Onset Of Adverse Events Research Articles

Evaluating corticosteroid treatment strategies for cardiac sarcoidosis: analysis of the nationwide claims-based JROAD-DPC dataset

Abstract Background Corticosteroid-based immunosuppressive therapy is the cornerstone of treatment for cardiac sarcoidosis (CS), aimed at preventing severe adverse events including death, heart failure and lethal arrhythmic events. Nevertheless, data on the optimal initial dosing, appropriate tapering schedules, suitable maintenance dosages, and the recurrence rates among patients are insufficient. Purpose This study sought to scrutinize real-world data on corticosteroid therapy regimen for CS and to reassess optimal treatment protocols. Methods From the Japanese Diagnosis Procedure Combination database, 6,282 patients with hospitalized CS were identified between 2012 and 2022. Among them, 3,067 CS patients who were initiated on corticosteroid therapy during hospitalization were analyzed. We examined the baseline patient characteristics and treatment strategies for corticosteroid therapy, including starting dose, tapering period, maintenance dose, and their correlation with the onset of adverse events. Results The cohort had a mean age was 63±11 years, and 1,256 patients (41.0 %) were female. The starting dose of corticosteroids was 30.3±6.9 mg, with 88.6% of patients receiving a dose of ≧30 mg/day. The doses of corticosteroids at 30, 60, 90, 120, 150 and 180 days post-discharge were 21.4±9.8, 15.7±6.9, 12.2±5.7, 10.4±5.0, 9.3±4.5 and 9.0±4.6 mg, respectively. By day 180, 83.7% of the patients were maintained on ≦10 mg/day. However, 17.1 % of patients required an increase in corticosteroid dosage during the tapering course, primarily due to exacerbation of sarcoidosis. When analyzing only the group without corticosteroid escalation up to 180 days post-discharge, the average corticosteroid dose was 8.7±3.8 mg, with 95.3% of patients on ≦10 mg/day. We observed 965 re-hospitalization (31.5 %) during follow-up, with 58.8% of these patients having corticosteroid escalation to ≧30 mg, and 12.8% of patients received second-line immunosuppressive therapy, such as methotrexate. Conclusion The majority of CS patients were initiated on a corticosteroid regimen of 30 mg/day, which was subsequently tapered to below 10 mg/day by day 180. However, non-negligible number of patients experienced clinical events or relapse, underscoring the necessity for vigilant follow-up during corticosteroid therapy.Figure

Adverse events associated with tezepelumab: a safety analysis of clinical trials and a pharmacovigilance system

ABSTRACT Background Tezepelumab is the first asthma biologic approved by the FDA that is not restricted by biomarker phenotypes. To date, there have been no studies reporting adverse events (AEs) associated with the real-world use of tezepelumab. Research design and methods This study included a comprehensive evaluation of AE reports related to tezepelumab since its approval (4th quarter of 2021 to 1st quarter of 2024) using the FAERS database, and compared with the currently reported clinical trial results (ClinicalTrials.gov). Results A total of 2153 reports of tezepelumab-related AEs were extracted. 256 preferred terms (PTs) of adverse reactions involving 27 system organ classes were identified. Significant AEs that were not reported on the drug label, such as ‘dyspnea,’ ‘body temperature,’ and ‘tongue pruritus,’ were reported. The median time to onset (TTO) of tezepelumab-related AEs was 35 days.The most frequent AEs in different sexes were ‘arthralgia’ and ‘dyspnea,’ with differences in signal strength ranking between the sexes. Conclusions This study represents the largest report to date on tezepelumab-related AEs, providing valuable insights into the potential side effects of tezepelumab. This work is crucial for the broader clinical application of this novel biologic and improving outcomes for patients with severe asthma.

Real-world safety profile of zanubrutinib: a disproportionality analysis based on the FAERS database

ObjectiveZanubrutinib is a second-generation Bruton’s tyrosine kinase inhibitor that has been approved for the treatment of several B cell malignancies. The aim of this study was to evaluate adverse events...

Exposure–response relationships of mirvetuximab soravtansine in patients with folate receptor‐α‐positive ovarian cancer: Justification of therapeutic dose regimen

AimsThis study aimed to investigate exposure–response (ER) relationships in efficacy and safety for mirvetuximab soravtansine (MIRV) which is a first‐in‐class antibody–drug conjugate approved for the treatment of folate receptor‐α‐positive platinum‐resistant ovarian cancer.MethodsMIRV was characterized in 4 clinical studies. Exposure metrics for MIRV, its payload and a metabolite were derived from a population pharmacokinetic model. Efficacy was analysed in MIRV‐treated patients (n = 215) in a recent confirmatory, randomized, chemotherapy‐controlled MIRASOL trial and safety was evaluated in patients pooled across all 4 clinical studies (n = 757).ResultsIn the MIRASOL trial (NCT04209855), MIRV demonstrated significant benefit over chemotherapy in progression‐free survival (PFS), objective response rate (ORR) and overall survival (OS). The most common adverse events (AEs) included ocular disorders, peripheral neuropathy and pneumonitis. For PFS, ORR and OS, the trough concentration of MIRV was the predictor consistently found in ER models for efficacy. In contrast, for ocular AEs (as well as the time to onset of ocular AEs) and peripheral neuropathy, the area under the concentration–time curve (AUC) of MIRV was identified as the exposure metric in ER models for safety. No exposure parameters were found to correlate with pneumonitis. Covariates in all models did not show clinically meaningful impact on efficacy or safety. Logistic regression models for ORR and ocular AEs based on AUC of MIRV were used to justify the clinical dose regimen approved for MIRV.ConclusionThe trough concentration of MIRV correlated with efficacy whereas the AUC of MIRV was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.

Safety assessment of anti-B cell maturation antigen chimeric antigen receptor T cell therapy: a real-world study based on the FDA adverse event reporting system database.

On April 18, 2024, the U.S. Food and Drug Administration officially required updating of the "boxed warning" for T cell malignancies for all chimeric antigen receptor T cell (CAR-T) therapies. Given the clinical significance of these therapies, a rigorous safety assessment is paramount. However, comprehensive real-world safety studies have been lacking for the newly marketed CAR-T products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which target B cell maturation antigen, especially regarding the risk of secondary malignancies. Therefore, we aimed to thoroughly analyze the adverse events (AEs) information in the FDA Adverse Event Reporting System (FAERS) database to comprehensively understand the safety risks of ide-cel and cilta-cel. We extracted AE reports related to ide-cel and cilta-cel from the FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.) from January 1, 2019 to December 31, 2023. Disproportionality analysis and Bayesian analysis were used to identify risk signals across subgroups and specific cases (including for death and secondary malignancies). Weibull distribution analysis was employed to determine the time to AE onset. A total of 695 AE reports for ide-cel and 848 for cilta-cel were included in the FAERS database. This analysis identified 81 positive signals for ide-cel and 74 for cilta-cel. Notably, comparisons with the drug labels revealed "unexpected signals," including febrile bone marrow aplasia (reporting odds ratio=69.10; confidence interval 39.12-122.03) and plasma cell myeloma (12.45; 8.18-18.95) for ide-cel, and increased serum ferritin (24.98; 8.0-77.58) and large intestine perforation (18.57; 5.98-57.69) for cilta-cel. Both drugs showed a higher AE incidence among male recipients and patients aged ≥65 years, although female recipients faced a greater risk. Most AEs occurred at the early stage of administration. However, secondary malignancies were detected for both drugs, primarily occurring one-year post-administration. This study provides a foundation for understanding the safety profile of CAR-T cell therapy, particularly in relation to the emergence of secondary malignancies. Such insights are helpful for clinical decision-making and the safe and effective utilization of these therapeutic agents.

A disproportionality analysis of sunitinib in the FDA adverse event reporting system (FAERS)

ObjectiveThis study aimed to analyze the FAERS database to identify adverse event associated with sunitinib to offer valuable insights for the judicious utilization of medication in clinical settings. MethodsVarious disproportionality analysis techniques, such as the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPN), and multi-gamma Poisson shrinkage (MGPS), were employed to analyze adverse drug reaction (ADR) reports pertaining to sunitinib in the FAERS database from its market introduction up to the first quarter of 2023. Subsequently, a secondary screening process was conducted to identify reliable positive signals. ResultsThe analysis of sunitinib adverse event signals at the system-organ classification level encompassed 27 organ systems, with gastrointestinal and endocrine disorders emerging as the predominant SOCs. A total of 237 significant adverse events meeting all four algorithms were detected. Notably, this study revealed previously unreported adverse events, including pleural effusion and ascites, while potential adrenal toxicity-related adverse events, highlighted in the drug's specification, were not identified in this analysis. The study examined the relationship between the duration of sunitinib dosing and the onset of adverse events, revealing a median onset of 48 days (IQR, 15–160 days). The findings indicated that a majority of adverse events manifested early in the dosing period, with tumor progression, disease progression, and mortality becoming more prevalent after one year of treatment. ConclusionIn the clinical utilization of sunitinib, vigilant monitoring of potential adverse reactions is imperative during the initial phase of drug administration. In addition to the documented adverse reactions outlined in the drug specification, healthcare providers should remain attentive to potential adverse reactions such as pleural effusion, ascites, and tumor development.

A targetable type III immune response with increase of IL-17A expressing CD4+ T cells is associated with immunotherapy-induced toxicity in melanoma.

Immune checkpoint inhibitors are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events. Proteomic analyses and multiplex cytokine and chemokine assays from serum at baseline and at the adverse event onset indicated aberrant T cell activity with differential expression of type I and III immune signatures. This was in line with the finding of an increase in the proportion of CD4+ T cells with IL-17A expression at the adverse event onset in the peripheral blood using flow cytometry. Multiplex immunohistochemistry and spatial transcriptomics on immunotherapy-induced skin rash and colitis showed an increase in the proportion of CD4+ T cells with IL-17A expression. Anti-IL-17A was administered in two patients with mild myocarditis, colitis and skin rash with resolution of the adverse events. This study highlights the potential role of type III CD4+ T cells in adverse event development and provides proof-of-principle evidence for a clinical trial using anti-IL-17A for treating adverse events.

Post-marketing safety of finerenone: a disproportionality analysis of the FDA adverse event reporting system

ABSTRACT Background Finerenone was approved for the treatment of type 2 diabetes patients with chronic kidney disease. However, the post-marketing safety of finerenone in the real world is unknown. Methods The quarterly reported data related to finerenone from the third quarter of 2021 to the second quarter of 2023 were collected by using the FAERS database. Two disproportionality analysis methods were estimated by using Reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN). Results A total of 1067 adverse events (AEs) were included. Twenty-four kinds of system organ classes (SOCs) were classified for the organs and systems involved and 39 AEs with significant safety signals were identified using ROR and BCPNN at the preferred terms (PTs) level. Most AEs originated from the United States, and the median time to onset of AEs was 13 days. Three hundred and fifty-one (55.5%) reported serious outcome. The proportion of medication combinations was 29.0%. The most commonly reported AEs were the glomerular filtration rate decreased. Safety signals have also been observed in new and unexpected AEs. Conclusion The analysis of the AE signals may contribute to minimizing the risks associated with its use.

Post-marketing safety surveillance of fostamatinib: an observational, pharmacovigilance study leveraging FAERS database

ABSTRACT Objective Fostamatinib, an FDA-approved oral small-molecule spleen tyrosine kinase (SYK) inhibitor, is used to treat thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have not responded to previous treatments. However, comprehensive safety data is lacking. This study uses the FDA Adverse Event Reporting System (FAERS) database to explore real-world adverse events (AEs) related to fostamatinib, aiming to inform its clinical use. Methods The FAERS database was retrospectively queried to extract reports associated with fostamatinib from 2019 to 2023. To identify and evaluate potential AEs in patients receiving fostamatinib, various disproportionality analyses such as the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed. Results A total of 23 AE signals were included in our analysis. Among them, hypertension, blood pressure increase, blood pressure abnormality, hepatic enzyme increase, and diarrhea were consistent with the common AEs described for fostamatinib in clinical trials. In addition, unexpected serious AEs were detected including cerebral thrombosis and necrotizing soft tissue infection. The median time to onset of fostamatinib-related AEs was 86 days. Conclusion Our investigation revealed several possibly emergent safety concerns associated with fostamatinib in real-world clinical practice, which might provide essential vigilance evidence for clinicians and pharmacists to manage the safety issues of fostamatinib.

Adverse event profile of memantine and donepezil combination therapy: a real-world pharmacovigilance analysis based on FDA adverse event reporting system (FAERS) data from 2004 to 2023.

Donepezil in combination with memantine is a widely used clinical therapy for moderate to severe dementia. However, real-world population data on the long-term safety of donepezil in combination with memantine are incomplete and variable. Therefore, the aim of this study was to analyze the adverse events (AEs) of donepezil in combination with memantine according to US Food and Drug Administration Adverse Event Reporting System (FAERS) data to provide evidence for the safety monitoring of this therapy. We retrospectively analyzed reports of AEs associated with the combination of donepezil and memantine from 2004 to 2023 extracted from the FAERS database. Whether there was a significant association between donepezil and memantine combination therapy and AEs was assessed using four disproportionality analysis methods, namely, the reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker methods. To further investigate potential safety issues, we also analyzed differences and similarities in the time of onset and incidence of AEs stratified by sex and differences and similarities in the incidence of AEs stratified by age. Of the 2,400 adverse drug reaction (ADR) reports in which the combination of donepezil and memantine was the primary suspected drug, most of the affected patients were female (54.96%) and older than 65years of age (79.08%). We identified 22 different system organ classes covering 100 AEs, including some common AEs such as dizziness and electrocardiogram PR prolongation; fall, pleurothotonus and myoclonus were AEs that were not listed on the drug label. Moreover, we obtained 88 reports of AEs in men and 100 reports of AEs in women; somnolence was a common AE in both men and women and was more common in women, whereas pleurothotonus was a more common AE in men. In addition, we analyzed 12 AEs in patients younger than 18years, 16 in patients between 18 and 65years, and 113 in patients older than 65years. The three age groups had distinctive AEs, but lethargy was the common AE among all age groups. Finally, the median time to AE onset was 19days in all cases. In both men and women, most AEs occurred within a month of starting donepezil plus memantine, but some continued after a year of treatment. Our study identified potential and new AEs of donepezil in combination with memantine; some of these AEs were the same as in the specification, and some of the AE signals were not shown in the specification. In addition, there were sex and age differences in some of the AEs. Therefore, our findings may provide valuable insights for further studies on the safety of donepezil and memantine combination therapy, which are expected to contribute to the safe use of this therapy in clinical practice.

Post-marketing safety of lorlatinib: a real-world study based on the FDA adverse event reporting system.

Lorlatinib displays marked systemic and intracranial efficacy against anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC). We aimed to establish the safety profile of lorlatinib based on the Food and Drug Administration Adverse Event Reporting System (FAERS). Reports from the FAERS between 2019 and 2023 were collected to conduct the disproportionality analysis. Reporting odds ratio (ROR) was employed to detect the potential adverse events (AEs) related to lorlatinib. The clinical characteristics, age and gender differences, time to onset of AEs were also investigated. A total of 2,941 AE reports were found to be associated with lorlatinib among the 8,818,870 AE reports obtained from the FAERS database. 167 lorlatinib-related AE signals were identified. The frequently reported AEs including hypercholesterolemia, oedema, and cognitive disorder were in line with those observed in clinical trials and drug instruction. However, AEs such as interstitial lung disease and AV block indicated in the drug label require further evaluation. More attention should be paid to the new potential unexpected AEs including pulmonary arterial hypertension and radiation necrosis. Furthermore, we examined the specific high-risk AEs of different ages and genders. In addition, majority of AEs occurred within the first 2months after lorlatinib initiation with a median onset time of 51days. Our study provides valuable insight into the post-marketing safety profile of lorlatinib, which can potentially benefit the rational and safe administration of lorlatinib in the clinic. Further prospective studies are needed to validate the associations between lorlatinib and the identified AEs.

A real-world pharmacovigilance analysis of the FDA adverse event reporting system events for polatuzumab vedotin

ABSTRACT Background Polatuzumab vedotin is the first antibody-drug conjugate approved by the US Food and Drug Administration (FDA) for patients with diffuse large B-cell lymphoma. This study evaluated adverse events (AEs) associated with polatuzumab vedotin by data mining of the FDA Adverse Event Reporting System (FAERS). Methods This study included AEs registered in FAERS between 2019 Q2 and 2023 Q2. Four algorithms were used to quantify the signals of polatuzumab vedotin-associated AEs, including reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker. Results A total of 7,609,450 reports were collected from the FAERS database, and 1,388 reports of polatuzumab vedotin were identified as primary suspected AEs. Polatuzumab vedotin-associated AEs involved 26 organ systems. According to the four algorithms, 108 significant disproportionality AEs were retained simultaneously. Unexpected significant AEs included gastrointestinal hemorrhage, ileus, gastrointestinal perforation, cholecystitis, hypogammaglobulinemia, hepatitis B reactivation, hypercalcemia, hydronephrosis, cystitis hemorrhagic, interstitial lung disease, and thrombophlebitis. The median time to onset of polatuzumab vedotin-associated AEs was 20 (interquartile range 4–56) days. Conclusions Our study identified significant new AE signals for polatuzumab vedotin through real-world disproportionality analysis data and may provide additional evidence for risk identification of polatuzumab vedotin.

Evaluation of time-to-onset and outcome of cardiac adverse events related to pembrolizumab using post-marketing surveillance in Japanese patients.

Pembrolizumab has been widely used in patients since its release, but information on cardiac Adverse Events (AEs) related to pembrolizumab remains lacking, particularly in Japanese populations. This study aims to evaluate time to onset, incidence rates, and outcomes for pembrolizumab-induced cardiac AEs in patients with cancer using the Japanese Adverse Drug Event Report database. We analysed data for the period from April 2004 to March 2022. Data on cardiac AEs were extracted and relative risks of AEs were estimated using the reporting odds ratio. We analysed 2,021,907 reports and identified 15,306 reports of AEs caused by pembrolizumab. Of these, 399 cardiac AEs were associated with pembrolizumab. Signals were detected for six cardiac AEs: myocarditis, immune-mediated myocarditis, pericardial effusion, cardiac tamponade, pericarditis, and pericarditis malignant. A histogram of median times to onset showed occurrence from 33 (21-97) days for immune-mediated myocarditis to 138 (67-168) days for pericarditis malignant, but some cases occurred even more than 1year after the start of administration. Among these, myocarditis was the most frequently reported (27.1%), with fatal cases also reported. This study focused on cardiac AEs caused by pembrolizumab as post-marketing AEs. Patients should be monitored not only at the time of administration, but also over time for signs of these AEs, especially myocarditis, as some patients may have serious outcomes.

A real-world pharmacovigilance study of amivantamab-related cardiovascular adverse events based on the FDA adverse event reporting system (FAERS) database

Amivantamab is the first dual-specificity antibody targeting EGFR and MET, which is approved for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations. Cardiovascular toxicities related to amivantamab have not been reported in the CHRYSALIS study. However, the occurrence of cardiovascular events in the real world is unknown. To comprehensively investigate the clinical characteristics, onset times, and outcomes of cardiovascular toxicities associated with amivantamab. The Food and Drug Administration Adverse Event Reporting System (FAERS) database from 1st quarter of 2019 to the 2nd quarter of 2023 was retrospectively queried to extract reports of cardiovascular adverse events (AEs) associated with amivantamab. To perform disproportionality analysis, the reporting odds ratios (RORs) and information components (ICs) were calculated with statistical shrinkage trans-formation formulas and a lower limit of the 95% confidence interval (CI) for ROR (ROR025) > 1 or IC (IC025) > 0 with at least 3 reports was considered statistically significant. A total of 20,270,918 eligible records were identified, among which 98 records were related to cardiovascular events associated with amivantamab. 4 categories of cardiovascular events exhibited positive signals: venous thrombotic diseases, abnormal blood pressure, arrhythmia, and pericardial effusion. Venous thrombotic diseases and abnormal blood pressure were the two most common signals. The median time to onset (TTO) for cardiovascular AEs was 33 days. The cumulative incidence within 90 days was 100% for cardiac failure, 75% for stroke, 63.16% for arrhythmia, 50% for sudden death, and 44.18% for venous thrombotic diseases. Death accounted for 16.3% of all cardiovascular AEs associated with amivantamab. The mortality rates for Major Adverse Cardiovascular Events (MACE) were up to 60%. This pharmacovigilance study systematically explored the cardiovascular adverse events of amivantamab and provided new safety signals based on past safety information. Early and intensified monitoring is crucial, and attention should be directed towards high-risk signals.

Post-marketing safety evaluation of lurbinectedin: a pharmacovigilance analysis based on the FAERS database.

Background: On 15 June 2020, the United States Food and Drug Administration (FDA) approved lurbinectedin for treating adult patients with metastatic small-cell lung cancer whose disease has progressed despite prior platinum-based chemotherapy. Following its market approval, safety data on lurbinectedin in large populations is currently lacking. Therefore, this study aims to evaluate adverse events (AEs) associated with lurbinectedin using the FDA's Adverse Event Reporting System (FAERS)database. Methods: Data concerning lurbinectedin from the FAERS database were extracted for the period from June 2020 to September 2023. Four disproportionality analysis algorithms were utilized to assess potential AEs linked to lurbinectedin: reporting odds ratio (ROR), proportional reporting ratio, disproportionate multi-item gamma Poisson shrinker, and Bayesian confidence propagation neural network. These algorithms were applied to quantify signals of lurbinectedin-related AEs. Result: A total of 5,801,535 AE reports were retrieved from the FAERS database, with 511 related to lurbinectedin. These lurbinectedin-induced AEs were observed in 23 system organ classes (SOCs). After simultaneously applying the four algorithms, 47 lurbinectedin-induced AE signals were detected in 23 SOCs. At the SOC level, blood and lymphatic system disorders (ROR, 6.70; 95% confidence interval [CI]: 5.47-8.22) were the only SOC that met all four algorithms. Lurbinectedin's most frequent adverse event was death (ROR: 6.11%, 95% CI: 4.86-7.68), while extravasation exhibited the strongest signal intensity in the ROR algorithm (ROR: 326.37%, 95% CI: 191.66-555.75). Notably, we identified a novel signals: tumor lysis syndrome (ROR: 63.22%, 95% CI: 33.87-117.99). The mean time of onset of AEs was 66 days, the median time of onset was 25days (interquartile range: 8-64days), and most AEs occurred within the first month of lurbinectedin treatment. Conclusion: Our study provided a comprehensive evaluation of lurbinectedin's safety profile in the post-marketing setting. In addition to the adverse events consistent with the existing clinical trials and labeling information, we have also identified an unreported signal related to tumor lysis syndrome. This finding will better guide the clinical practice of lurbinectedin and provide valuable evidence for future research.

“The crackers challenge”: A reassuring low-dose gluten challenge in adults on gluten-free diet without proper diagnosis of coeliac disease

BackgroundGluten-free diet (GFD) is the one therapy in coeliac disease (CeD). Unfortunately, some patients adopt GFD before the diagnostic work-up. The guidelines suggest a 14-day gluten intake > 3 gr to get CeD diagnosis, although many subjects refuse this approach. Other evidence showed that the intake of 50 mg/day of gluten for 3 months could be useful for CeD diagnosis. AimsWe performed a dietary study, administering a low dose of gluten in form of “crackers” (about 60–120 mg of gluten/day) for 3 months, to get a final diagnosis of CeD in subjects already on GFD. MethodsWe enrolled adult patients with a suspicion of CeD on self-prescribed GFD. All subjects performed the crackers challenge for 3 months. At the end, all patients were analysed for CeD serology and if positive underwent endoscopy/histology. Also, we recorded the grade of satisfaction for the gluten challenge and the onset of adverse events. ResultsWe enrolled 120 patients. All patients concluded the challenge without relevant adverse events. Serological positivity was detected in 54 patients (45%). Histology showed atrophy in 87% and Marsh 1–2 grade in 13% of patients. Ninety-nine patients (83%) were satisfied by this challenge. ConclusionsThe “crackers challenge” is a useful and safe diagnostic approach in people on self-administered GFD.

Psychiatric adverse events associated with GLP-1 receptor agonists: a real-world pharmacovigilance study based on the FDA Adverse Event Reporting System database.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used due to their profound efficacy in glycemic control and weight management. Within real-world contexts, the manifestation of certain psychiatric adverse events (AEs) has been observed, which is potentially linked to the administration of GLP-1 RAs. The objective of this study was to undertake a comprehensive investigation and characterization of the psychiatric AEs associated with GLP-1 RAs. We retrieved reports of AEs associated with treatment with GLP-1 RAs during the period from the first quarter (Q1) of 2004 to Q1 2023 from the FDA Adverse Event Reporting System (FAERS) database. Descriptive analysis was performed to examine the clinical characteristics and time to onset of the psychiatric AEs caused by GLP-1 RAs. Moreover, disproportionality analyses were performed using the reporting odds ratio (ROR) to identify GLP-1 RA-related psychiatric AEs. A total of 8,240 reports of psychiatric AEs were analyzed out of 181,238 AE reports with treatment with GLP-1 RAs. Among these cases, a higher percentage was represented by women compared to men (65.89% vs. 30.96%). The median age of these patients was 56 years, with an interquartile range (IQR) of 48-67 years, based on data available in 286 case reports. This study showed that the median time to onset of the overall GLP-1 RA-related AEs was 31 days (IQR = 7-145.4 days), which varied among GLP-1 RA regimens. Specifically, exenatide had a significantly longer onset time at 45 days (IQR = 11-213 days), with statistically significant differences from the onset times of the other five GLP-1 RAs (p< 0.0001). Moreover, eight categories of psychiatric AEs, namely, nervousness (ROR = 1.97, 95% CI = 1.85-2.11), stress (ROR = 1.28, 95% CI = 1.19-1.38), eating disorder (ROR = 1.57, 95% CI = 1.40-1.77), fear of injection (ROR = 1.96, 95% CI = 1.60-2.40), sleep disorder due to general medical condition-insomnia type (ROR = 2.01, 95% CI = 1.60-2.52), binge eating (ROR = 2.70, 95% CI = 1.75-4.16), fear of eating (ROR 3.35, 95% CI = 1.65-6.78), and self-induced vomiting (ROR = 3.77, 95% CI = 1.77-8.03), were defined as GLP-1 RA-related psychiatric AEs through disproportionality analysis. Our findings demonstrate a significant association between GLP-1 RAs and the development of specific psychiatric AEs. Despite the observational nature of this pharmacovigilance study and the inherent limitations of the FAERS database, our preliminary findings in this work could provide a better basis for understanding the potential psychiatric AEs that may occur with GLP-1 RA treatment, assisting clinicians to focus on these AEs and provide early intervention for optimal risk management.

Evaluation of the effectiveness and safety of single-operator cholangiopancreatoscopy with the SpyGlass™ system

Background and study aimsThe single-operator cholangiopancreatoscopy (SOCP) with the SpyGlass™ system is a endoscopy technique whose use has grown exponentially in recent years. The aims of this study were to evaluate the efficacy and safety of SOCP with SpyGlass™ and determine the factors related to the onset of adverse events (AEs). Patients and methodsRetrospective study at a single tertiary institution with inclusion of all consecutive patients undergoing SOCP with SpyGlass™ from February-2009 to December-2021. No exclusion criteria were considered. A descriptive statistical analysis was performed. The factors associated with the existence of AE were analyzed using Chi-square and Student's t-test. ResultsA total of 95 cases were included. The most common indications were biliary strictures (BS) evaluation (66.3%) or treatment of difficult common bile duct stones (27.4%). Technical and clinical success was attained in 98.9%. Single-session stone clearance was obtained in 84%. The AE rate was 7.4%. To detect malignancy in BS, optical diagnosis presents a sensitivity and specificity of 100% and 91.2%, respectively; while histology results were 36.4% and 100% respectively. A previous endoscopic sphincterotomy was associated with a lower rate of AEs (2.4% vs 41.7%; p<0.001). ConclusionsSOCP with SpyGlass™ is a safe and effective technique to diagnose and treat pancreatobiliary pathology. The presence of sphincterotomy performed prior to the procedure could improve the technique's safety.

Utilizing temporal pattern of adverse event reports to identify potential late-onset adverse events

ABSTRACT Objectives Through the use of FDA adverse event reporting system (FAERS) dataset, this study analyzes the pattern of time-to-event (TTE) for drugs and adverse events, and suggest ways to identify candidate late-onset events for monitoring. Methods The duration between administration date of the drug and the onset of adverse events was explored with using FAERS data from 2012–2021. The fold change of proportional reporting ratios or reporting odds ratios were calculated to identify enriched events in the later period and to suggest the late-onset events for further monitoring. To compare the findings, we used the claims database of the Korean National Health Insurance Service (NHIS). Results A total of 1,426,781 reports were included. The median TTE was 10 days (interquartile range [IQR]: 0–98 days), with 11.5% (n = 164,093) reporting events that occurred at least one year after administration. TTE and fold change analysis captured historical cases of late-onset events, while generating an additional less-explored list of events. The results for tumor necrosis factor (TNF) inhibitors were compared using the NHIS dataset. Conclusion Our study provides a comprehensive analysis of the FAERS dataset, focusing on TTE data. Periodic summarization of reports would be helpful in monitoring the late-onset events.

P540 Non-serious adverse events in patients with ulcerative colitis receiving etrasimod: An analysis of the phase 2 OASIS and phase 3 ELEVATE UC 52 and ELEVATE UC 12 clinical trials

Abstract Background Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Adverse events (AEs) pertaining to tolerability, laboratory and serious AEs are described elsewhere1,2; we present a post hoc analysis of the incidence, onset and duration of the most commonly occurring non-serious AEs in the etrasimod UC clinical programme. Methods Data from the pooled Placebo-controlled UC cohort, derived from the phase 2 OASIS (NCT02447302) and phase 3 ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) double-blind clinical trials, were included. Cohorts comprised OASIS and ELEVATE UC 12 12-week induction periods alongside the ELEVATE UC 52 12-week induction and 40-week maintenance periods utilising a "treat-through" design. Patients (pts) with moderately to severely active UC were eligible for the etrasimod UC clinical programme. Pts were randomised to etrasimod 1 mg once daily (QD; OASIS only), etrasimod 2 mg QD or placebo. Proportions and incidence rates (IRs) of non-serious AEs (MedDRA v24.1 Preferred Terms of headache, pyrexia, nausea, fatigue and dizziness) were analysed in the Placebo-controlled UC cohort. Results Among 943 pts (any dose of etrasimod, N=629 [288.1 pt years (PY)]; placebo, N=314 [115.1 PY]), there were 77, 36, 30, 15 and 23 headache, pyrexia, nausea, fatigue and dizziness AEs, respectively. All were non-serious and did not lead to treatment discontinuation, apart from one case of pyrexia in which early termination visits were incomplete. Proportions and IRs (per 100 PY) for headache and dizziness AEs were higher with etrasimod (any dose) vs placebo (IRs: 13.45 vs 8.63 and 6.52 vs 1.69, respectively); IRs for other non-serious AEs were similar in etrasimod (any dose) and placebo groups (Table). Onset of AEs varied over time and most AEs were short in duration (Figure shows onset and duration for headache and dizziness AEs). Most AEs were deemed not related to study treatment by the site investigator. Pts with dizziness on Days 1–3 had similar changes in heart rate vs those with dizziness after Day 3. No consistent trend in heart rate was observed in pts receiving etrasimod with early dizziness. Conclusion Among pts in the etrasimod UC clinical programme, all headache, pyrexia, nausea, fatigue and dizziness events were non-serious. IRs were similar for most non-serious AEs across treatment groups, excluding headache and dizziness. Most non-serious AEs were short in duration and judged as not related to study treatment, suggesting they may not impact on the overall tolerability of etrasimod.