes for both induction and average maintenance VDZ levels. Statistically, analysis was carried out using the Fisher exact test. Key demographics are 57% CD, 43% UC; Baseline HBI score: 11; Baseline Partial Mayo score: 9; Concurrent Immunomodulator: 55%

Results: (
1) Week 6 induction levels: At week 52, 69% of patients were in clinical remission. Those patients in remission had a higher mean and median trough VDZ levels (Figure A). When the induction serum trough VDZ level ≥ 27 μg/ml 30% more patients were in clinical remission at week 52, although this failed to reach statistical significance (p = 0.40) (Figure C). (2) Average maintenance VDZ levels: At week 52, 63% of patients were in clinical remission. Those patients in remission had a higher mean and median average maintenance trough VDZ levels (Figure B). When the average maintenance trough VDZ level was ≥ 27 μg/ml 17% more patients were in clinical remission, this failed to reach statistical significance (p = .0.39) (Figure D).

Conclusion
High levels of clinical remission in both CD and UC were seen. In our study, we could use a similar cut-off for induction trough VDZ levels to those used in the literature that correlated with positive outcomes.1 Although the observed levels used to predict remission did not reach statistical significance, this may represent a type 2 error in view of the small numbers of patient. Furthermore, it was not possible to assess whether there is a difference between CD and UC. For maintenance levels, our cut-off of 27 μg/ml was higher than that used in the literature that correlated with positive outcomes.1 Our data suggest there is some correlation between trough VDZ levels for both induction and average maintenance levels and long-term clinical remission. Our induction cut-off was similar to currently available data associated with positive outcomes.1 Further studies are required to fully establish the role of TDM.

References
P476 Efficacy and safety of 2 vedolizumab IV regimens in patients with perianal fistulising Crohn’s disease: results of the ENTERPRISE study
Authors: Schwartz D , Peyrin-Biroulet L , Lasch K , Adsul S , Danese S 
Published: January 2020

Abstract

Background
Perianal fistulae occurring with Crohn’s disease (CD) are a challenge to treat. Vedolizumab (VDZ) is a gut-selective, monoclonal α 4β7 integrin antibody approved to treat patients (patients) with moderately to severely active CD. Here we report results from ENTERPRISE (NCT02630966; EudraCT 2015-000852-12), a randomised, double-blind, phase 4 trial to evaluate 2 VDZ IV dosing regimens in patients with fistulising CD.

Methods
Patients with moderately to severely active CD and 1–3 draining perianal fistulae received either VDZ 300 mg IV at Weeks (Week) 0, 2, 6, 14, and 22 (VDZ), or the same regimen plus an additional VDZ dose at Wk10 (VDZ+Wk10). The primary endpoint was the proportion of patients with a ≥50% reduction from baseline (BL) in the number of draining fistulae (absence of draining despite gentle finger compression) at Wk30. Secondary endpoints were the proportion of patients with a ≥50% reduction from BL in the number of draining fistulae at Wk22 and Wk30, and the proportion of patients with 100% fistulae closure at Wk30. Patients with missing data at study visits were counted as non-responders. Perianal disease activity index (PDAI), perianal pain score, Van Assche score, gadolinium contrast enhancement by pelvic MRI, and safety were assessed. Study enrolment closed early due to slow recruitment; thus, all analyses are descriptive.

Results
Of the 32 patients with post-BL assessment of fistulae healing (full analysis set, FAS), 28 had ≥1 draining fistula at BL (modified FAS). Median CD duration was 8.5 years (VDZ [n = 14]: 11.2 years; VDZ+ Week 10 [n = 14]: 6.1 years). In each arm, 11 patients (78.6%) had prior anti-tumour necrosis factor therapy at BL; concomitant corticosteroid use was 21.4% (VDZ) and 14.3% (VDZ+ Week 10), and concomitant immunosuppressant use was 28.6% (VDZ) and 21.4% (VDZ+ Week 10). At Wk30, 53.6% of all patients achieved ≥50% decrease in the number of draining fistulae (VDZ: 64.3%; VDZ+ Week 10: 42.9%; Figure 1). The proportion of patients with fistulae response increased rapidly and remained high through Week 30 (Figure 2); 46.4% of patients (VDZ: 57.1%; VDZ+Week 10: 35.7%) achieved ≥50% decrease in the number of draining fistulae at both Weeks 22 and 30. Closure of all fistulae draining at BL was observed at Week 30 in 42.9% of patients (VDZ: 50.0%; VDZ+ Week 10: 35.7%). In the FAS, mean (SD) PDAI scores changed from BL to Weeks 30–4.1 (3.3) and perianal pain scores changed –2.2 (2.7) (table). At Wk30, mean (SD) Van Assche scores and contrast enhancement scores changed –1.1 (3.1) and –9.5 (69.4) from screening, respectively. No new safety signals were observed.

Conclusion
Over half of CD patients treated with VDZ had reductions of ≥50% in the number of draining perianal fistulae. Clinically relevant reductions in draining fistulae were seen as early as Wk2 and maintained through Wk30.
P485 Switching infliximab biosimilar: No adverse impact on inflammatory bowel disease control or drug levels with the first or second switch
Authors: Luber R , O’Neill R , Singh S , Arkir Z , Irving P 
Published: January 2020

Abstract

Background
Biological medicines account for a significant cost to healthcare systems. With the advent of anti-tumour necrosis factor biosimilars, switching from originator to biosimilar has enabled cost saving in inflammatory bowel disease (IBD) without compromising disease control. However, with more biosimilars entering the market, the effect on IBD activity and pharmacokinetics (PK) of a second switch to another biosimilar is uncertain. This study aims to assess the effect on disease activity and drug levels associated with switching from infliximab (IFX) biosimilar Remsima® (Celltrion, Hungary) to another biosimilar, Flixabi® (Samsung Bioepis, The Netherlands), and to compare those switching for the first and second time.

Methods
All IBD patients on IFX biosimilar Remsima® were prospectively followed during their switch to Flixabi® in a single centre. Baseline data including C-reactive protein (CRP), trough IFX level, and clinical disease activity indices were collected; Harvey Bradshaw Index for Crohn’s disease (CD) and Simple Clinical Colitis Activity Index for ulcerative colitis (UC). These indices were repeated after at least two infusions of Flixabi®.

Results
221 patients (179 CD, 42 UC) on stable IFX treatment were included in the study. 174 (79%) were on a concomitant immunomodulator. 5 (2%) patients ceased IFX prior to follow-up due to sustained remission, and 3 (1%) patients discontinued due to factors not directly related to drug or disease. 112 patients had PK analysis performed pre and post switch. An increase in IFX trough level was observed after switching IFX biosimilars; baseline median (IQR) trough level of 4.5µg/ml (2.9–6.3) compared with post switch of 5.1µg/ml (3.4–7.0) (p = 0.02). There was no difference in clinical scores or CRP post switch, and no new anti-IFX antibodies were detected. 107 patients (48%) were switching IFX agent for the second time, of which 51 had PK analysis performed. A similar increase in median IFX trough level was observed post switch in those switching for the first (4.7 vs. 6.1 µg/ml, p = 0.03) and second (4.0 vs. 4.5µg/ml, p = 0.05) times (Figure 1). No change in clinical disease activity or CRP occurred in either group. Concomitant immunomodulator and disease classification had no impact on change in IFX level (p = 0.72 and 0.37, respectively, on univariate analysis).

Conclusion
In a cohort of IBD patients switching to a new IFX biosimilar either for the first or second time, an increase in IFX level was observed with no impact on clinical and biochemical disease activity indices. Switching IFX biosimilars in IBD appears safe in the short term with respect to maintaining drug pharmacokinetic profile and disease control whether switching for the first or second time.
P490 Assessment of body weight changes in patients with inflammatory bowel diseases initiating biologic therapy: A prospective cohort study
Authors: Borren N , Tan W , Jess A , Li P H M , Garber J , Luther J , Colizzo F , Khalili H , Ananthakrishnan A 
Published: January 2020

Abstract

Background
Biologic therapies are effective in inducing sustained clinical and endoscopic remission in inflammatory bowel diseases. While side effects are infrequent, prior studies have inconsistently suggested that tumour necrosis factor α (anti-TNF) therapy may be associated with weight gain. We performed this prospective study to compare weight gain across different biologic therapy classes with distinct mechanisms of action.

Methods
This prospective cohort study recruited patients with moderate to severe IBD initiating outpatient biologic therapy with anti-TNF (infliximab, adalimumab), vedolizumab or ustekinumab. Weight measurements were performed at weeks 0, 14, 30 and 54. Disease activity at these time points was assessed using the Harvey Bradshaw Index (HBI) for CD and Simple Clinical Colitis Activity Index (SCCAI) for UC. Remission was defined as HBI &lt;4 or SCCAI 2. Changes in weight between baseline and each of the follow-up visits were modelled as a continuous variable and multivariate regression assessed the independent effect of therapeutic class on this outcome.

Results
Our study enrolled 314 patients (197 CD, 117 UC) initiating biologic therapy with 120 patients starting anti-TNF (38%), 140 patients started vedolizumab (45%) and 54 patients on ustekinumab (17%). All patients provided their weight and height at baseline; 261, 184 and 131 patients provided data on weight at week 14, week 30 and week 54, respectively. The mean baseline body weight was similar among all therapeutic classes. Patients initiating UST were more likely to have Crohn’s disease (CD), have perianal involvement and have prior biologic exposure. From baseline, the weight significantly increased at week 14 with a mean of 0.36 kg ( ± 3.8kg, p = 0.004) and continued to increase compared with baseline with 0.96 kg ( ± 3.9kg, p &lt; 0.001) and 1.29 kg ( ± 4.2kg, p &lt; 0.001) at week 30 and 54, respectively (Figure 1). On univariate and multivariable analysis, no significant differences between any of the biologic therapies for weight gain was seen at any time point (weight gain anti-TNF: 0.31 kg, 1.06 kg, 1.33 kg; VDZ: 0.30 kg, 0.83 kg, 1.10 kg; UST: 0.63 kg, 1.21 kg, 2.31 kg at week 14, week 30, week 54, respectively) (Figure 2). Weight gain at week 14 was significantly higher in those with CD (+1.25 kg, 95% CI 0.19–2.30, p = 0.021) and being on steroids at baseline (+1.07kg, 95% CI 0.03–2.10, p = 0.043). Early weight gain predicted continued weight gain at week 30 (+0.83kg, 95% CI 0.63–1.03, p &lt; 0.001) and week 54 (+0.48, 95% CI 0.21–0.74, p = 0.001). Neither clinical response to therapy nor disease activity parameters showed any statistical association with weight gain.

Conclusion
There was no difference in weight gain between the different biologic therapeutic classes.
P505 Different failure rates after non-medical switching of 744 patients from adalimumab originator to 2 different adalimumab biosimilars at Cambridge University Hospitals, UK: real-world experience
Authors: Rosembert D , Malaviya A , How J , Tomlison J , Toh F , Roe M , Nightingale A , Garcia-Sueiro C , Herbert P , Jadon D , Norris P , Thomas J , Magsino J , Negoescu A , Raine T 
Published: January 2020

Abstract

Background
Biosimilar adalimumab became available in the UK in October 2018, with payers introducing a series of measures to drive the adoption of the ‘best value’ adalimumab.1 Consideration of value should include risk of loss of efficacy and adverse reactions, which might drive further biologic switches or ‘reverse switches’ to originator. Managing potential ‘nocebo effect’ requires high levels of patient engagement, whilst the presence or absence of citrate buffer may affect patient-reported discomfort, hence patient treatment perceptions.

Methods
Patients were switched to 2 different biosimilar adalimumabs, one buffered with citrate (ADA1) and one in a citrate-free buffer (ADA2). The choice of adalimumab biosimilar was made for clinical and economic reasons. Patients were informed of the switch to either ADA1 or ADA2 in advance via letter and at clinic visits. Patients who reported problems after switching were reviewed.

Results
A total of 744 patients were switched from originator adalimumab (ADA0) to ADA1 or ADA2. Rheumatology and dermatology patients were switched to ADA1, whilst gastroenterology patients were switched to ADA2, except for those with a latex allergy, where ADA1 was used (or ADA2 in a latex-free syringe). A total of 49 (6.6%) patients reported problems and a further switch of drug was judged necessary in 48 (Table 1). Switch failure was significantly more likely with ADA1 than ADA2 (7.7% vs. 1.8%; p = 0.006). The median time to switch failure was 97 days (range 5–196 days). The commonest reason for switch failure was disease flare (23 patients, 48%), followed by injection site pain or reaction (21 patients, 44%). Disease flare and injection site problems were more likely to be reported with ADA1 than ADA2 (flare: 23/583 vs. 0/161, p = 0.008; injection site pain 20/583 vs. 1/161, p = 0.06). For patients reporting disease flare, clinicians tended to select a reverse switch to ADA0, whilst for those with injection site problems, a further switch to a different biosimilar was the preferred approach; both strategies were effective at recapture.

Conclusion
In the context of an effective patient communication strategy, adalimumab biosimilar switching was associated with overall low rates of patient-reported problems in a large cohort. Despite an identical communication strategy, significantly higher rates of injection site problems and disease flares were seen between 2 different biosimilars, reflected in a higher need for further switches. These differences may impact the cost-effectiveness of any chosen strategy.

Reference