Overall Rate Of Adverse Events Research Articles

Abstract PO4-12-10: Sacituzumab Govitecan Toxicity Outcomes In Arab Patients with Metastatic Breast Cancer

Abstract Background: The Arab population is often underrepresented in clinical trials, which limits our knowledge of drug safety and efficacy in this population due to genetic variability that can affect drug metabolism and adverse events (AEs). Sacituzumab govitecan (SG) is approved for metastatic triple negative breast cancer (mTNBC), and recently hormone receptor positive metastatic breast cancer (HR+ MBC). Here we report toxicity outcomes and RDI in Arab population. Methods: A multi-center retrospective study of patients with mTNBC and HR+ MBC treated with SG from January 2021 until May 2023 was conducted. Demographics and clinical variables including site of metastases, prior lines of therapy, relative dose intensity (RDI), adverse events (AEs) were collected. For continuous variables, Mann-U Whitney and Kruskal Wallis tests were used to compare mean, median, standard deviation, and range. For categorical variables, Fisher's exact tests and Pearson Chi-square tests were used. SAS v9.4 was used to perform statistical analysis at a significance level of 0.05. Results: A total of 35 patients was enrolled. The median age at diagnosis of metastatic breast cancer was 39 years interquartile range (IQR) (35, 44). The median age at starting SG was 44.5 years IQR (38,50). The majority of patients (65%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1, (21%) of the patients had an ECOG PS of 0, and (15%) had an ECOG PS of 2. 48.6% received 3 or more lines of prior therapy in the metastatic setting while 51.4% received less than 3 lines of prior therapy in the metastatic setting. 77.1% of patients had 3 or > organs involved with metastatic disease, while 22.9% of patients had < 3 organ involved. The most common metastatic sites were the lung (54.3%), liver (62.9%), bone (68.6%), and brain (45.7%). The median RDI of SG was 100% for a sample of 34 individuals, with one missing value IQR (94%,100%). The rate of overall AEs was (77.1%), with the most common AEs being; neutropenia (44.4%), diarrhea (37.0%), anemia (22.2%), thrombocytopenia (22.2%), nausea (14.8%), and vomiting (7.4%). Garde 3 AEs rate was 34.3%. The most common grade 3 adverse events were diarrhea (11.4%), fatigue (5.7%), and alopecia (2.9%). The rate of treatment interruption and dose reduction due to AEs was 31.4%. Only one patient (2.9%) had to discontinue SG treatment due to adverse events. Conclusion: The study suggests that SG is safe and well-tolerated in young Arab patient population. The sample consisted of relatively young patients, which may reflect a reluctance to prescribe SG to older Arab patients. Caution should be exercised when generalizing the findings due to limitations of the study. Further studies with larger sample sizes are needed to validate these findings and to explore the efficacy of SG in Arab patients with mTNBC and HR+ MBC. Citation Format: Maymouna Altarturi, Kausar Suleman, Adhar AlSayed, Humaid Al-Shamsi, Aydah Alawadhi, Bassam Basuliamn, Sabah Alaklabi. Sacituzumab Govitecan Toxicity Outcomes In Arab Patients with Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-10.

Patients With Psoriatic Arthritis-Related Enthesitis and Persistence on Tofacitinib Under Real-World Conditions.

Information on the persistence of tofacitinib (TOF) in psoriatic arthritis (PsA) is scarce in real-world conditions. Our objective was to analyze the persistence and safety of TOF under these conditions. This was a single-center retrospective longitudinal observational study of all patients with PsA who received at least 1 dose of TOF. The main focus was on adverse events (AEs) and drug survival. Drug survival was analyzed by Kaplan-Meier curves and persistence explanatory factors by multivariate Cox regression models. The hazard ratio (HR) was used to measure association. Seventy-two patients were included, 54 women and 18 men, mean age 51.9 (SD 11.1) years, mean disease duration of 10.4 (SD 6.99) years. TOF was ≥ third line of therapy in > 70% of cases. The median survival was 13.0 (IQR 5.3-29.0) months. One-year retention rate was 52.7% (95% CI 42.4-65.6). TOF survival was not influenced by sex, disease duration, comorbidities, or line of treatment. Younger patients (HR 0.96, P = 0.01) and those with enthesitis (HR 0.37, P = 0.03) showed lower odds of drug discontinuation. The overall rate of AEs was 52.9 (95% CI 38.5-70.6)/100 person-years. Most AEs occurred during the first 6 months of exposure. In this real-world study, TOF showed a reasonably good retention rate in a PsA population that was mostly refractory to biologic and oral targeted synthetic disease-modifying antirheumatic drugs. There were no new causes for concern regarding safety. Patients with refractory PsA and enthesitis might be a specific target population for this drug.

OP06 Risankizumab Maintenance Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Efficacy and Safety in the Randomised Phase 3 COMMAND Study

Abstract Background Risankizumab (RZB), a monoclonal antibody targeting interleukin-23 p19, was evaluated for maintenance therapy in patients with moderately to severely active ulcerative colitis (UC) and clinical response to RZB intravenous (IV) induction treatment in a phase 3 double-blind, placebo (PBO)-controlled withdrawal (WD) maintenance study, COMMAND (NCT03398135). Methods Patients with moderately to severely active UC who achieved a clinical response per Adapted Mayo score after 12 or 24 weeks (wks) of RZB IV treatment in the phase 2b and phase 3 INSPIRE induction studies (NCT03398148)1 were randomized 1:1:1 in COMMAND to RZB 180 mg (RZB180), 360 mg (RZB360), or PBO (RZB withdrawal) subcutaneous (SC) treatment every 8 wks for 52 wks. The efficacy analysis included responders to 12 wk of RZB IV, while the safety analysis included responders to 12 or 24 wk of RZB IV. The primary endpoint was clinical remission per Adapted Mayo score at wk 52. Key secondary endpoints included endoscopic improvement, HEMI, endoscopic remission, steroid-free clinical remission, maintenance of clinical remission, no bowel urgency, and no abdominal pain at wk 52. Results At baseline of induction, demographics and disease characteristics were similar between treatment groups; 75% of 548 patients had history of inadequate response or intolerance to ≥ 1 advanced therapy (AT). Patients receiving RZB180 (40.2%) and RZB360 (37.6%) achieved significantly higher rates of clinical remission vs WD (25.1%) (adjusted treatment difference vs WD: 16.3% and 14.2%, respectively; P ≤ .01) (Fig. 1A). Greater proportions of patients achieved endoscopic improvement, HEMI, endoscopic remission, steroid-free clinical remission, maintenance of clinical remission, no bowel urgency, and no abdominal pain with RZB180 and RZB360 vs WD (Fig. 1B). The overall rates of adverse events (AEs), and serious infections were similar among treatment groups (Table 1). Serious (presented as events/100 patient-years [E/100 PY]) (RZB180: 5.9; RZB360: 6.3; WD: 11.4) and severe AEs (RZB180: 1.6; RZB360: 4.0; WD: 8.0) were lower in the RZB arms vs WD. No active tuberculosis, adjudicated anaphylaxis, serious hypersensitivity, or adjudicated major adverse cardiovascular events were reported in any treatment group. Conclusion In patients with moderately to severely active UC responding to 12-week RZB induction therapy, RZB maintenance dosing with 180 mg and 360 mg SC was superior to placebo in achieving clinical remission as well as other key clinical, endoscopic, and histological-endoscopic endpoints. RZB was well-tolerated, with no new safety concerns observed.

Prophylactic Lactulose Therapy in Patients with Cirrhosis and Upper Gastrointestinal Bleeding: A Meta-analysis of Randomized Trials.

Lactulose is the first-line drug for both treatment and secondary prophylaxis for overt hepatic encephalopathy (HE). The use of lactulose for the primary prophylaxis of HE in patients with cirrhosis and acute upper gastrointestinal bleeding (AUGIB) has been debated. Hence, we conducted this meta-analysis to assess the role of lactulose in HE prophylaxis in patients with cirrhosis and AUGIB. A comprehensive search of literature from inception to December 2022 was performed of three databases for randomized studies comparing lactulose and placebo in patients with cirrhosis and AUGIB. Risk ratios (RR) with 95% confidence intervals were calculated for all the dichotomous outcomes. A total of five studies were included in the final analysis, out of which three studies had a low risk of bias, and two had a moderate risk of bias. Lactulose therapy was associated with a significantly lower risk of OHE compared to placebo, with a RR of 0.38 (0.23-0.62) and a number needed to treat of 6. There was no difference in the risk of mortality between the groups, with a RR of 0.71 (0.29-1.76). The pooled incidence rates of overall adverse events (AEs) and diarrhea with the use of lactulose therapy were 53.2% (42.2- 64.2) and 34.7% (17.7-51.7), but a majority did not require drug discontinuation. The certainty of the evidence was moderate to low. Prophylactic lactulose reduces the incidence of HE after AUGIB but has no effect on mortality. Diarrhea and abdominal discomfort are common AEs but do not need drug discontinuation.

Safety and Efficacy of Upadacitinib for Atopic Dermatitis in Japan: Analysis of the 3-Year Phase 3 Rising Up Study.

Upadacitinib is an oral Janus kinase inhibitor approved in multiple countries for moderate-to-severe atopic dermatitis (AD). Here we present long-term data for up to 3years of continuous upadacitinib treatment in Japanese patients with AD. Rising Up was a phase 3, randomized, multicenter study in Japan investigating the safety and efficacy of upadacitinib in patients with moderate-to-severe AD. Patients aged 12-75years (weight ≥ 40kg if < 18years) were randomized 1:1:1 to receive upadacitinib 15mg, upadacitinib 30mg, or placebo through week16 (all in combination with topical corticosteroids). At week16, patients who received placebo were rerandomized 1:1 to upadacitinib 15mg or 30mg; topical corticosteroids were optional per investigator discretion from weeks16-160. Safety was assessed by monitoring adverse events (AEs). Efficacy assessments included patients who achieved ≥ 75%/≥ 90% improvement from baseline in Eczema Area and Severity Index (EASI 75/90), clear/almost clear on the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD 0/1), or a ≥ 4-point improvement from baseline in Worst Pruritus Numerical Rating Scale (WP-NRS). Of 272 patients enrolled, 230 completed the study. Through week160, the long-term incidence rate of overall AEs was numerically higher with upadacitinib 30mg than 15mg; rates of serious AEs, AEs considered possibly related to study drug, AEs leading to discontinuation, and AEs of special interest were generally low and similar between dose groups. EASI 75, EASI 90, vIGA-AD 0/1, and WP-NRS response rates were generally greater with upadacitinib 30mg than 15mg and maintained through week160 with either dose. For up to 3years of continuous treatment, upadacitinib was well tolerated in Japanese patients, with a similar safety profile to that of short-term studies and durable long-term response rates for skin clearance and itch improvement. ClinicalTrials.gov identifier, NCT03661138.

Effectiveness and safety of vedolizumab induction with or without budesonide in patients with moderately to severely active Crohn’s disease in Europe: a retrospective observational study

BackgroundVedolizumab (VDZ), a gut-selective anti-lymphocyte trafficking integrin antibody, is effective in treating patients with moderately to severely active Crohn’s disease (CD). In this study, we examined the real-world effectiveness and safety of induction therapy using VDZ alone or in combination with budesonide (VDZ + BUD) among patients with CD in Belgium, Israel, and Switzerland.MethodsThis retrospective chart review analysis included adult patients with moderately to severely active CD who started induction treatment with VDZ or VDZ + BUD (January 2015 through January 2019). The primary objective of this study was to assess the effectiveness in terms of clinical remission of VDZ alone or VDZ + BUD using patient-reported outcomes (PRO) of abdominal pain (AP) and/or loose stool frequency (LSF) (PRO-2) at weeks 0, 2, 6, 10, and 14. Regression models were used to assess differences and associations between the treatment groups.ResultsOverall, 123 patients were included (VDZ, n = 73; VDZ + BUD, n = 50). Clinical remission rates at week 14 were 71.4% (50/70) and 68.0% (34/50) with VDZ and VDZ + BUD, respectively. Mean percentage change in AP and LSF from baseline to week 14 was comparable between the groups. Median (95% confidence interval [CI]) time to clinical remission was 91 [70.0–98.0] and 95 [70.0–98.0] days, respectively. One patient in each group discontinued VDZ and 68.0% of patients in the VDZ + BUD group discontinued BUD before week 14. The rates of overall adverse events were similar between the groups (VDZ, 23.3%; VDZ + BUD, 26.0%).ConclusionsIn this retrospective study, VDZ alone and VDZ + BUD showed similar high remission rates in patients with moderately to severely active CD. Prospective randomized studies are needed to conclude on the role of combining VDZ with BUD.Trial registrationNot applicable.

Efficacy and safety of venetoclax in patients with relapsed/refractory multiple myeloma: a meta-analysis

BackgroundVenetoclax is clinically active in treating relapsed/refractory multiple myeloma (RRMM). This study evaluated the efficacy and safety of venetoclax or venetoclax with other agents in treating RRMM.MethodsPubMed, Web of Science, Embase, and Cochrane Library were comprehensively searched. We included studies investigating the efficacy and safety of venetoclax or venetoclax with other agents in treating RRMM. Overall response rates (ORR), stringent complete response rates (sCR), complete response rates (CR), very good partial response rates (VGPR), partial response rates (PR), stable disease (SD), progressive disease (PD) and adverse events were synthesized using either a random-effects model or a fixed-effects model.ResultsA total of 7 clinical trials with 482 patients with RRMM were included. Concerning venetoclax with other agents, the pooled ORR, sCR, CR, VGPR, PR, SD, and PD were 0.76 (95% CIs: 0.62, 0.87), 0.11 (95% CIs: 0.04, 0.21), 0.18 (95% CIs: 0.11, 0.26), 0.16 (95% CIs: 0.12, 0.25), 0.29 (95% CIs: 0.25, 0.34), 0.07 (95% CIs: 0.05, 0.10), and 0.11 (95% CIs: 0.04, 0.23). The overall rate of adverse events ≥ Grade 3 was 0.84 (95% CIs: 0.77, 0.91). The most common non-hematologic adverse events were nausea, diarrhea, fatigue, back pain, and vomiting; hematologic adverse events included thrombocytopenia, neutropenia, anemia, leukopenia, and lymphopenia.ConclusionsThis study indicates that venetoclax alone or in combination with other agents reveals favorable treatment responses and acceptable adverse events in treating RRMM.

Safety of microneurosurgical interventions for superficial and deep-seated brain metastases: single-center cohort study of 637 consecutive cases

PurposeMicroneurosurgical techniques have greatly improved over the past years due to the introduction of new technology and surgical concepts. To reevaluate the role of micro-neurosurgery in brain metastases (BM) resection in the era of new systemic and local treatment options, its safety profile needs to be reassessed. The aim of this study was to analyze the rate of adverse events (AEs) according to a systematic, comprehensive and reliably reproducible grading system after microneurosurgical BM resection in a large and modern microneurosurgical series with special emphasis on anatomical location.MethodsProspectively collected cases of BM resection between 2013 and 2022 were retrospectively analyzed. Number of AEs, defined as any deviations from the expected postoperative course according to Clavien–Dindo-Grade (CDG) were evaluated. Patient, surgical, and lesion characteristics, including exact anatomic tumor locations, were analyzed using uni- and multivariate logistic regression and survival analysis to identify predictive factors for AEs.ResultsWe identified 664 eligible patients with lung cancer being the most common primary tumor (44%), followed by melanoma (25%) and breast cancer (11%). 29 patients (4%) underwent biopsy only whereas BM were resected in 637 (96%) of cases. The overall rate of AEs was 8% at discharge. However, severe AEs (≥ CDG 3a; requiring surgical intervention under local/general anesthesia or ICU treatment) occurred in only 1.9% (n = 12) of cases with a perioperative mortality of 0.6% (n = 4). Infratentorial tumor location (OR 5.46, 95% 2.31–13.8, p = .001), reoperation (OR 2.31, 95% 1.07–4.81, p = .033) and central region tumor location (OR 3.03, 95% 1.03–8.60) showed to be significant predictors in a multivariate analysis for major AEs (CDG ≥ 2 or new neurological deficits). Neither deep supratentorial nor central region tumors were associated with more major AEs compared to convexity lesions.ConclusionsModern microneurosurgical resection can be considered an excellent option in the management of BM in terms of safety, as the overall rate of major AEs are very rare even in eloquent and deep-seated lesions.

Evaluating Sex Differences in Efficacy, Safety and Pharmacokinetics in Patients Treated with Cannabis by a Metered-Dose Inhaler.

Clinical studies on medical cannabis (MC) treatment have shown sex-related differences, including higher susceptibility to adverse events among women and greater analgesia among men. Here, we used the Syqe metered-dose inhaler (MDI) and a single chemovar to analyze sex differences. A total of 1249 Israeli chronic pain patients were assessed for pain intensity, sleep and adverse events (AEs) over 240 days. Following the first two weeks, no significant sex differences were found in the effectiveness or safety of MC treatment (p > 0.05). Inhaled Δ9-THC doses did not vary significantly between sexes (p > 0.05) except in the first month of treatment. Pain reduction and sleep improvement were similar for both sexes (p > 0.05). The overall rate of AEs was equal and relatively low at 10% (n = 65, 10% of women and n = 60, 10% of men; χ2 (1) = 0.05, p = 0.820). A secondary analysis of pharmacokinetic data showed no significant differences between sexes in Δ9-THC and its metabolite pharmacokinetics, cardiovascular measures, or AE severity (p > 0.05). Uniform MC treatment via the Syqe MDI showed no sex differences in short-term effectiveness, safety and pharmacokinetics, nor in long-term effects, under "real-life" conditions. These findings provide insights into MC treatment which may inform clinical practice and policy-making in the field.

Effect of Delayed Endoscopy Protocol on Timing and Safety of Endoscopy for Foreign Body Ingestion and Esophageal Food Impaction.

Endoscopic procedures for foreign body ingestion (FBI) and esophageal food impactions (EFI) performed during on-call hours are associated with increased stress, risk, and cost. We implemented a Foreign Body Algorithm (FBA) designed to delay all but the most urgent endoscopy for EFI and FBI until regular working hours. Using endoscopy records from multiple academic and community hospitals within a large integrated health system in the United states, we identified esophagogastroduodenoscopy (EGD) performed for food impactions and foreign body ingestions occurring between May 2011 and February 2021. We identified 479 EGDs performed for FBI and EFI. The introduction of the FBA was associated with a shorter length of stay (LOS) for overall cases (0.35 vs. 0.8d P<0.001), day cases (0.16 vs. 1.0d P<0.001), and night cases (0.40 vs. 0.6d P=0.03). The introduction of the FBA did not change the rate of overall adverse events (AE) or night AE. AE from the entire cohort was rare (3%; 16 total). Of the AE, most were sedation related. The introduction of the FBA did not affect the overall rate of night cases or AE, but the rate of after-hours endoscopy for intentional ingestions decreased from 17.2% to 3.1% (P=0.01). This is one of the largest studies of esophageal impactions and foreign bodies in adults in the United States, and the first to examine the effects of a protocol designed to avoid after-hours endoscopy. These results suggest that postponing after-hours EGD until the daytime is not associated with adverse safety outcomes or increased LOS.

Chronic Limb-Threatening Ischemia Is Associated With Higher Mortality and Limb Revascularization After Transcatheter Aortic Valve Replacement

Peripheral arterial disease (PAD) is common in patients with symptomatic aortic stenosis. PAD exists as a spectrum, and patients with chronic limb-threatening ischemia (CLTI), the most severe form of PAD, are at high risk for limb loss and death. We seek to determine patient characteristics and clinical outcomes among patients who underwent TAVR with or without CLTI. We identified all hospitalizations for TAVR from October 2015 to December 2018 using the National Inpatient Sample database. Patients with any diagnosis of CLTI were identified using the International Classification of Diseases 10th Revision codes. The primary outcome was in-hospital mortality, and secondary outcomes were major complications, open revascularization, and endovascular revascularization after TAVR. During the study period, a total of 31,335 hospitalizations for TAVR procedures were included, including 7,048 (22.5%) in patients with CLTI. CLTI was associated with higher in-hospital mortality (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.13 to 1.74, p=0.002) and major complications (OR 1.2, 95% CI 1.09 to 1.25, p <0.001). CLTI was also associated with a significantly higher rate of open limb revascularization (OR 5.1, 95% CI 3.94 to 6.48, p <0.001) and endovascular revascularization (OR 4.0, 95% CI 3.54 to 4.59, p <0.001). CLTI among patients who underwent TAVR is associated with higher in-hospital mortality, major complications, and longer lengths of stay compared with patients without CLTI. However, the overall rates of adverse events remain low. Further studies are needed to optimize the multidisciplinary care of these patients before TAVR with a focus on shared decision-making.

Drug-eluting beads bronchial arterial chemoembolization/bronchial arterial infusion chemotherapy with and without PD-1 blockade for advanced non-small cell lung cancer: a comparative single-center cohort study.

Drug-eluting beads bronchial arterial chemoembolization (DEB-BACE)/bronchial artery infusion chemotherapy (BAI) have been investigated as treatment options for advanced non-small cell lung cancer (NSCLC), especially for those patients who develop refractoriness to or are intolerant to systemic chemotherapy. This retrospective study aimed to compare the outcomes of DEB-BACE/BAI with and without programmed cell death protein 1 (PD-1) blockade for advanced NSCLC, and to investigate the effectiveness and safety of combination regimens. This retrospective cohort study included advanced NSCLC patients who were intolerant to or were resistant to systemic chemotherapy, radiotherapy, or molecular targeted therapy and underwent DEB-BACE/BAI between October 2016 and October 2021 in Beijing Hospital, National Center of Gerontology. A total of 84 advanced NSCLC patients (DEB-BACE/BAI + PD-1 blockade group: group A, n=27; DEB-BACE/BAI: group B, n=57) were enrolled finally. The embolic agent CalliSpheres (100-300, 300-500, or 500-700 µm) loaded with gemcitabine (800 mg) was administered during the DEB-BACE procedure. The adverse events (AEs) and outcomes were compared. Of these, the median progression-free survival (PFS) and overall survival (OS) were compared via Kaplan-Meier (KM) methods. Univariate and multivariate Cox regression analyses were used to investigate the predictors of PFS and OS. KM methods showed that group A had longer median PFS (12.0 vs. 3.0 months, P<0.001) and OS (27.0 vs. 8.0 months, P<0.001) than group B. The predictors of PFS for DEB-BACE/BAI included tumor diameter (P=0.013), immunotherapy (P<0.001), and DEB-BACE/BAI cycles (P=0.012), whereas the predictors of OS included tumor diameter (P=0.021), extrapulmonary metastases (P=0.041), immunotherapy (P<0.001), and DEB-BACE/BAI cycles (P=0.020). The incidence rates of overall AEs in groups A and B were 40.7% (11/27) and 36.8% (21/57), respectively, and no significant difference was found (P=0.731). Group A had an incidence rate of 11.1% for grade 3 immunotherapy-related AEs (irAEs). There were no incidences of ectopic embolization or spinal artery injury. Compared with DEB-BACE/BAI, PD-1 blockade plus DEB-BACE/BAI could improve the prognosis for advanced NSCLC despite the associated risk of grade 3 irAEs. The combination regimens are promising and safe approaches for advanced NSCLC.

Single-Dose Psilocybin Treatment for Major Depressive Disorder

Psilocybin shows promise as a treatment for major depressive disorder (MDD). To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD. In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing. Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support. The primary outcome was change in central rater-assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment. A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,-12.3 [95% CI, -17.5 to -7.2]; P <.001) and from baseline to day 8 (mean difference, -12.0 [95% CI, -16.6 to -7.4]; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, -2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs. Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin-when administered with psychological support-may hold promise as a novel intervention for MDD. ClinicalTrials.gov Identifier: NCT03866174.

Endoscopic ultrasound-rendezvous versus percutaneous-endoscopic rendezvous endoscopic retrograde cholangiopancreatography for bile duct access: Systematic review and meta-analysis.

Endoscopic ultrasound (EUS) or percutaneous-assisted antegrade guidewire insertion can be used to achieve biliary access when standard endoscopic retrograde cholangiopancreatography (ERCP) fails. We conducted a systematic review and meta-analysis to evaluate and compare the effectiveness and safety of EUS-assisted rendezvous (EUS-RV) and percutaneous rendezvous (PERC-RV) ERCP. We searched multiple databases from inception to September 2022 to identify studies reporting on EUS-RV and PERC-RV in failed ERCP. A random-effects model was used to summarize the pooled rates of technical success and adverse events with 95% confidence interval (CI). In total, 524 patients (19 studies) and 591 patients (12 studies) were managed by EUS-RV and PERC-RV, respectively. The pooled technical successes were 88.7% (95% CI 84.6-92.8%, I2 = 70.5%) for EUS-RV and 94.1% (95% CI 91.1-97.1%, I2 = 59.2%) for PERC-RV (P = 0.088). The technical success rates of EUS-RV and PERC-RV were comparable in subgroups of benign diseases (89.2% vs. 95.8%, P = 0.068), malignant diseases (90.3% vs. 95.5%, P = 0.193), and normal anatomy (90.7% vs. 95.9%, P = 0.240). However, patients with surgically altered anatomy had poorer technical success after EUS-RV than after PERC-RV (58.7% vs. 93.1%, P = 0.036). The pooled rates of overall adverse events were 9.8% for EUS-RV and 13.4% for PERC-RV (P = 0.686). Both EUS-RV and PERC-RV have exhibited high technical success rates. When standard ERCP fails, EUS-RV and PERC-RV are comparably effective rescue techniques if adequate expertise and facilities are feasible. However, in patients with surgically altered anatomy, PERC-RV might be the preferred choice over EUS-RV because of its higher technical success rate.

E088 Safety of guselkumab in patients with psoriatic disease: an integrated analysis of 11 Phase 2 and 3 clinical studies in psoriasis and psoriatic arthritis

Abstract Background/Aims Guselkumab is a monoclonal antibody approved to treat moderate-to-severe plaque psoriasis and active psoriatic arthritis (PsA). In this analysis, safety data from 11 Phase 2/3 studies of guselkumab were pooled to evaluate guselkumab safety in a large population of patients with psoriatic disease. Methods Guselkumab was generally administered as 100-mg injections at Week (W)0, W4, then Q8W in 7 psoriasis studies and at W0, W4, then Q4W or Q8W in 4 PsA studies. Patients randomized to placebo crossed over to guselkumab Q8W at W16 in 5 PsO studies and to guselkumab Q4W or Q8W at W24 in all PsA studies. Safety data were summarized for the placebo-controlled period (W0-W16 in PsO; W0-W24 in PsA) and through the end of the reporting period (up to 5 years in PsO; up to 2 years in PsA). Incidence rates of key safety events were integrated post-hoc, adjusted for duration of follow-up, and reported per 100 patient-years (PY). Results During the placebo-controlled periods, 1061 patients received placebo (395 PY) and 2257 received guselkumab (856 PY). Through the long-term reporting periods, 4399 guselkumab-treated patients (PsO: 2891; PsA: 1508) contributed 10787 PY of follow-up (PsO: 8662 PY; PsA: 2125 PY). In PsO and PsA studies, pooled incidence rates of overall adverse events (AEs) were similar between guselkumab- and placebo-treated patients. Rates of serious AEs, AEs leading to discontinuation, serious infections, malignancy, and major adverse cardiovascular events were low and generally similar between guselkumab- and placebo-treated patients. Rates of safety events remained consistent through the long-term reporting period for guselkumab-treated patients (Table). No cases of Crohn’s disease or ulcerative colitis were reported in guselkumab-treated patients. No serum sickness-like or anaphylactic reactions related to guselkumab were reported. No opportunistic infections were reported in any guselkumab-treated PsO patient. Three cases of opportunistic infection were reported in pooled PsA studies (0.14/100 PY; all post-W52 in DISCOVER-2). No cases of active tuberculosis were reported across all studies. Conclusion In the most comprehensive analysis of guselkumab safety to date, AE rates in guselkumab-treated patients were similar to those observed with placebo and were stable throughout long-term follow-up. Disclosure B. Strober: Grants/research support; AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Eli Lilly, Meiji Seika Pharma, Novartis, Pfizer, UCB Pharma, Sun Pharma, Regeneron, Dermira, Leo Pharma, Inc, Arcutis, Are. L. Coates: Grants/research support; AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer, and UCB; grant/research support from AbbVie, Amgen, Celgene, Eli Lilly, Jan. J. Yu: Shareholder/stock ownership; Janssen Research &amp; Development, LLC, Johnson &amp; Johnson. K. Rowland: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson &amp; Johnson; E. Leibowitz, Janssen Scientific Affairs, LLC, Johnson &amp; Johnson. E. Leibowitz: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson &amp; Johnson; E. Leibowitz, Janssen Scientific Affairs, LLC, Johnson &amp; Johnson. M. Miller: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson &amp; Johnson; E. Leibowitz, Janssen Scientific Affairs, LLC, Johnson &amp; Johnson. A. Kollmeier: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson &amp; Johnson; E. Leibowitz, Janssen Scientific Affairs, LLC, Johnson &amp; Johnson. S. Li: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson &amp; Johnson; E. Leibowitz, Janssen Scientific Affairs, LLC, Johnson &amp; Johnson. Y. Wang: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson &amp; Johnson; E. Leibowitz, Janssen Scientific Affairs, LLC, Johnson &amp; Johnson. D. Chan: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson &amp; Johnson. S. Chakravarty: Shareholder/stock ownership; Janssen Scientific Affairs, LLC, Johnson &amp; Johnson; Y. Yang, Janssen Pharmaceutical Companies, Johnson &amp; Johnson. Y. Yang: Shareholder/stock ownership; Janssen Pharmaceutical Companies, Johnson &amp; Johnson. M. Shawi: Shareholder/stock ownership; Janssen Pharmaceutical Companies of Johnson and Johnson. M. Lebwohl: Grants/research support; Arcutis, Boehringer Ingelheim, Bristol Myers Squibb, Verrica, AbbVie, Amgen, Eli Lilly, Janssen, Ortho Dermatologics, Pfizer, UCB Pharma, Avotres Therapeutics, AnaptysBio, Aristea Therapeutics, BioMX, Cara Therapeutics, Castle Biosciences, Dermavant, Evommune, Facilitatation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Hexima, Meiji Seika Pharma, Mindera Health, Regeneron, Seanergy, Incyte, Arrive Technologies, Dr Reddy's Laboratories, Evelo Biosciences, Helsinn Therapeutics, LEO Pharma, Mount Sinai, CorEvitas (formerly Cor. P. Rahman: Shareholder/stock ownership; Janssen, Novartis, AbbVie, Eli Lilly and Company, Pfizer.

Safety and Durability of Accelerated Infliximab Dosing Strategies in Pediatric IBD: A Single Center, Retrospective Study.

Infliximab (IFX) is commonly used to treat children with inflammatory bowel disease (IBD). We previously reported that patients with extensive disease started on IFX at a dose of 10 mg/kg had greater treatment durability at year one. The aim of this follow-up study is to assess the long-term safety and durability of this dosing strategy in pediatric IBD. We performed a retrospective single-center study of pediatric IBD patients started on IFX over a 10-year period. Two hundred ninety-one patients were included (mean age = 12.61, 38% female) with a follow-up range of 0.1-9.7 years from IFX induction. One hundred fifty-five (53%) were started at a dose of 10 mg/kg. Only 35 patients (12%) discontinued IFX. The median duration of treatment was 2.9 years. Patients with ulcerative colitis ( P ≤ 0.01) and patients with extensive disease ( P = 0.01) had lower durability, despite a higher starting dose of IFX ( P = 0.03). Adverse events (AEs) were observed to occur at a rate of 234 per 1000 patient-years. Patients with a higher serum IFX trough level (≥20 µg/mL) had a higher rate of AEs ( P = 0.01). Use of combination therapy had no impact on risk of AEs ( P = 0.78). We observed an excellent IFX treatment durability, with only 12% of patients discontinuing therapy over the observed timeframe. The overall rate of AEs was low, the majority being infusion reactions and dermatologic conditions. Higher IFX dose and serum trough level> 20 µg/mL were associated with higher risk of AEs, the majority being mild and not resulting in cessation of therapy.

Systematic review and meta-analysis of randomized control trials addressing efficacy and safety of desmopressin for females with nocturia

Aim:To conduct a systematic review and meta-analysis of all randomized placebo-controlled trials (RCTs) that evaluated the efficacy and safety of desmopressin versus placebo among females with nocturia. Methods:PubMed, Scopus, Web of Science, CENTRAL, and Google Scholar databases were searched from inception until 15-November-2022. The included studies were evaluated for risk of bias (Cochrane Tool). The endpoints were summarized as mean difference (MD) or risk ratio (RR) with 95% confidence interval (CI). Subgroup analysis based on the dose of desmopressin ( ≤50μg and >50μg) was conducted. In addition, meta-regression was performed to examine the impact of age and body mass index (BMI) on the endpoints. Results:Nine RCTs with 2852 patients (desmopressin=1110, placebo=1742) were analyzed. The overall risk of bias was low. Compared with placebo, desmopressin significantly reduced the mean number of nocturnal voids (MD=-0.51, 95% CI [-0.70, -0.31], p<0.001), prolonged the duration of the first sleep period (MD=69.06 min, 95% CI [46.54, 91.59], p<0.001), and increased the 33% responder rate (RR=1.30, 95% CI [1.13, 1.50], p<0.001). Subgroup analyses according to desmopressin dose ( ≤50μg and >50μg) showed similar significant differences compared with placebo. Meta-regression showed less improvement in the number of nocturnal voids with the increased age and BMI. There was no significant difference between both groups regarding the rate of overall adverse events (RR=1.11, 95% [0.94, 1.32], p=0.22). Conclusion:Desmopressin was safe and effective in improving nocturia among females. Higher dose of desmopressin (>50μg) correlated with better efficacy. Age and BMI impacted the mean number of nocturnal voids.

Current situation and risk factors for Helicobacter pylori eradication failure in Northwest China: a real-world evidence study.

Current situation and risk factors for Helicobacter pylori eradication failure in Northwest China: a real-world evidence study.

Medication-Attributable Adverse Events in Heart Failure Trials

BackgroundInitiation and up-titration of guideline-directed medical therapies (GDMTs) for heart failure with reduced ejection fraction (HFrEF) remains suboptimal, in part because of concerns regarding tolerability and adverse events (AEs). ObjectivesThe authors sought to compare rates of AE in patients randomized to GDMT medication vs placebo in a meta-analysis of landmark cardiovascular outcomes trials. MethodsThe authors assessed rates of reported AE in 17 landmark HFrEF clinical trials across each class of GDMT in the placebo and intervention arms. The overall rates of AE for each drug class, the absolute difference in frequency in AEs between the placebo and intervention arms, and the odds of each AE according based on randomization strata were calculated. ResultsAE were reported commonly in trials across each class of GDMT, with 75% to 85% of participants reporting at least 1 AE. There was no significant difference in the frequency of AE between the intervention and placebo arms, except for angiotensin-converting enzyme inhibitors (87.0% [95% CI: 85.0%-88.8%] vs 82.0% [95% CI: 79.8%-84.0%], absolute difference: +5% with intervention; P < 0.001). There was no significant difference in drug discontinuation because of AE between placebo and intervention arms in angiotensin-converting enzyme inhibitors, mineralocorticoid receptor antagonists, sodium glucose cotransporter 2 inhibitors, or angiotensin receptor neprilysin inhibitor/angiotensin II receptor blocker trials. Patients randomized to beta-blocker were significantly less likely to stop study drug because of AE than placebo (11.3% [95% CI: 10.3%-12.3%] vs 13.7% [95% CI: 12.5%-14.9%], absolute difference: −1.1%; P = 0.015). When individual types of AE were assessed, the initiation of an intervention vs placebo resulted in small differences in absolute frequency of AE that were largely not statistically significant. ConclusionsIn clinical trials of GDMT for HFrEF, AEs are observed frequently. However, rates of AE are similar between active medication and control, suggesting these may reflect the high risk nature of the heart failure disease state rather than be attributive to a specific therapy.

P560 Curcumin-QingDai combination for patients with active ulcerative colitis: A randomized double-blinded placebo-controlled trial

Abstract Background The herbal extracts Curcumin and QingDai (QD, Indigo) were previously shown to be effective in mild-moderate and in moderate-severe ulcerative colitis (UC), respectively. We evaluated the efficacy and safety of a combination of curcumin-QingDai (CurQD) in patients with active UC. Methods This was a two parts trial. Part 1 was an open label study of 4 weeks CurQD in patients with active UC, defined by a Simple Clinical Colitis Activity Index (SCCAI) score ≥5 and a modified Mayo endoscopic sub-score≥2. Part 2 was a placebo-controlled trial conducted in two centers in Israel and Greece, that randomized active UC patients at a 2:1 ratio to either enteric-coated CurQD 3gr/day or an identical placebo for eight weeks. The co-primary outcome at week 8 was clinical response (reduction in SCCAI of ≥3 points) and an objective evidence of response (Mayo endoscopic subscore improvement of ≥1 or 50% calprotectin reduction from baseline). Responding patients continued either curcumin or placebo alone for additional 8 weeks as maintenance treatment. Expression of Cyp1A1 in rectal mucosa was assessed as a measure of aryl-hydrocarbon receptor (AhR) pathway activation. Curcumin purity, and indigo and indirubin content in CurQD were confirmed by LC-MS/MS. Results There were 59 patients enrolled in the two study parts. In efficacy analysis of part 1, 7/10 responded including 3/10 who achieved clinical remission. For part 2, 95 patients were screened and 42 were included and randomized (48.8% biologics and/or immuno-modulators experienced, 36.6% biologics-experienced). The co-primary outcome was achieved in 43% and 8% of CurQD and placebo patients, respectively (p=0.033). Clinical response was observed in 85.7% versus 30.7% (p&amp;lt;0.001), 50% calprotectin-reduction in 46.4% versus 15.4% (p=0.08) and endoscopic improvement in 75% versus 20% (p=0.036), in the CurQD and placebo groups, respectively. The overall rate of adverse events was comparable between the groups. Among week-8 responders to CurQD, additional 8 weeks of treatment with curcumin alone resulted in 93%, 80% and 40% with maintained clinical response, clinical remission and clinical-biomarker response, respectively, at week 16. CurQD treatment uniquely resulted in activation of the AhR pathway, as gauged by a signficantly up-regulated expression of CYP1A1 in the rectal mucosa, which was not observed among patients receiving placebo, 5ASA or biologic drugs. Conclusion In this randomized controlled trial, combination CurQD was found to be effective for inducing remission in active UC patients. Induction of AhR may merit further study as a potential treatment target in active UC