Clinical Endpoints Research Articles

P1141 Guselkumab efficacy and safety in East Asian participants with moderate to severely active Ulcerative Colitis: Subgroup analysis of the Phase 2b/3 QUASAR induction and maintenance studies

Abstract Background The global QUASAR studies demonstrated efficacy and safety of guselkumab (GUS), a dual-acting interleukin-23p19 subunit inhibitor, as induction and maintenance therapy in participants (pts) with moderately to severely active ulcerative colitis (UC).1-3 We report a subgroup analysis in East Asian pts. Methods The QUASAR Ph 2b/3 clinical development programme for GUS in UC (NCT04033445) included adults with moderately to severely active UC (induction baseline modified Mayo score ≥5 to ≤9) with inadequate response/intolerance to conventional and/or advanced UC therapy. Two placebo (PBO)-controlled, 12-week studies evaluated intravenous (IV) GUS induction therapy: a Phase (Ph) 2b dose-ranging study (GUS 200 mg or 400 mg every 4 weeks [q4w]) and a Ph3 confirmatory study (GUS 200 mg q4w) (Figure 1). Pts from either study who were in clinical response at induction Week (W) 12 were re-randomised (1:1:1) at start of the maintenance study to subcutaneous (SC) GUS 200 mg q4w, GUS 100 mg q8w, or PBO. Primary endpoints were clinical response (Ph2b) or clinical remission (Ph3) at induction W12 and clinical remission at maintenance W44. This subgroup analysis included pts from QUASAR study sites located in East Asia (China, Japan, Korea, and Taiwan). Results This analysis included 71 (Ph2b: China, n=11; Japan, n=36; Korea, n=18; Taiwan, n=6) and 135 (Ph3: China, n=61; Japan, n=58; Korea, n=13; Taiwan, n=3) East Asian pts from the induction studies and 106 East Asian pts (China, n=34; Japan, n=52; Korea, n=13; Taiwan, n=7) who responded to IV GUS induction and participated in the maintenance study. At induction W12, higher proportions of pts in the IV GUS cohorts achieved clinical response and clinical remission relative to PBO pts (Figure 2A). At maintenance W44, higher proportions of pts achieved clinical remission and other meaningful clinical, patient-reported outcome, and endoscopic endpoints, including endoscopic normalisation, with both SC GUS maintenance dose regimens compared with PBO (Figure 2B). Safety results were consistent with the overall population. Frequencies of pts with treatment-emergent adverse events (TEAEs) were generally consistent with rates reported in the overall global population in the maintenance study through W44. No cases of death, active tuberculosis, opportunistic infections, or anaphylactic or serum sickness-like reactions were reported. Conclusion Efficacy of GUS as IV induction and SC maintenance therapy in the subgroup of East Asian pts from QUASAR was consistent with that observed in the global study population. The safety profile of GUS was also favourable and consistent with previous reports. This study was supported by Janssen Scientific Affairs, LLC.

P0831 Improving efficiency in early phase clinical trials for inflammatory bowel disease through use of external control arms

Abstract Background Although randomised controlled trials (RCTs) are the gold standard for evaluating medical interventions, enrolling enough patients in early-phase trials in inflammatory bowel disease (IBD) to provide sufficient efficacy and safety information prior to confirmatory trials can be difficult.1,2 In a landscape where combination therapies frequently require monotherapy controls and where placebo responses are well-understood, improving trials with external control (EC) data may enhance phase 1-2 trial designs. Methods Current possibilities of using EC data in IBD trials from both methodological and statistical perspectives were explored. Methods of utilising EC data were reviewed, including results of a systematic review of immune-mediated inflammatory disease (IMID) trials that utilised external control arms (ECAs)3, and an example of Bayesian analyses integrating EC data used in an RCT comparing combination treatment to monotherapy benchmarks.4 How EC data fits into the intersection between operational efficiency and good clinical practice was examined. Results Multiple simultaneous ongoing IBD studies, strict objective clinical endpoints (eg, endoscopic remission), and declining enrolment rates have led to increasing difficulty in meeting IBD trial recruitment goals. The prevalence of add-on and combination therapies suggests that trials may need multiple control arms to fully explore efficacy and safety of investigational treatments. Using EC data can increase power and allow for exploratory comparisons across multiple controls in modest-sized trials. Techniques and considerations on how to ethically and effectively use EC data to improve clinical trials, however, are not as thoroughly discussed in the literature. Systematic review of controlled trial databases for IMID studies utilising ECAs resulted in 18 IBD studies that met the search criteria, over three-fourths of which did not control for baseline characteristics between external and trial data (Table 1).1 Furthermore, half of the quality assessment items during evaluation could not be assigned a rating due to insufficient methodology details provided in publications. Conclusion Multiple factors have led to increasing difficulty for IBD trials reaching their recruitment goals. In early phase trials particularly, the use of EC data may allow studies to increase power and decision-making information. More comprehensive reporting, as well as the creation of a validated instrument for appraising ECA methodology, are required to thoroughly understand and evaluate EC data use in studies. References 1Harris MF, Wichary J, Zadnik M, Reinisch W. Competition for clinical trials in inflammatory bowel diseases. Gastroenterology. 2019;157(6):1457-1461. doi:10.1053/j.gastro.2019.08.020 2Ma C, Solitano V, Danese S, Jairath V. The future of clinical trials in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2024;Jul 16:S1542-3565(24)00635-9. doi:10.1016/j.cgh.2024.06.036 3 ayadi A, Edge R, Parker CE, Macdonald JK, Neustifter B, Chang J, et al. Use of external control arms in immune-mediated inflammatory diseases: a systematic review. BMJ Open. 2023;13(12):e076677. doi:10.1136/bmjopen-2023-076677 4Colombel JF, Ungaro RC, Sands BE, Siegel CA, Wolf DC, Valentine JF, et al. Vedolizumab, adalimumab, and methotrexate combination therapy in Crohn’s disease (EXPLORER). Clin Gastroenterol Hepatol. 2024;22(7):1487-1496. doi:10.1016/j.cgh.2023.09.010

P0514 Assessing the relationship between physician perspective and subjective disabilities in IBD patients: a comparative study using IBD-Disk and IBD-Q

Abstract Background Inflammatory Bowel Diseases (IBD) are chronic conditions that often affect young patients throughout their lives. Treating patients with IBD, it is essential not only to achieve deep remission (clinical, biochemical, and mucosal) but also to completely restore the patient’s quality of life. Addressing and reducing the cumulative burden of disease, enabling a return to a “normal life,” and preventing disability have become major therapeutic goals in the management of patients with IBD management. Recently, a brief and patient-friendly questionnaire, the IBD-Disk, has been proposed as a tool for monitoring disability in IBD outpatients. This study aims to assess the relationship between gastrointestinal symptoms, biochemical parameters, and subjective disabilities in patients affected by IBD. Methods In this prospective study, we enrolled consecutive patients with IBD who completed the IBD-Disk during an in-person visit. We also recorded demographic data, clinical features, disease activity, biochemical data, and ongoing treatments. Clinical activity was evaluated using the partial Mayo score (p-Mayo) for Ulcerative Colitis (UC) and the Harvey-Bradshaw index (HBI) for Crohn’s disease (CD). The IBD-Q was also administered at the time of evaluation and a cut-off of 170 was considered to define symptomatic remission. Results We included 95 patients with IBD (49 males, 51.6%), median age of 52.9 years (IQR 37-61), with 45 (47.4%) having CD and 50 (52.6%) having UC. 76 patients (80 %) of patients were on conventional therapy, and 12.6% were receiving concomitant steroids. At the time of evaluation, 29 (30.5%) patients had clinically active disease, and 31 (32.6%) had biochemically active disease. An inverse linear correlation was found between the IBD-Disk and IBD-Q (r² = 0.66, p<0.001). Patients with clinically active disease had significantly higher IBD-Disk scores (40, IQR 24-60 vs. 26, IQR 10-51, p=0.016) and lower IBD-Q (148, IQR 140-176 vs. 180, IQR 159-200) compared to those in clinical remission. The AUROC for clinical remission for IBD-Disk and IBD-Q were 0.650 (95% CI 0.54-0.76) and 0.755 (95% CI 0.65-0.85), respectively. Among patients in remission, 39.3% had an IBD-Q score below 170, while the median IBD-Disk value was 26 (IQR 10-51). The majority of patients preferred completing the IBD-Disk (71, 74.7%). Conclusion Both the IBD-Disk and IBD-Q are associated with objective disease activity, with the IBD-Q demonstrating slightly superior performance. However, most patients preferred the IBD-Disk. Despite achieving satisfying clinical endpoint, doctors often fail to perceive patient’s quality of life.

P1001 Efficacy and safety of an oral tyrosine kinase 2 inhibitor VTX958 in moderately to severely active Crohn’s disease: a randomised, double-blind, placebo-controlled, phase 2 trial

Abstract Background Tyrosine kinase 2 inhibitors (TYK2i) are a novel class of therapies for immune-mediated inflammatory disorders, including Crohn’s disease (CD). A phase 2, multicentre, randomised, double-blind, placebo-controlled trial assessed the efficacy and safety of the oral selective TYK2i VTX958 in CD. Methods Adults (N=109) with moderately-to-severely active CD (CD Activity Index [CDAI] 220-450; Simple Endoscopic Score for CD [SES-CD] ≥6 [≥4 for isolated ileal CD]) and inadequate/loss of response or intolerance to conventional or biologic therapies were randomised 1:1:1 to 12-weeks twice daily treatment with placebo or VTX958 (225mg or 300mg). The primary endpoint was CDAI change from baseline at week 12. Additional secondary endpoints are described in the Table. Changes from baseline in C-reactive protein (CRP) and faecal calprotectin (FCP) concentrations at week 12 were exploratory endpoints. Results Mean CDAI change from baseline at week 12 was -113.6, -134.1, and -104.3 for VTX958 300mg, 225mg, and placebo, respectively (p>0.05; see Table). Conversely, significantly greater SES-CD reductions from baseline at week 12 were observed for VTX958 300mg (-2.7) and 225mg (-3.5) compared to placebo (2.1; p=0.0005 and p<0.0001, respectively), and significantly greater proportions of patients achieved endoscopic response with VTX958 300mg (32.4%) and 225mg (24.3%) treatment compared to placebo (5.7%; p=0.007 and p=0.026, respectively). Although secondary clinical endpoints alone were not significantly different between VTX958 and placebo (Table), combined endoscopic response and clinical remission and clinical-biomarker response rates were significantly higher for VTX958 300mg compared to placebo (18.9% vs 2.9%, p=0.041, and 43.2% vs 14.3%, p=0.011, respectively). Greater reductions in CRP and FCP concentrations compared to placebo were observed with both VTX958 doses. Most adverse events (AE) were mild-to-moderate and comparable across treatment groups. No serious infections, thromboembolic, major adverse cardiovascular events, or deaths occurred in the VTX958 groups. Overall rates of skin reactions were also similar between treatment groups. Rash and acne occurred at a higher rate in the VTX958 groups compared to placebo, most of which were mild, except for one moderate AE of acne in the VTX958 225mg group. Conclusion Twelve weeks treatment with VTX958 was well-tolerated in patients with CD. Although the primary endpoint of CDAI change from baseline was not met, higher rates for most objective outcomes were observed with VTX958 300mg, including endoscopic response and combined clinical remission and endoscopic response. Additional data are needed to determine the long-term safety and efficacy of VTX958 in CD.

OP34 Mirikizumab demonstrates rapid improvements in bowel urgency severity, bowel urgency frequency, and stool deferral time in patients with moderately-to-severely active Ulcerative Colitis: 12-week interim results from the phase 3b LUCENT-URGE trial

Abstract Background Bowel urgency (BU) is a common, under-recognized and debilitating symptom among patients with ulcerative colitis (UC). LUCENT-URGE is a Phase 3b, open-label, single-arm 28-week (W) study in adults with moderately-to-severely active UC and BU (Urgency Numeric Rating Scale [UNRS] ≥3) at baseline treated with mirikizumab (MIRI) (NCT05767021). BU was assessed using the validated UNRS1 and 2 new BU assessments: BU Frequency (BUF) and Stool Deferral Time (SDT). These 3 BU measures (UNRS, BUF, SDT) and clinical endpoints provide a more comprehensive understanding of BU and the impact of MIRI treatment. Here, we report W12 interim analysis results. Methods Patients were treated with intravenous (IV) MIRI 300 mg at W 0, 4 and 8, followed by 200 mg subcutaneous at W12 and every 4 weeks up to W28. The primary endpoint, BU severity (UNRS) at W12, was assessed by change from baseline. BUF improvement was assessed by change from baseline at W12. SDT was reported in minutes and categorized as (4) Severe: <1 min; (3) Moderate-Severe: 1-2 min: (2) Moderate: 2-5 min; (1) Mild: 5-15 min; (0) None: ≥15 minutes. Results 172 patients were enrolled from 8 countries. At baseline, mean (± standard deviation [SD]) modified Mayo score [MMS]) was 6.8±1.3; 64% of patients had severe disease activity (MMS 7-9), mean duration of UC was 8.0±8.2 years, mean UNRS score was 6.9 ±1.6, mean BUF was 6.9±3.7. UNRS, BUF, and SDT improved from baseline to W12 (Figure 1). At W12, 63% patients achieved clinical response and 44% achieved both clinical response and UNRS clinically meaningful improvement (≥3 point decrease). Correlations between UNRS and BUF, and between UNRS and SDT at baseline, W12, and W12 change from baseline were of similar magnitude (Spearman correlation coefficient range: 0.43-0.68). The safety profile of MIRI observed in LUCENT-URGE was consistent with the profile previously reported. Conclusion In patients with moderately-to severely active UC and BU, MIRI demonstrated improvement in BU measures with a decrease by more than 50% in BUF after 12W of treatment. Selecting patients with urgency and targeting BU improvement is a novel strategy to assess response to therapy for UC. Broader associations between BU and quality of life, UC symptoms, histopathologic findings, and gene expression data will be explored upon completion of the W28 LUCENT-URGE study.

P0918 Identification of a serum proteomics signature linked with anti-TNF therapy response outcomes in Inflammatory Bowel Disease

Abstract Background While treatment options for active disease in IBD become diverse, the choice of therapies is mostly based on patient characteristics, disease course and severity but restrained by economic rationales. To maximize treatment effectiveness, predictive biomarkers are needed to guide therapies either ex ante or at the earliest possible time point after therapy initiation. Previously, we identified dynamic blood-based RNA and DNA methylation signatures that are linked with therapy response to anti-TNF in IBD1. Here, we aim to identify serum proteome biomarkers associated with therapeutic outcomes in IBD patients receiving anti-TNF treatment. Methods 31 ulcerative colitis (UC) and 27 Crohn’s disease (CD) patients with active clinical and endoscopic disease were recruited and followed at baseline (W0) and at weeks 2 (W2), 6 (W6), and 14 (W14) after initiating infliximab therapy. The clinical endpoint of interest was defined as a combination of clinical remission (partial Mayo ≤ 2/CDAI < 150) and endoscopic response (reduction in endoscopic Mayo ≥ 1/SES-CD ≥ 50%) at W14. Serum was collected at each time point and subjected to proximity extension assays (Olink® Explore 3072 panel) to screen for 2,944 proteins. Linear mixed models (LMM) were applied to identify differentially expressed proteins (DEPs) between endpoint achievers/non-achievers over time. Additionally, post-analysis of DEPs was performed using cv.glmnet with least absolute shrinkage and selection operator (LASSO) regression to identify candidate predictive marker sets. Results A total of 229 DEPs were identified over time between UC responders and non-responders: 8 at W0, 22 at W2, 181 at W6, and 78 at W14. In CD patients, 23 DEPs were identified: 9 at W0, 7 at W2, 13 at W6, and 13 at W14. These DEPs were disease-specific and linked to Gene Ontology (GO) terms related to inflammatory response and cell differentiation. Using LMM and machine learning, we identified 5 baseline proteins in UC and 6 in CD patients that differentiated combined endpoint achievers from non-achievers (AUROC: UC: 0.958, CD: 0.800). Additionally, we identified dynamic changes from W0 to W2 in 7 proteins associated with immune regulation in UC patients (1 in CD), which were linked to therapeutic outcomes at W14. Conclusion Detecting specific ex ante biomarkers or early dynamic molecular signatures are critical for precision medicine in IBD. Our data suggest that serum proteomics profiling enables the differentiation of patients who will attain therapeutic success under anti-TNF therapy from those who will not. This study warrants further investigations in larger, independent datasets to confirm the potential clinical utility of the proteomics signature. References (1) Mishra N, et al. Longitudinal multi-omics analysis identifies early blood-based predictors of anti-TNF therapy response in inflammatory bowel disease. Genome Med. 2022 Sep 24;14(1):110. doi: 10.1186/s13073-022-01112-z. PMID: 36153599; PMCID: PMC9509553. This project has received funding from the DFG Cluster of Excellence 2167 "Precision medicine in chronic inflammation", the BMBF (e:Med Network iTREAT 01ZX2202A, and GUIDE-IBD 031L0188A), and the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 831434 (3TR) and No 853995 (ImmUniverse).The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. The content provided in this publication reflects the author’s views only. Neither the Innovative Medicines Initiative (IMI JU) nor the European Commission are responsible for any use that may be made of the information it contains.

P0928 Patient endotypes in ulcerative colitis revealed by longitudinal symptom trajectories under therapy

Abstract Background Ulcerative colitis (UC) poses unique challenges in patient care. Although therapies have led to better outcomes, only 20-30% of patients enter remission, and even fewer sustain it over time. A critical need remains in addressing three key areas: i) predicting which patients will enter remission, ii) tailoring treatments to individual patient needs, and iii) identifying novel therapeutic targets that can sustain long-term remission. Symptom trajectories under therapy offer an accessible approach to addressing these challenges and this work investigates their alignment with molecular responses to assess their clinical value. Methods Using a reverse translation approach, this study analyses longitudinal data from the etrolizumab phase 3 trials to gain insights into the UC patient population. Symptom response trajectories of 437 UC patients were tracked over 54 to 66 weeks using the partial Mayo Clinical Score (pMCS). Through unsupervised clustering of pMCS, we identified distinct subpopulations based on their patterns of disease activity. Clinical outcomes within these clusters were then examined, allowing us to uncover significant predictors of rapid and sustained remission. Molecular profiling using gene expression data was then performed, revealing the biological mechanisms that differentiate these patient groups and providing insights into their treatment responses. Results Our analysis revealed five distinct patterns of disease response and progression, from patients achieving rapid and deep remission to those with persistently high disease activity. These five symptom-based subgroups match closely with traditional clinical endpoints. We found that predictors of sustained remission, such as elevated albumin levels, low endoscopic scores, and reduced markers of inflammation (faecal calprotectin and C-reactive protein) aligned with these subgroups. In addition, molecular profiling highlighted specific differences in gene expression and immune cell activity, notably showing that patients with deep remission had an enrichment of anti-inflammatory signalling pathways, suggesting a biological basis for their favourable outcomes. Conclusion Longitudinal monitoring of symptom trajectories offers a non-invasive, easily measured and reliable proxy for early assessment of the likelihood of achieving deep, sustained remission in UC patients. These symptom patterns show strong concordance with endoscopic, laboratory, and molecular remission profiles. This approach aligns with the principles of personalised medicine by enabling i) dynamic symptom monitoring ii) application in Phase II trials to guide drug development by assessing if a patient is on the right path toward therapeutic success and iii) identification of novel therapeutic targets.

Imaging predictors of adverse prognosis in Fabry disease cardiomyopathy: A systematic review and meta-analysis.

Cardiac involvement represents the main cause of death in patients with Fabry disease (FD). Echocardiography and cardiovascular magnetic resonance (CMR) have an established diagnostic role, but their prognostic value remains unresolved. This systematic review and meta-analysis sought to assess the prognostic implications of imaging parameters in FD. PubMed, ClinicalTrials.gov, Embase, Cochrane Library and Web of Science databases were searched for studies from inception through 1 May 2024. Studies including FD patients undergoing baseline imaging assessment and clinical follow-up were selected. Pre-defined study outcomes were a cardiovascular endpoint and a composite clinical endpoint. The study protocol was registered in PROSPERO (ID CRD42022342394). Fourteen studies, including 1713 FD patients (44.7% males), were selected. At pooled analysis, late gadolinium enhancement (hazard ratio [HR]: 4.45; 95% CI: 2.82-7.02), left atrium volume indexed (HR: 1.02 per mL/m2; 95% CI: 1.01-1.03), E/e' (HR: 1.14 per unit increase; 95% CI: 1.08-1.21), left ventricular (LV) mass indexed (HR: 1.01 per mg/m2; 95% CI: 1.00-1.02), maximum LV wall thickness (HR: 1.19 per mm, 95% CI: 1.04-1.36) and LV-global longitudinal strain (HR: 1.20 per unit increase; 95% CI: 1.16-1.25) were significantly associated with the cardiovascular endpoint, whereas T1-mapping and LV-ejection fraction were not. T1-mapping was associated with the composite endpoint (HR: 0.99 per msec increase; 95% CI: 0.98-1.00). Meta-regression analysis did not show any significant interaction between each of the potential effect modifiers. Several imaging parameters were significant predictors of adverse clinical outcomes in patients with FD. Late gadolinium enhancement showed the strongest association with adverse prognosis.

DOP099 Prolonged Pharmacodynamic Effects of Risankizumab Following Withdrawal in Patients with Moderately to Severely Active Ulcerative Colitis

Abstract Background Risankizumab (RZB) is a high-affinity humanized IgG1 monoclonal antibody that selectively binds to the p19 subunit of human IL-23 cytokine, thereby inhibiting its interaction with the IL-23 receptor.1 RZB was intentionally designed with modifications to the antibody that could contribute to prolonged half-life, low immunogenicity, and increased stability and bioavailability.1 The objective of this post-hoc analysis was to characterise the pharmacokinetic (PK) and pharmacodynamic (PD) effects of RZB following withdrawal in patients with moderately to severely active ulcerative colitis (UC). Methods In the UC maintenance trial (COMMAND, NCT03398135), 272 patients who responded to 12 weeks of intravenous (IV) RZB 1200 mg induction therapy were re-randomised to receive subcutaneous (SC) RZB maintenance dosing (180 mg or 360 mg) or placebo (PBO; RZB withdrawal).2 This analysis evaluated clinical endpoints, PK, and biomarkers of the SC PBO/withdrawal. Change from baseline in partial modified Mayo score, serum RZB concentrations and levels of high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP) were assessed at each predetermined study visits throughout the maintenance trial. Results A total of 90 patients were re-randomised to receive PBO (withdrew from RZB induction) in COMMAND. Predicted PK profiles of exposure over time in the PBO/withdrawal group showed that, following the third and final RZB induction dose, residual RZB concentrations lasted for at least 16 weeks before complete washout.3 The PBO/withdrawal group did not have meaningful increases from baseline in partial modified Mayo score until after about week 24 of maintenance (36 weeks since the last dose of RZB) (Figure). Levels of hs-CRP and FCP in the PBO/withdrawal patients remained low throughout maintenance and did not meaningfully increase until week 52. Conclusion Patients with moderately to severely active UC who received IV RZB 1200 mg induction therapy and were re-randomised to PBO exhibited continued response to RZB as demonstrated by disease activity and biomarkers for at least 6 months, exceeding the time of PK washout. hs-CRP and FCP did not increase until week 52 of maintenance and remained below baseline values. This durability of response may have important clinical implications and warrants continued investigation.

P0610 Comparison of endoscopic remission and MRI defined remission using the simplified MaRIA score at week 48 from the PROFILE trial

Abstract Background In the PROFILE trial patients newly-diagnosed with Crohn’s disease on “top-down” (infliximab + immunomodulator) treatment had significantly higher rates of ulcer-free endoscopic remission (SES-CD ulcer subscore = 0) at week 48 compared to those on “accelerated step-up” therapy (67% vs 44%, p<0.0001) [1]. Here, we explored the utility of MRI-defined remission as an alternative week 48 endpoint. Methods PROFILE enrolled 386 patients with endoscopically active new-diagnosis Crohn’s disease. MRI-enterography was performed at week 48 and centrally-read by a validated pool of 5 GI radiologists. Endoscopic and MRI defined remission was compared between “top-down” and “accelerated step-up” groups. Detection of remission and ulceration were compared pairwise between MRI and colonoscopy using McNemar’s test. MRI remission was defined by a simplified Magnetic Resonance Index of Activity (MARIAs) global score of 0 or ulcer subscore of 0; and endoscopic remission by SES-CD ulcer subscore of 0 (no ulcers - as published) and ≤1 (i.e. permitted ulcers 1-5mm). MARIAs sigmoid + descending colon scores were merged to enable comparison to SES-CD in five segments (terminal ileum, right, transverse, left colon and rectum). Data were analysed using Python 3.12.1 packages numpy, pandas, matplotlib (VS Code). Results Week 48 endoscopic data were available for 252 participants. Endoscopic remission using SES-CD ulcer subscore ≤1 at week 48 was more frequent in “top-down” compared to “accelerated step-up” (86% [115/134] vs 71% [84/118] patients, p=0.004). Week 48 MRI data were available for 208 of these participants. MRI remission at week 48 was similar between “top-down” and “accelerated step-up” groups by global MARIAs score (81% [89/109] vs 79% [79/99], p=0.720) and MARIAs ulcer subscore (95% [104/109] vs 96% [95/99], p=0.728). McNemar’s pairwise comparison demonstrated endoscopy had superior sensitivity for detecting ulcers compared to MRI at week 48 (p<0.0001). Comparing SES-CD vs MARIAs across 1035 segments in 208 patients: 43 segments had ulcers >5mm (SES-CD ulcer subscore >1) on colonoscopy of which 1/43 was detected by MRI; and 96 segments had ulcers 1-5mm (SES-CD ulcer subscore = 1), with 4/96 detected by MRI. The remaining 884 segments were normal (SES-CD ulcer subscore = 0). Conclusion MRI had low sensitivity for detecting ulceration compared to colonoscopy. The difference in week 48 outcomes in PROFILE between “top-down” and “accelerated step-up” treatment arms using endoscopic definitions of remission were not seen on MRI. As even mild endoscopic activity correlates with adverse long-term prognosis in Crohn’s [2] so MARIAs-defined trial endpoints may have low utility compared to the endoscopic gold-standard.

Short-term modification of breathprint by Elexacaftor/Tezacaftor/Ivacaftor in a paediatric cohort.

The triple combination Elexacaftor/Tezacaftor/Ivacaftor (ETI) translates into major respiratory improvements in adults; yet current clinical endpoints may prove insufficiently sensitive in young children. We hypothesised that ETI rapidly modifies the lungs' metabolism, resulting in changes in breath composition. Eleven children with CF were enrolled in a longitudinal pilot study at the paediatric Necker hospital. Breath was collected on sorbent tubes using a ReCIVA® device before, after one week and one month of ETI. Samples were analysed by 2D-gas chromatography-mass spectrometry (2D-GC-MS). A linear mixed-effect model, corrected for clinical confounding factors, identified exhaled metabolites differentially expressed throughout the visits. Correlations were calculated between these and clinical indicators. Breath collection was successful in all children from six years old. They presented a decreased sweat chloride and improved lung function as early as within one week of ETI. Breath composition gradually evolved over the visits. ETI induced significant modifications in the level of 12 breath metabolites. Amongst those, dimethyl sulphide and tetradecene changes correlated with improvements in forced expiratory volume in one second (FEV1) and forced expiratory flow (FEF25-75), whilst 3-methyldecane and 3-(chloromethyl)-heptane were predictive of changes in lung clearance index (LCI2.5). ETI impacts the breath profile from the first week of treatment. Not only could "breathomics" bring mechanistic insights into the metabolic impact of ETI, but it may also offer novel non-invasive options to monitor CF disease and predict therapeutic response.

Individualization of piperacillin dosage based on therapeutic drug monitoring with or without model-informed precision dosing: a scenario analysis.

Model-informed precision dosing (MIPD) combines population pharmacokinetic knowledge with therapeutic drug monitoring (TDM) to optimize dosage adjustment. It could improve target concentration attainment over empirical TDM, still widely practised for broad-spectrum antibiotics. To evaluate the respective performance of TDM and MIPD in achieving target piperacillin exposure. Measurements from 80 courses of intermittent piperacillin infusions, each with two TDM samples, were retrospectively submitted to our MIPD software TUCUXI. We considered six dosage adjustment strategies: identical dosage for all (4000 mg q8h), actual initial dosage (chart-based), actual empirical adjustment following first TDM, a priori MIPD-based dosage, a posteriori MIPD-based adjustment after first TDM and MIPD including both TDM measurements. Dosing strategies were compared regarding daily dosage, trough levels distribution and PTA (with target trough 8-32 mg/L). Median trough concentration fell within 8-32 mg/L for all strategies except a priori MIPD-based dosage (42 mg/L). Distributions of trough concentrations predicted with the six dosage adjustment strategies showed significant differences, with both a posteriori MIPD-based strategies best reducing their standard deviation (P < 0.001). PTA of 32%, 32%, 55%, 29%, 83% and 94% were estimated, respectively for the six strategies (P < 0.001). Poor performance of a priori MIPD-based dosage did not hinder a posteriori MIPD-based strategies from significantly improving target attainment. Whilst empirical TDM improves exposure standardization and target attainment compared with no TDM, MIPD can still bring further improvement. Prospective trials remain warranted to confirm MIPD benefits not only on target attainment but also on clinical endpoints.

Diffuseness of coronary artery disease impacts on immediate hemodynamic and predicted clinical outcomes

Diffuse coronary artery disease (CAD) impacts the immediate hemodynamic and clinical outcomes of percutaneous coronary intervention (PCI). We evaluated whether the diffuse pattern of CAD derived from angiographic Quantitative flow ratio (QFR) impacts the immediate hemodynamic outcome post-PCI and the medium term predicted vessel-oriented composite endpoint (VOCE). Paired pre-procedure QFRs were assessed in 503 patients and 1022 vessels in the Multivessel TALENT (MVT) trial. The pathophysiological pattern of CAD was defined as “predominantly diffuse” or “focal” according to a virtual QFR pullback pressure gradient (PPG) index < 0.78 and ≥ 0.78, respectively. Physiological “focal severity” was assessed using the QFR gradient per mm (dQFR/ds), with a value ≥ 0.025/mm the threshold for a “major gradient”. A post-PCI QFR ≥ 0.91 was considered optimal. Median pre-PCI PPG index was 0.70 (IQR 0.59–0.80). The prevalence of “predominantly diffuse” CAD and “major gradient” were 68.6% and 85.8%, respectively. A “Predominantly diffuse” pattern with a major gradient had a higher risk of a post-PCI QFR < 0.91 (OR 1.52,95%CI 1.47–1.58). In multivariable analysis, low QFR PPG index (diffuse disease) was an independent determinant of a post-PCI QFR < 0.91 (per 0.1 decrease of QFR PPG index, OR:9.8, 95% CI 3.0–32.2, p < 0.001). Based on post-PCI QFR the predicted 2-year VOCE, a powered endpoint in the MVT trial, was 6.1% and 4.2% in diffuse and focal lesions, respectively. A pre-procedure physiological pattern of diffuse CAD is an independent determinant of an unfavourable immediate hemodynamic outcome post-PCI, and detrimentally affects the predicted 2-year VOCE.Clinical Trial Registration URL: https://www.clinicaltrials.gov/ct2/show/NCT04390672Unique Identifier: NCT04390672 (registration date 15/05/2020)

A comprehensive review of structure-function correlations in age-related macular degeneration: Contributions of microperimetry.

Age-related macular degeneration (AMD) is a leading cause of visual impairment and irreversible blindness worldwide. High-resolution imaging techniques have been pivotal in characterizing the morphological alterations in the retina and in identifying structural biomarkers with prognostic significance. In clinical practice, visual function is primarily assessed through visual acuity testing, which, however, does not completely reflect the functional deficits experienced by patients. Microperimetry provides a more comprehensive evaluation of macular function, enabling a direct correlation with retinal structure. We examine the current literature on the correlation between morphological biomarkers - identified via optical coherence tomography, optical coherence tomography angiography, and fundus autofluorescence - and retinal sensitivity, as assessed by microperimetry. By encompassing all stages of AMD, we explore the association between retinal sensitivity and a broad spectrum of structural parameters, including distinct drusen phenotypes, hyperreflective foci, the integrity and thickness of various retinal layers, the junctional zone of geographic atrophy, exudative features of neovascular AMD, choriocapillaris flow deficits, and diverse patterns of autofluorescence, among numerous other relevant structural markers. By offering a deeper understanding of the structure-function correlations in disease progression, we provide critical up-to-date insights into the underlying mechanisms of AMD. Moreover, as novel therapeutic strategies continue to emerge, these correlations may serve as more robust endpoints for future clinical trials.

Advancing Hydrocephalus Management: Pathogenesis Insights, Therapeutic Innovations, and Emerging Challenges.

Hydrocephalus is a prevalent neurological disorder, particularly impactful in older adults, characterized by high incidence and numerous complications that impose a significant burden on healthcare systems. This review aims to provide a comprehensive description of hydrocephalus pathogenesis, focusing on cellular and molecular insights derived from animal models. We also present the latest advances in hydrocephalus research and highlight potential therapeutic targets. Lastly, the review advocates the integration of findings from both animal and human studies to achieve better outcomes and examines the potential of emerging technologies. We wish to raise public attention about this disease in an aging society. Current animal models for hydrocephalus involve acquired hydrocephalus models and genetic/congenital hydrocephalus models. Studies from animals have shown that the main mechanisms of models can be broadly classified into nine types. A variety of drug-targeted therapy methods and non-surgical treatment methods have been used in clinical practice. But current treatment approaches primarily focus on symptomatic relief and intracranial pressure control rather than addressing the underlying pathological mechanisms. We call for the development of more accurate and representative animal models to achieve better outcomes and examine the potential of emerging technologies, such as artificial intelligence and neuroimaging. In summary, this review synthesizes recent findings in hydrocephalus research, identifies promising therapeutic targets and interventions, and critically evaluates the limitations of current research paradigms, aiming to align preclinical studies with clinical endpoints. Continued studies and multidisciplinary collaboration are essential to develop effective interventions and facilitate new treatments into bedside.

Biomarkers of disease progression in progressive supranuclear palsy for use in clinical trials

Abstract Progressive supranuclear palsy is a rare neurodegenerative disease with no current disease-modifying treatments approved. Longitudinal research and clinical trials for progressive supranuclear palsy are ongoing and require reliable measures which are sensitive to disease progression. Despite susceptibility to subjective limitations clinical and cognitive assessments are the most used instruments in therapeutic trials in progressive supranuclear palsy. The objective of this review is to identify measures which have been studied longitudinally as measures of progression and which are suitable for use as clinical trial endpoints. We reviewed the measures currently used as trial endpoints, identifying the clinical, cognitive, fluid and imaging measures which have previously been studied longitudinally, and discussing current diagnostic and emerging measures which are yet to be studied longitudinally but which may be sensitive to disease progression. We found that many fluid and imaging measures require further research to validate their use as longitudinal measures of change, including emerging measures which have not yet been studied specifically in progressive supranuclear palsy. We also summarise the sample size estimates required to detect changes in a 2-arm, 52-week therapeutic trial and found that specific MRI volumes require the smallest sample sizes to detect change.

The Clinical Significance of PCI-Related Myocardial Infarctions in Stable Ischemic Heart Disease Patients in the Era of hs-Troponin

The definition and clinical relevance of percutaneous coronary intervention (PCI)-related myocardial infarction (MI) has been a topic of significant debate and controversy. It has particularly garnered widespread attention recently due to a contemporary trend of including it as a component of primary end points in major trials. The study aimed to assess the clinical relevance of PCI-related MI (PMI) according to the Fourth Universal Definition of MIusing a high-sensitivity troponin (hs-Tn) assay in a real-world setting. This was a single centre, retrospective registry analysis of consecutive patients who underwent elective PCI for stable ischaemic heart disease between January 2014 to December 2018. The primary end point was major adverse cardiovascular events (MACEs)-the composite of death, spontaneous MI, stent thrombosis and the need for repeat revascularisation within 12 months from the index procedure. We treated 858 patients with a mean age of 67.6 years and 78.3% were men. The incidence of PMI in our cohort was 12.8%. On univariable analysis, contrast volume >150 mL, prior coronary artery bypass graft, final thrombolysis in MI flow 0-2, total stent length and stent length >20 mm were significantly associated with increased risk of PMI. There were 46 (5.4%) MACE in total with seven (6.4%) in the PMI group and 39 (5.2%) in the non-PMI group (p=0.6). Kaplan-Meier survival curves were used to estimate 1-year MACE-free survival for the patients with PMI versus non-PMI and there was no significant difference. On multivariable Cox proportional hazards analysis, contrast volume >150 mL, prior coronary artery bypass graft and estimated glomerular filtration rate <60 (mL/min/1.73 m2) were independent predictors of MACE during 1-year follow-up, whereas PMI was not an independent predictor. PMI defined according to the Fourth Universal Definition of MI and using hs-Tn was common, occurring in 12.8% of patients, but not independently predictive of MACE in 1 year. As PMIs are increasingly used as a component of composite primary end points in major, practice-changing trials, establishing a clinically relevant definition of PMI is of utmost importance.

A physiologically-based quantitative systems pharmacology model for mechanistic understanding of the response to alogliptin and its application in patients with renal impairment.

Alogliptin is a highly selective inhibitor of dipeptidyl peptidase-4 and primarily excreted as unchanged drug in the urine, and differences in clinical outcomes in renal impairment patients increase the risk of serious adverse reactions. In this study, we developed a comprehensive physiologically-based quantitative systematic pharmacology model of the alogliptin-glucose control system to predict plasma exposure and use glucose as a clinical endpoint to prospectively understand its therapeutic outcomes with varying renal function. Our model incorporates a PBPK model for alogliptin, DPP-4 activity described by receptor occupancy theory, and the crosstalk and feedback loops for GLP-1-GIP-glucagon, insulin, and glucose. Based on the optimization of renal function-dependent parameters, the model was extrapolated to different stages renal impairment patients. Ultimately our model adequately describes the pharmacokinetics of alogliptin, the progression of DPP-4 inhibition over time and the dynamics of the glucose control system components. The extrapolation results endorse the dose adjustment regimen of 12.5mg once daily for moderate patients and 6.25mg once daily for severe and ESRD patients, while providing additional reflections and insights. In clinical practice, our model could provide additional information on the in vivo fate of DPP4 inhibitors and key regulators of the glucose control system.

Radial Artery Used as Conduit for Coronary Artery Bypass Grafting

It was in 1989 that we first reported on the use of the radial artery (RA) as a secondary arterial graft for coronary artery bypass grafting (CABG). Nevertheless, discrepancies in clinical endpoints between the RA and alternative conduits have been reported in consecutive randomised trials. With over fifty years of accumulated practice in RA bypass grafting, we sought to identify the second-best option for CABG by reviewing the literature. A consistently successful second-best conduit for CABG has been demonstrated using the radial artery. Compared to saphenous vein grafts, the findings indicate improved outcomes and better patency results. Furthermore, it has been demonstrated to be a safe and effective conduit in the territory of the right coronary artery. The lack of available literature and the scarcity of similar case series restrict the application of the gastroepiploic artery. After five decades of utilisation, it can be unequivocally stated that the radial artery is the optimal conduit for coronary bypass surgery following the left internal thoracic artery to the left anterior descending artery.

Assessing patient-reported outcomes in primary sclerosing cholangitis: an update.

Patient-reported outcome (PRO) measures validated in primary sclerosing cholangitis (PSC) are needed for clinical trials. This review describes the recent US Food & Drug Administration (FDA) Patient-Focused Drug Development (PFDD) guidelines, existing PRO measures used in PSC studies, and the design of PSC-specific symptom measures adherent with the guidelines. FDA released updated guidance reflecting best practices for the design and evaluation of clinical outcome assessments (including PROs) and the design of trial endpoints. Two recent systematic reviews (2018, 2020) identified multiple PRO measures used in PSC studies, with two additional measures published since. Of these, four were developed in samples inclusive of PSC patients and six have been psychometrically evaluated in PSC. Published evidence to sufficiently support alignment with the recent guidance is sparse. We review the design of three symptom measures for PSC to illustrate alignment with FDA guidance, including qualitative and quantitative studies to provide evidence for their validity for use in adult PSC trials. Investigators planning to use PRO measures as study endpoints for PSC need to be adherent with the recent FDA guidelines and build the evidence base to support the measure as fit-for-purpose as an endpoint for clinical trials.