ABSTRACT
Background: Infections are an important safety concern in patients with IBD and may be due to its therapies, such as corticosteroids. Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). The biologic effect of etrasimod leads to selective and reversible lymphocyte retention in lymph nodes with a decrease in peripheral lymphocyte count. We report the infection events from the phase 3 ELEVATE programme. Method(s): Infection events were evaluated in the pivotal UC pooled safety analyses set comprising two phase 3 studies: ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369). Subjects (16- 80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). We report the n (%) and exposure-adjusted incidence rate (EAIR) of infections including serious infections, severe infections, opportunistic infections (including tuberculosis), and herpes infections. Infections were considered adverse events of special interest (AESI) if they were severe (>= CTCAE Grade 3), were opportunistic infections, or were herpes zoster or herpes simplex infections. Result(s): From the pooled ELEVATE UC 12 and ELEVATE UC 52 trials, 527 subjects received >=1 dose of etrasimod 2 mg (265.6 subject-years of exposure) and 260 subjects were randomised to PBO (103.0 subjectyears of exposure). Infections were similar between treatment groups (etrasimod: 99 [18.8%], EAIR=0.41;PBO: 46 [17.7%], EAIR=0.52). The most frequent infections in both groups were COVID-19, urinary tract infections, and nasopharyngitis (Table 1). Serious infections occurred in 3 (0.6%) subjects in the etrasimod arm (EAIR=0.01) and 5 (1.9%) in PBO arm (EAIR=0.05). Two cases of herpes zoster were reported in each treatment group (etrasimod: 0.4%, EAIR<0.01;PBO: 0.8%, EAIR=0.02);these were localised and nonserious. One opportunistic infection was reported in each arm (etrasimod: Subject withdrew from the study on day 20, the AE of Cytomegalovirus infection [Grade 2] was reported on day 36;PBO: Tuberculosis [Grade 2]). Overall, 3 cases of infection led to discontinuation: 2 in the etrasimod arm (both mild) and 1 in the PBO arm (Table 2). No subject with an absolute lymphocyte count <0.2x109/L subsequently reported a serious/ severe or opportunistic infection. There were no deaths. Downloaded from https://academic.oup.com/ecco-jcc/article/17/Supplement-1/i689/7010119 by guest on 04 February 2023 Sample output to test PDF Combine only i690 Poster presentations In these trials, etrasimod-treated subjects reported no in-crease in infections relative to PBO. Serious infections and herpes zoster were more commonly reported in the PBO-treated group. Longer-term follow-up data from the ongoing 5-year open-label extension will fur-ther characterize the etrasimod safety profile.
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Introduction Treatment of perianal fistulizing Crohn's disease (PFCD) is a major unmet need. Filgotinib (FIL) is a oncedaily, oral, preferential JAK1 inhibitor in development as a CD treatment. The efficacy and safety of FIL for the treatment of PFCD was evaluated in the phase 2, double-blind, randomized, placebo (PBO)-controlled DIVERGENCE2 study (NCT03077412). Methods Patients 18-75years with PFCD (documented diagnosis of CD for >3months and 1-3 external openings [EOs] with drainage [spontaneous or on compression] for ≥4weeks before screening) previously treated with antibiotics, immunomodulators and/or TNFi were randomized (2:2:1) to receive FIL 200mg, 100mg or PBO once daily for <24weeks. Active luminal CD was permitted providing that CDAI score was ≤300 at screening. The primary endpoint was combined fistula response (reduction of ≥1 from baseline in the number of draining EOs determined by investigator assessment and no fluid collections 1cm on centrally read pelvic MRI) at Week24. Combined fistula remission (closure of all draining EOs present at baseline and no fluid collections >1cm) at Week24 was a key secondary endpoint. The study was not powered for statistical comparisons and was prematurely terminated owing to low recruitment rates during the COVID-19 pandemic. Results Baseline characteristics were broadly similar across treatment groups. Overall, 91% (52/57) patients had complex perianal fistulae;TNFi treatment had previously failed in 65% (37/57) patients. A lower proportion of patients randomized to FIL200mg than PBO discontinued the study. The proportion of patients who achieved a combined fistula response at Week24 was numerically higher in the FIL200mg than the PBO group (Figure 1a), with similar results observed for combined fistula remission (Figure 1b). Treatment-emergent severe AEs were highest in the FIL200mg group. AE rates were otherwise similar across groups. Conclusion In this phase 2 study, numerically higher fistula response and remission rates were observed after 24weeks of treatment with FIL200mg vs PBO in patients with active PFCD and a history of multiple medical treatment failures. FIL was well tolerated. Further studies of FIL for PFCD treatment are warranted.
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Introduction Objective evaluation of treatment response is the gold standard in ulcerative colitis (UC). In this setting, intestinal ultrasound (IUS) is a non-invasive alternative to endoscopy. Recent studies showed change in IUS parameters after treatment initiation but studies with an endoscopic reference standard are scarce. The aim of this study was to evaluate early change of IUS parameters and determine cut-off values for endoscopic endpoints in UC patients starting anti-inflammatory treatment. Methods In this longitudinal prospective study consecutive patients with moderate-severe UC (baseline endoscopic Mayo score (EMS)≥2) starting an anti-inflammatory treatment were included. Clinical scores, biochemical parameters and IUS parameters were collected at baseline, after 2 (T1), 6 (T2) and 8-26 weeks (T3) around time of the second sigmoidoscopy/colonoscopy. Bowel wall thickness (BWT), Colour Doppler signal (CDS), haustrations, inflammatory fat and wall layer stratification were measured as previously established1. Endoscopic remission (ER) and mucosal healing (MH) were evaluated in the sigmoid and defined as EMS=0 and EMS≤1, respectively. The ultrasonographist and endoscopist were blinded for the outcomes of endoscopy and IUS, respectively. Results 51 consecutive patients were included (Table 1) of whom 31 underwent a second endoscopy. Two additional patients underwent colectomy and were considered non-responders. 18 patients did not undergo second endoscopy due to the COVID-19 pandemic (n=2), refusal (n=5), loss to follow-up (n=1) or treatment escalation because of clinical deterioration confirmed by IUS and biomarkers before second endoscopy was performed (n=10). BWT was significantly lower from T2 onwards in patients reaching MH (p=0.026) and ER (p=0.002) at T3 (Fig 1). A significant decrease in BWT was already visible at T1 in patients receiving infliximab (median DBWT T0-T1: -26% [-43% - -6%], p=0.001) or tofacitinib (median ∆BWT T0-T1: -33% [-46% - -5%], p=0.001) but not in patients treated with vedolizumab (median ∆BWT T0-T1: -14% [-43% - 5%], p=0.11). Most accurate BWT cut-off values at T3 to determine MH and ER were 3.52 mm (AUROC: 0.95, 95% CI: 0.86-1.00, p<0.0001, sens:91%, spec:91%) and 2.98 mm (AUROC: 0.94, 95% CI: 0.85-1.00, p=0.001, sens:87%, spec:100%), respectively. At T2, BWT per 1 mm increase and CDS were inversely associated with MH (BWT: OR: 0.48 (0.24-0.96, p=0.038);CDS: OR 0.16 (0.03-0.83), p=0.028) and ER (BWT: OR: 0.30 (0.11-0.76), p=0.01). Conclusion BWT and CDS 6 weeks after start of treatment could predict MH and ER. In addition, treatment response at IUS is drug-specific. Furthermore, we have provided accurate BWT cut-off values for endoscopic outcomes. In a point-of-care setting, (early) treatment evaluation with IUS could guide treatment decision in UC in order to optimize treatment response. 1. Bots et al. JCC 2021
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Background: Objective evaluation of treatment response is the gold standard in ulcerative colitis (UC). In this setting, intestinal ultrasound (IUS) is a non-invasive alternative to endoscopy. Recent studies showed change in IUS parameters after treatment initiation but studies with an endoscopic reference standard are scarce. The aim of this study was to evaluate early change of IUS parameters and determine cut-off values for endoscopic endpoints in UC patients starting anti-inflammatory treatment. Methods: In this longitudinal prospective study consecutive patients with moderate-severe UC (baseline endoscopic Mayo score (EMS)≥2) starting an anti-inflammatory treatment were included. Clinical scores, biochemical parameters and IUS parameters were collected at baseline, after 2 (T1), 6 (T2) and 8-26 weeks (T3) around time of the second sigmoidoscopy/colonoscopy. IUS parameters were measured as previously established1. Endoscopic remission (ER) and mucosal healing (MH) were evaluated in the sigmoid and defined as EMS=0 and EMS≤1, respectively. The ultrasonographist and endoscopist were blinded for the outcomes of endoscopy and IUS, respectively. Results: 51 consecutive patients were included (Table 1) of whom 31 underwent a second endoscopy (MH: n=15 (45%), ER: n=9 (27%)). Two additional patients underwent colectomy and were considered non-responders. 18 patients did not undergo second endoscopy due to the COVID-19 pandemic (n=2), refusal (n=5), loss to follow-up (n=1) or treatment escalation because of clinical deterioration confirmed by IUS and biomarkers before second endoscopy was performed (n=10). Bowel wall thickness (BWT) was significantly lower from T2 onwards in patients reaching MH (p=0.026) and ER (p=0.002) at T3 (Fig 1). A significant decrease in BWT was already visible at T1 in patients receiving infliximab (p=0.001) or tofacitinib (p=0.007), but not in patients treated with vedolizumab (p=0.11) (Fig 2). Most accurate BWT cut-off values at T3 to determine MH and ER were 3.52 mm (AUROC: 0.95, 95% CI: 0.86-1.00, p<0.0001, sens: 91%, spec: 91%) and 2.98 mm (AUROC: 0.94, 95% CI: 0.85-1.00, p=0.001, sens: 87%, spec: 100%), respectively. Other IUS parameters at T3 did not improve association with MH or ER. IUS parameters at T2 that predict MH and ER are demonstrated in Table 2. Conclusion: BWT and Colour Doppler Signal 6 weeks after start of treatment are associated with and could predict MH and ER. In addition, treatment response patterns at IUS are drug-specific. Furthermore, we have provided accurate BWT cut-off values for endoscopic outcomes. In a point-of-care setting, (early) treatment evaluation with IUS could guide treatment decision in UC in order to optimize treatment response.
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Background: Treatment of perianal fistulizing Crohn's disease (PFCD) is a major unmet need. Filgotinib (FIL) is a once-daily, oral, preferential Janus kinase 1 inhibitor in development for the treatment of inflammatory bowel diseases. The efficacy and safety of FIL for the treatment of PFCD was evaluated in the phase 2, double-blind, randomized, placebo (PBO)-controlled DIVERGENCE 2 study (NCT03077412). Methods: Patients (18-75 years old) with PFCD (documented diagnosis of CD for at least 3 months and 1-3 external openings [EOs] with drainage [spontaneous or on compression] for ≥ 4 weeks before screening) previously treated with antibiotics, immunomodulators and/or tumour necrosis factor inhibitors (TNFi) were randomized (2:2:1) to receive FIL 200 mg, FIL 100 mg or PBO once daily for up to 24 weeks. Active luminal CD was permitted providing that the Crohn's Disease Activity Index score was ≤ 300 at screening. The primary endpoint was combined fistula response (reduction of ≥ 1 from baseline in the number of draining EOs determined by investigator assessment and no fluid collections > 1 cm on centrally read pelvic magnetic resonance imaging [MRI]) at Week 24. Combined fistula remission (closure of all draining EOs present at baseline and no fluid collections > 1 cm) at Week 24 was a key secondary endpoint. The study was not powered for statistical comparisons and was prematurely terminated owing to low recruitment rates during the COVID-19 pandemic. Results: Baseline characteristics were broadly similar across the treatment groups (Table 1). Overall, 91.2% of patients had complex perianal fistulae and TNFi treatment had previously failed in 64.9% of patients. A lower proportion of patients randomized to receive FIL 200 mg discontinued the study compared with those who received PBO (Table 2). The proportion of patients who achieved a combined fistula response at Week 24 was numerically higher in the FIL 200 mg group (47.1%;90% confidence interval [CI]: 26.0-68.9) than in the PBO group (25.0%;90% CI: 7.2-52.7) (Figure 1), with similar results observed for combined fistula remission (FIL 200 mg [47.1%;CI: 26.0-68.9] versus PBO [16.7%;CI: 3.0-43.8]) (Figure 2). Treatment-emergent severe adverse events were highest in the FIL 200 mg group (Table 2). Adverse event rates were otherwise similar across treatment groups. Conclusion: In this phase 2 study, numerically higher fistula response and remission rates were observed after 24 weeks of treatment with FIL 200 mg versus PBO in patients with active PFCD and a history of multiple medical treatment failures. FIL was well tolerated overall. Further studies of FIL for the treatment of PFCD are warranted.
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Background: Based on fMRI studies midcingulate cortex (MCC) has been proposed to have a role in conflict monitoring and response inhibition, or more general in cognitive control [1]. However, it is not known whether this activation predicts real world psychological functioning. Actual stressors like the COVID-19 pandemic and its concomitants can easily generate negative emotions and trigger ruminative thoughts [2]. Frequent or increased ruminative thoughts to an actual naturalistic stressor might reflect deficits in cognitive control function. Thus, the aim of our study was to explore whether the recruitment of MCC when cognitive control is needed, measured before the pandemic, was associated with state and content specific ruminative thoughts during the first wave of pandemic. Methods: In our study 30 healthy subjects (16 female;mean age: 27) participated. They were enrolled in the fMRI study before the Covid-19 pandemic. In the scanner, we used the Emotion-Face Stroop Task [3] in which happy or fear word is overlaid on happy or fearful facial expression resulting congruent or incongruent conditions. In this task participants are instructed to identify the facial expression while ignoring the emotional label on the face, thus participants have to inhibit the prepotent response. Incongruent trials – when there is a mismatch between the facial expression and the label on it – generate emotional interference and requires control to successfully inhibit the prepotent response. We contacted our participants in June 2020 and asked them to fill out questionnaires on trait level rumination and Covid-related ruminative thoughts [2]. Results: In our analysis, we focused on the contrast of incongruent versus congruent trials and used a mask for MCC to test our a-priori hypothesis. We performed a small volume correction (SVC) analysis in Statistical Parameter Mapping using voxel-wise threshold p<0.05, FWE corrected. We found that Covid-related rumination was associated positively with the recruitment of MCC (peak MNI coordinates x/y/z = -6/-1/32;t(1,28) = 5.20, SVC, pFWE = 0.008), implying that those who scored higher on Covid-related ruminative thoughts showed higher involvement of MCC when more effort was needed to exert control over the prepotent response. The results did not change when gender and trait level brooding – the maladaptive component of rumination – were controlled for. Conclusion: Our result is in line with a recent study [4] showing that ruminative thoughts after a stressful task was predicted by cognitive control. Our results might suggest that healthy subjects who have to recruit MCC more to incongruent trials versus congruent one are more vulnerable to stress related (state) ruminative thoughts. Thus, those who need more inhibitory control to inhibit a prepotent response or more responsive to emotional interference might have difficulties in regulating their thoughts or emotions in an enduring stressful situation. Cognitive control trainings targeting inhibitory control over negative emotional information might help those who react to an actual naturalistic stressors with increased rumination, pointing out the need for identifying people who are at risk in times of stress. Conflict of interest Disclosure statement: This study was supported by the Hungarian Brain Research Program (Grants: 2017-1.2.1-NKP-2017-00002 KTIA_NAP_13-2- 2015-0001) and by the Thematic Excellence Programme (Tématerületi Kiválósági Program, 2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary, within the framework of the Neurology and Translational Biotechnology thematic programmes of the Semmelweis University. The preparation of this poster for GK was supported by the Hungarian National Research, Development and Innovation Office (FK128614).