Frequency Of Serious Adverse Events Research Articles

Safe Continuation of Glucagon-like Peptide 1 Receptor Agonists at Endoscopy: A Case Series of 57 Adults Undergoing Endoscopic Sleeve Gastroplasty.

Glucagon-like receptor agonists (GLP1-RAs) have raised peri-procedural concerns due to their potential to delay gastric emptying. The American Association of Anesthesiologists has advised pausing a single dose before elective endoscopy. However, a subsequent directive from multiple gastroenterology societies underscored the need for further assessment to substantiate this practice. We aimed to evaluate the frequency of serious adverse events and retained gastric products during endoscopic sleeve gastroplasty (ESG) with uninterrupted GLP1-RA use. We conducted a retrospective evaluation of all patients undergoing ESG while on GLP1-RAs at three centers from August 2022 to February 2024. Per standard protocol, all patients had refrained from solid foods for at least 24h and maintained nil per os for 12h preceding their ESG. Records were reviewed for patient characteristics and medication type and doses. Primary outcomes included serious adverse events and retained gastric products based on patient records, procedure reports, and procedural videos. Fifty-seven consecutive adults (89.5% women, mean age of 44 ± 9years, mean BMI of 40.1 ± 8.1kg/m2, 35.1% with T2DM, and 26.3% with pre-T2DM) underwent ESG without stopping GLP1-RAs, which included semaglutide (45.6%), liraglutide (19.3%), dulaglutide (22.8%), and tirzepatide (12.3%). During intubation, endoscopy, and recovery, there were no instances of retained gastric solids, pulmonary aspiration, gastroesophageal regurgitation, or hypoxia. A ≥ 24-h pre-endoscopy liquid-only diet with ≥ 12-h pre-endoscopy fast may negate the need for GLP1-RA interruption for routine upper endoscopy in adults with native gastric anatomy.

Patient Preferences for Treatment Attributes in Inflammatory Bowel Disease: Results From a Large Survey Across Seven European Countries Using a Discrete Choice Experiment.

Inflammatory bowel disease requires long-term treatment; therefore, understanding patient preferences is important in aiding informed treatment decision making. This study explored patients' preferences for treatment attributes of available inflammatory bowel disease therapies. Adult patients from 7 European countries who self-reported previous/current treatment for Crohn's disease (CD) or ulcerative colitis (UC) participated in an online survey via the Carenity platform. In a discrete choice experiment, the relative importance of treatment attributes for CD and UC was estimated using conditional logit models. Latent class analysis was conducted to estimate heterogeneous treatment preferences based on patient profiles. Patients' perspectives and preferences regarding their quality of life were assessed. Across 686 completed survey responses (CD, n = 360; UC, n = 326), the mean patient age was 48 and 50 years, respectively. Patients with CD ranked route of administration as the most important attribute (attribute importance: 32%), preferring subcutaneous over intravenous treatment (P < .001). Patients with UC ranked route of administration and frequency of serious adverse events as the most important attributes (attribute importance: 31% and 23%, respectively), preferring oral (P < .001) and subcutaneous (P < .001) over intravenous treatment and treatment that minimized the risk of serious adverse events (P < .001) or mild adverse events (P < .01). Latent class analyses confirmed the impact of patients' sociodemographic profile on their preferences. All patients prioritized general well-being, energy level, and daily activities as the most important aspects for improvement through treatment. Patient preferences for treatment attributes varied among patients with CD or UC, highlighting the importance of personalized care and shared decision making to maximize treatment benefits.

Cefepime–Taniborbactam in Complicated Urinary Tract Infection

BackgroundCarbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime–taniborbactam is an investigational β-lactam and β-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-β-lactamases.MethodsIn this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime–taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority.ResultsOf the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime–taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime–taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P=0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime–taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime–taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups.ConclusionsCefepime–taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.)

Safety and efficacy of dihydroartemisinin–piperaquine for intermittent preventive treatment of malaria in pregnant women with HIV from Gabon and Mozambique: a randomised, double-blind, placebo-controlled trial

The cornerstone of malaria prevention in pregnancy, intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine, is contraindicated in women with HIV who are receiving co-trimoxazole prophylaxis. We assessed whether IPTp with dihydroartemisinin-piperaquine is safe and effective in reducing the risk of malaria infection in women with HIV receiving co-trimoxazole prophylaxis and antiretroviral drugs. For this randomised, double-blind, placebo-controlled clinical trial, women with HIV attending the first antenatal care clinic visit, resident in the study area, and with a gestational age up to 28 weeks were enrolled at five sites in Gabon and Mozambique. Participants were randomly assigned (1:1) to receive either IPTp with dihydroartemisinin-piperaquine at each scheduled antenatal care visit plus daily co-trimoxazole (intervention group) or placebo at each scheduled antenatal care visit plus daily co-trimoxazole (control group). Randomisation was done centrally via block randomisation (block sizes of eight), stratified by country. IPTp was given over 3 days under direct observation by masked study personnel. The number of daily IPTp tablets was based on bodyweight and according to the treatment guidelines set by WHO (target dose of 4 mg/kg per day [range 2-10 mg/kg per day] of dihydroartemisinin and 18 mg/kg per day [range 16-27 mg/kg per day] of piperaquine given once a day for 3 days). At enrolment, all participants received co-trimoxazole (fixed combination drug containing 800 mg trimethoprim and 160 mg sulfamethoxazole) for daily intake. The primary study outcome was prevalence of peripheral parasitaemia detected by microscopy at delivery. The modified intention-to-treat population included all randomly assigned women who had data for the primary outcome. Secondary outcomes included frequency of adverse events, incidence of clinical malaria during pregnancy, and frequency of poor pregnancy outcomes. All study personnel, investigators, outcome assessors, data analysts, and participants were masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT03671109. From Sept 18, 2019, to Nov 26, 2021, 666 women (mean age 28·5 years [SD 6·4]) were enrolled and randomly assigned to the intervention (n=332) and control (n=334) groups. 294 women in the intervention group and 308 women in the control group had peripheral blood samples taken at delivery and were included in the primary analysis. Peripheral parasitaemia at delivery was detected in one (<1%) of 294 women in the intervention group and none of 308 women in the control group. The incidence of clinical malaria during pregnancy was lower in the intervention group than in the control group (one episode in the intervention group vs six in the control group; relative risk [RR] 0·12, 95% CI 0·03-0·52, p=0·045). In a post-hoc analysis, the composite outcome of overall malaria infection (detected by any diagnostic test during pregnancy or delivery) was lower in the intervention group than in the control group (14 [5%] of 311 women vs 31 [10%] of 320 women; RR 0·48, 95% CI 0·27-0·84, p=0·010). The frequency of serious adverse events and poor pregnancy outcomes (such as miscarriages, stillbirths, premature births, and congenital malformations) did not differ between groups. The most frequently reported drug-related adverse events were gastrointestinal disorder (reported in less than 4% of participants) and headache (reported in less than 2% of participants), with no differences between study groups. In the context of low malaria transmission, the addition of IPTp with dihydroartemisinin-piperaquine to co-trimoxazole prophylaxis in pregnant women with HIV did not reduce peripheral parasitaemia at delivery. However, the intervention was safe and associated with a decreased risk of clinical malaria and overall Plasmodium falciparum infection, so it should be considered as a strategy to protect pregnant women with HIV from malaria. European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) and Medicines for Malaria Venture. For the Portuguese and French translations of the abstract see Supplementary Materials section.

Clinical Challenges of the COVID-19 Vaccines: Frequency of Serious Adverse Events After Immunization in Hospitalized Patients

Background and aims: Today, the role of coronavirus disease 19 (COVID-19) vaccines in preventing the disease and reducing the severity of the disease is undeniable; however, there is a possibility of serious adverse events following immunization (sAEFI) that might be life-threatening. The present study was designed to identify the frequency of the most common sAEFI in hospitalized people after receiving the COVID-19 vaccine in the south of Iran. Methods: This cross-sectional study was conducted in 2022. In total, since the start of the COVID-19 vaccination program in the city of Larestan, in the south of Iran, a total of 68 sick people have been hospitalized due to complications caused by the vaccine. The research tool of the present study was a standard checklist called the sAEFI of the COVID-19 vaccine. Results: A total of 68 hospital cases were reviewed. The mean age of the individuals with sAEFI was 59.78±12.70 years, and 21 (56.8%) of them were females. Acute respiratory distress syndrome (ARDS) was the most common 24 (64.9%) sAEFI. Based on the results, 2 (5.4%) had acute coronary syndrome (ACS), 2 (5.4%) had Guillain-Barré syndrome, and 2 (5.4%) had a stroke. Conclusion: It can be mentioned that there is always a possibility of sAEFI, but its frequency in the general population is extremely rare. However, the most common sAEFIs included adverse drug reactions, stroke, and Guillain-Barré syndrome. The readiness of health care staff for early detection of possible sAEFI can be effective in reducing the severity of the sAEFI.

The safety and adverse event profile of favipiravir in the treatment of COVID-19 patients, Turkey.

Favipiravir (FVP) is an antiviral and used to treat COVID-19. We aimed to document the safety and adverse events associated with FVP on the outcome of COVID-19 treatment. The study included 225 adult patients with moderate COVID-19 infection (World Health Organization scale-5). The adverse events (AEs) were evaluated using a grading scale supported by the Food and Drug Administration. Safety was assessed by the frequency of serious AEs. The AEs associated with FVP treatment were hepatotoxicity (87/225, 38.7%), weakness (32/225, 14.2%), nephrotoxicity (26/225, 11.6%), nausea (18/225, 8.0%), diarrhea (8/225, 3.6%), vomiting (5/225, 2.2%), and insomnia (4/225, 1.8%); rash was not detected. Hepatotoxicity was observed more frequently in patients who also developed nephrotoxicity (57.7% vs 36.2%, p = 0.03). The deceased patients were significantly older and had higher prevalence of hypertension, congestive heart failure (CHF), coronary artery disease, cancer, nephrotoxicity. and angiotensin- converting enzyme inhibitors/angiotensin receptor blocker use. While male gender (OR: 5.38 CI: 1.64-17.67) and CHF (OR: 6.8 CI: 1.92-24.74) were significantly associated with nephrotoxicity, age (OR: 1.06 CI: 1.02-1.10), cancer (OR: 3.9 CI: 1.10-14.22) and nephrotoxicity (OR: 5.5 CI: 1.74-17.74) were associated with mortality. Serious AEs were detected at very low levels that would not require discontinuation of treatment or any AE-related death. Since SARS-CoV-2 itself and drug interactions may differ, FVP-related AEs might vary in COVID-19 patients. Our study shows that FVP can be used safely with a low AE profile. More extensive evidence is required to evaluate the long-term AEs of FVP.

Assessing Sustained B-Cell Depletion and Disease Activity in a French Multiple Sclerosis Cohort Treated by Long-Term IV Anti-CD20 Antibody Therapy

Few studies have investigated sustained B-cell depletion after long-term intravenous (IV) anti-CD20 B-cell depleting therapy (BCDT) in multiple sclerosis (MS) with respect to strict and/or minimal disease activity. The main objective of this study was to investigate how sustained B-cell depletion after BCDT influences clinical and radiological stability as defined by “no evidence of disease activity” (NEDA-3) and “minimal evidence of disease activity” (MEDA) status in MS patients at 12 and 18 months. Furthermore, we assessed the frequency of serious adverse events (SAE), and the influence of prior lymphocytopenia-inducing treatment (LIT) on lymphocyte subset counts and gammaglobulins in MS patients receiving long-term BCDT. We performed a retrospective, prospectively collected, study in a cohort of 192 MS patients of all clinical phenotypes treated by BCDT between January 2014 and September 2021. Overall, 84.2% and 96.9% of patients attained NEDA-3 and MEDA status at 18 months, respectively. Sustained CD19+ depletion was observed in 85.8% of patients at 18 months. No significant difference was observed when comparing patients achieving either NEDA-3 or MEDA at 18 months and sustained B-cell depletion. Compared to baseline levels, IgM and IgG levels on BCDT significantly decreased at 6 months and 30 months, respectively. Patients receiving LIT prior to BCDT showed significant CD4+ lymphocytopenia and lower IgG levels compared to non-LIT patients. Grade 3 or above SAEs were rare. As nearly all patients achieved MEDA at 18 months, we suggest tailoring IV BCDT after 18 months given the occurrence of lymphocytopenia, hypogammaglobulinemia, and SAE after this time point.

Fragmentation of Care in Patients with Peritoneal Metastases Undergoing Cytoreductive Surgery.

The delivery of multimodal treatment at a high-volume center is known to optimize the outcomes of gastrointestinal malignancies. However, patients undergoing cytoreductive surgery (CRS) for peritoneal metastases often must 'fragment' their surgical and systemic therapeutic care between different institutions. We hypothesized that this adversely affects outcomes. Adults undergoing CRS for colorectal or appendiceal adenocarcinoma at our institution between 2016 and 2022 were identified retrospectively and grouped by care network: 'coordinated care' patients received exclusively in-network systemic therapy, while 'fragmented care' patients received some systemic therapy from outside-network providers. Factors associated with fragmented care were also ascertained. Overall survival (OS) from CRS and systemic therapy-related serious adverse events (SAEs) were compared across the groups. Among 85 (80%) patients, 47 (55%) had colorectal primaries and 51 (60%) received fragmented care. Greater travel distance [OR 1.01 (CI 1.00-1.02), p = 0.02] and educational status [OR 1.04 (CI 1.01-1.07), p = 0.01] were associated with receiving fragmented care. OS was comparable between patients who received fragmented and coordinated care in the colorectal [32.5 months versus 40.8 months, HR 0.95 (CI 0.43-2.10), p = 0.89] and appendiceal [31.0 months versus 27.4 months, HR 1.17 (CI 0.37-3.74), p = 0.55] subgroups. The frequency of SAEs (7.8% versus 17.6%, p = 0.19) was also similar. There were no significant differences in survival or SAEs based on the networks of systemic therapy delivery. This suggests that patients undergoing CRS at a high-volume center may safely receive systemic therapy at outside-network facilities with comparable outcomes.

Safety and tolerability of agalsidase beta infusions shorter than 90 min in patients with Fabry disease: post-hoc analysis of a Japanese post-marketing study

BackgroundAgalsidase beta, an enzyme replacement therapy for Fabry disease, is dosed biweekly at 1 mg/kg body weight, with increasing infusion rates based on tolerability. The US label specifies ≥ 90-min infusions for all patients; the US and EU labels require ≤ 15 mg/hr infusions in patients < 30 kg. The Japanese label allows infusions up to 30 mg/hr, allowing < 90-min dosing for some patients weighing < 45 kg. Japanese post-marketing data were analyzed for rate of infusion-associated reactions (IARs), adverse events (AEs), and serious AEs (SAEs) based on infusion rate and patient attributes (weight, antibody status).ResultsData were available for 436 reduced-duration infusions (< 90 min) and 2242 standard infusions (≥ 90 min). SAEs were rare (0.6%), and the frequency of all safety events decreased over the treatment course. Little impact of infusion duration on safety outcomes was observed: IARs and AEs were numerically more common when infusion duration was ≥ 90 min compared to < 90 min (IARs: 2.0% vs 0.9%; AEs: 2.9% vs 1.4%), while the rate of SAEs was similar (0.4% vs 0.5%). IAR, AE, and SAE frequencies decreased significantly with increasing infusion rates, and this trend was consistent in patients < 30 kg. Safety events tended to be less frequent in patients < 30 kg vs those ≥ 30 kg (IARs: 1.8% vs 2.1%; AEs: 2.3% vs 3.6%; SAEs: 0.0% vs 0.6%), although the differences were not statistically significant. IARs occurred in < 1% of all infusions in the < 30 kg group, 84% of which were < 90 min. More anti-agalsidase beta antibody-positive patients experienced IARs (41.9% vs 30.7%; P = 0.0445) and AEs (61.1% vs 49.3%; P = 0.0497) vs antibody-negative patients; however, there was no significant difference in the frequency of SAEs. In patients with available data, no changes in antibody status were observed after infusion durations were reduced to < 90 min.ConclusionsThe results of this post-hoc analysis demonstrated no significant impact of infusion duration on safety outcomes, and no significant difference in outcomes between patients of different weights. These findings suggest that infusion times in patients who are tolerating treatment can, with careful monitoring, be gradually decreased.

Cannabis-based medicines and medical cannabis for adults with cancer pain.

Cannabis-based medicines and medical cannabis for adults with cancer pain.

Phase II trial of delta-tocotrienol in neoadjuvant breast cancer with evaluation of treatment response using ctDNA

Neoadjuvant treatment of breast cancer is applied to an increasing extent, but treatment response varies and side effects pose a challenge. The vitamin E isoform delta-tocotrienol might enhance the efficacy of chemotherapy and reduce the risk of side effects. The aim of this study was to investigate the clinical effect of delta-tocotrienol combined with standard neoadjuvant treatment and the possible association between detectable circulating tumor DNA (ctDNA) during and after neoadjuvant treatment with pathological treatment response. This open-label, randomized phase II trial included 80 women with newly diagnosed, histologically verified breast cancer randomized to standard neoadjuvant treatment alone or in combination with delta-tocotrienol. There was no difference in the response rate or frequency of serious adverse events between the two arms. We developed a multiplex digital droplet polymerase chain reaction (ddPCR) assay for the detection of ctDNA in breast cancer patients that targets a combination of two methylations specific for breast tissue (LMX1B and ZNF296) and one cancer specific methylation (HOXA9). The sensitivity of the assay increased when the cancer specific marker was combined with the ones specific to breast tissue (p < 0.001). The results did not show any association between ctDNA status and pathological treatment response, neither at midterm nor before surgery.

Palbociclib in Acute Leukemias With KMT2A-rearrangement: Results of AMLSG 23-14 Trial

Palbociclib in Acute Leukemias With KMT2A-rearrangement: Results of AMLSG 23-14 Trial

Supply and quality of colonoscopy according to the characteristics of gastroenterologists in the French population-based colorectal-cancer screening program.

Since its complete roll-out in 2009, the French colorectal cancer screening program (CRCSP) experienced 3 major constraints [use of a less efficient Guaiac-test (gFOBT), stopping the supply of Fecal-Immunochemical-Test kits (FIT), and suspension of the program due to the coronavirus disease 2019 (COVID-19)] affecting its effectiveness. To describe the impact of the constraints in terms of changes in the quality of screening-colonoscopy (Quali-Colo). This retrospective cohort study included screening-colonoscopies performed by gastroenterologists between Jan-2010 and Dec-2020 in people aged 50-74 living in Ile-de-France (France). The changes in Quali-colo (Proportion of colonoscopies performed beyond 7 mo (Colo_7 mo), Frequency of serious adverse events (SAE) and Colonoscopy detection rate) were described in a cohort of Gastroenterologists who performed at least one colonoscopy over each of the four periods defined according to the chronology of the constraints [gFOBT: Normal progress of the CRCSP using gFOBT (2010-2014); FIT: Normal progress of the CRCSP using FIT (2015-2018); STOP-FIT: Year (2019) during which the CRCSP experienced the cessation of the supply of test kits; COVID: Program suspension due to the COVID-19 health crisis (2020)]. The link between each dependent variable (Colo_7 mo; SAE occurrence, neoplasm detection rate) and the predictive factors was analyzed in a two-level multivariate hierarchical model. The 533 gastroenterologists (cohort) achieved 21509 screening colonoscopies over gFOBT period, 38352 over FIT, 7342 over STOP-FIT and 7995 over COVID period. The frequency of SAE did not change between periods (gFOBT: 0.3%; FIT: 0.3%; STOP-FIT: 0.3%; and COVID: 0.2%; P = 0.10). The risk of Colo_7 mo doubled between FIT [adjusted odds ratio (aOR): 1.2 (1.1; 1.2)] and STOP-FIT [aOR: 2.4 (2.1; 2.6)]; then, decreased by 40% between STOP-FIT and COVID [aOR: 2.0 (1.8; 2.2)]. Regardless of the period, this Colo_7 mo's risk was twice as high for screening colonoscopy performed in a public hospital [aOR: 2.1 (1.3; 3.6)] compared to screening-colonoscopy performed in a private clinic. The neoplasm detection, which increased by 60% between gFOBT and FIT [aOR: 1.6 (1.5; 1.7)], decreased by 40% between FIT and COVID [aOR: 1.1 (1.0; 1.3)]. The constraints likely affected the time-to-colonoscopy as well as the colonoscopy detection rate without impacting the SAE's occurrence, highlighting the need for a respectable reference time-to-colonoscopy in CRCSP.

Abstract Number ‐ 95: Common Data Elements Analysis of Mechanical Thrombectomy Clinical Trials for Acute Ischemic Large Core Stroke

Introduction Various clinical trials addressing large core acute ischemic stroke (AIS) are ongoing from multiple international groups. Future development of clinical guidelines depends on meta‐analyses of these trials calling for a degree of homogeneity of elements across the different studies. The aim of this common data element study was to provide an overview of the key features of pertinent large core infarct trials. Methods PubMed and ClinicalTrials.gov databases were screened for published and ongoing clinical trials assessing mechanical thrombectomy in patients with AIS with large core infarct. Nested Knowledge AutoLit living review platform was utilized to categorize primary and secondary outcomes as well as inclusion and exclusion criteria for patient selection in the clinical trials. Results The most reported data element was ASPECTS score, but with varied definitions of what compromises large core. Non‐utility‐weighted modified Rankin Score (mRS) was reported in 6/7 studies as the primary outcome, while the utility‐weighted mRS was the outcome of interest in the TESLA trial, all of them at the 3‐months mark, with only LASTE looking for mRS shift at the 6‐months mark. Secondary outcomes had more variations. Mortality is reported separately only in 4/7 trials, all at the 3‐month mark. Additionally, the TENSION trial reports the frequency of serious adverse events, including mortality, at the 1‐week and 12‐month mark. Conclusions In the published and the ongoing large core trials, there is a large degree of variability in the collected data elements. Differences in definition and timepoints renders reaching a unified standard difficult, which hinders high quality meta‐analyses and cohesive evidence‐driven synthesis.

Efficacy and Safety of an Ad26.RSV.preF–RSV preF Protein Vaccine in Older Adults

BackgroundRespiratory syncytial virus (RSV) can cause serious lower respiratory tract disease in older adults, but no licensed RSV vaccine currently exists. An adenovirus serotype 26 RSV vector encoding a prefusion F (preF) protein (Ad26.RSV.preF) in combination with RSV preF protein was previously shown to elicit humoral and cellular immunogenicity.MethodsWe conducted a randomized, double-blind, placebo-controlled, phase 2b, proof-of-concept trial to evaluate the efficacy, immunogenicity, and safety of an Ad26.RSV.preF–RSV preF protein vaccine. Adults who were 65 years of age or older were randomly assigned in a 1:1 ratio to receive vaccine or placebo. The primary end point was the first occurrence of RSV-mediated lower respiratory tract disease that met one of three case definitions: three or more symptoms of lower respiratory tract infection (definition 1), two or more symptoms of lower respiratory tract infection (definition 2), and either two or more symptoms of lower respiratory tract infection or one or more symptoms of lower respiratory tract infection plus at least one systemic symptom (definition 3).ResultsOverall, 5782 participants were enrolled and received an injection. RSV-mediated lower respiratory tract disease meeting case definitions 1, 2, and 3 occurred in 6, 10, and 13 vaccine recipients and in 30, 40, and 43 placebo recipients, respectively. Vaccine efficacy was 80.0% (94.2% confidence interval [CI], 52.2 to 92.9), 75.0% (94.2% CI, 50.1 to 88.5), and 69.8% (94.2% CI, 43.7 to 84.7) for case definitions 1, 2, and 3, respectively. After vaccination, RSV A2 neutralizing antibody titers increased by a factor of 12.1 from baseline to day 15, a finding consistent with other immunogenicity measures. Percentages of participants with solicited local and systemic adverse events were higher in the vaccine group than in the placebo group (local, 37.9% vs. 8.4%; systemic, 41.4% vs. 16.4%); most adverse events were mild to moderate in severity. The frequency of serious adverse events was similar in the vaccine group and the placebo group (4.6% and 4.7%, respectively).ConclusionsIn adults 65 years of age or older, Ad26.RSV.preF–RSV preF protein vaccine was immunogenic and prevented RSV-mediated lower respiratory tract disease. (Funded by Janssen Vaccines and Prevention; CYPRESS ClinicalTrials.gov number, NCT03982199.)

Phase 2 multi-institutional prospective feasibility study of uracil-tegafur and leucovorin as adjuvant chemotherapy for patients aged 80 years or more after curative resection of colorectal cancer: The HiSCO-03 study.

101 Background: There is no consensus on the safety and effectiveness of adjuvant chemotherapy for patients with stage III colorectal cancer (CRC) aged ≥80 years who underwent curative resection. We conducted a prospective phase II feasibility study of uracil-tegafur and leucovorin (UFT/LV) as adjuvant chemotherapy in this population. Methods: This study involved 15 institutions of the Hiroshima Surgical Oncology Study Group (HiSCO). Patients with stage III CRC aged ≥80 years who underwent curative resection with an Eastern Cooperative Oncology Group performance status of 0–1 were enrolled. Eligible patients received UFT/LV therapy (UFT, 300 mg/m2 per day as tegafur; LV, 75 mg/day on days 1–28, every 35 days for five courses). Primary endpoint was feasibility, and secondary endpoints were safety and relative dose intensity. Results: Sixty-nine patients were enrolled in the study between December 2013 and June 2021. Of the 69 patients, 65 were included in the analysis, excluding two ineligible patients and two who discontinued before treatment commenced. There were 32 males and 33 females with a median age of 82 years (range, 80–88 years). There were four patients with stage IIIA CRC, 49 with stage IIIB, and 12 with stage IIIC. In the primary endpoint, administration completion rate was 67.3% (95% confidence interval: 54.9The median relative dose intensities were 84% (range, 4–100%) for UFT, and 100% (range, 4–100%) for LV. Incidence of grade three or higher adverse events were neutropenia (1.5%), aspartate transaminase elevation (3%), alanine transaminase elevation (1.5%), oral mucositis (3%), anemia (1.5%), and diarrhea (4.6%). No treatment-related deaths occurred. An independent risk factor was not identified in the background risk factor analysis for treatment discontinuation. Conclusions: Uracil-tegafur and leucovorin are not recommended as standard adjuvant therapy for patients with stage III CRC ≥80 years of age because of the possibility of lower completion rates. The frequency of serious adverse events was acceptable, and safety was confirmed in the treated patients. It is necessary to clarify the background of patients in which administration is discontinued and to investigate the impact on long-term prognosis. Clinical trial information: R000013902 .

Abstract TMP92: Effect Of Serious Adverse Events After Endovascular Thrombectomy On Clinical Outcome In Acute Ischemic Stroke With Large Vessel Occlusion: A Pooled Analysis From DEVT And Rescue BT Trial

Background: Using the pooled database of the DEVT and the RESCUE BT Trial, the objective of this study was to assess the serious adverse events (SAE) profile and their clinical impacts among patients with ischemic stroke due to large vessel occlusion treated with endovascular thrombectomy. Methods: A post hoc analysis was performed by using database of the multicenter, randomized DEVT and RESCUE BT clinical trials. SAEs as reported by investigators at any time-point during the hospitalization and the 90-day follow-up period were analyzed on their frequency and that of any of their outcomes (death, and life threatening, new and/or prolonged hospitalization, disability/incapacity). The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale (mRS) of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. Logistic regression analysis was used to determine the effect of SAE on clinical outcome and the predictors of SAE. Results: Among 1182 randomized patients undergone endovascular thrombectomy, 1758 SAE occurrences were identified, affecting 828 (70.1%) patients. The three most frequent SAEs were pneumonia (n=620, 52.5%), intracranial hemorrhage within 48 hours (n=359, 30.4%) and systemic bleeding (n=174, 14.7%). Patients suffering from at least one SAE had a lower odds of reaching a favorable outcome at 90 days (adjusted odds ratio, 0.350 [95% CI, 0.249-0.492], P &lt;0.001). Higher age ( P =0.001), higher NIHSS ( P &lt;0.001), intracranial segment of internal carotid artery (ICA) ( P =0.012) and puncture to recanalization time ( P &lt;0.001) were predictors for the occurrence of SAE. Conclusions: SAEs were observed in about 7 in ten patients, and were more frequent in elderly, functionally-impaired, longer procedure time, and intracranial ICA-occluded among patients with ischemic stroke treated with endovascular thrombectomy. These findings may provide clinicians and patients with more accurate risk of SAEs after endovascular thrombectomy.

330 Safety of abrocitinib in 3582 patients with moderate-to-severe atopic dermatitis with over 900 patients exposed for almost 2 years

Abstract Abrocitinib is an oral Janus kinase 1 inhibitor with demonstrated efficacy in moderate-to-severe atopic dermatitis (AD). To evaluate the long-term safety profile of abrocitinib and provide relevant information for practitioners. Data from patients who received ≥1 dose of abrocitinib 200 mg or 100 mg in the JADE clinical program were pooled in two cohorts. The consistent-dose (CD) cohort comprised patients who received the same abrocitinib dose during the entire exposure time in parent phase 3 studies and/or the long-term extension study JADE EXTEND (NCT03422822). Parent studies were: JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871), JADE TEEN (NCT03796676), JADE COMPARE (NCT03720470), JADE DARE (NCT04345367; 200 mg only) and JADE REGIMEN (NCT03627767); in JADE REGIMEN only patients from the open-label run-in phase (200 mg only) who did not subsequently enter the randomized phase were included. Patients from the phase 2b study (NCT02780167) were also included in the CD cohort. The variable-dose (VD) cohort comprised patients who received different doses of abrocitinib (200 and 100 mg) throughout exposure time in the parent study JADE REGIMEN and in JADE EXTEND, if enrolled. Patients included in the VD cohort completed the open-label period of JADE REGIMEN (abrocitinib 200 mg only) and entered the randomized phase (abrocitinib 200 mg, abrocitinib 100 mg or placebo); some patients subsequently entered the JADE REGIMEN rescue phase (abrocitinib 200 mg) and/or JADE EXTEND (abrocitinib 200 or 100 mg). The data cutoff was 16 April 2021. A Cox regression analysis evaluated risk factors for specific events of interest. Data from 3582 patients (4313.4 patient-years) were analysed: 2784 patients in the CD cohort (abrocitinib 200 mg, n = 1761, abrocitinib 100 mg, n = 1023) and 798 patients in the VD cohort. Duration of exposure was ≥48 weeks in 43.6%, 66.9% and 86.1% and ≥96 weeks in 18.0%, 23.2% and 45.4% of patients in the CD 200 mg, 100 mg and VD cohorts, respectively. In the CD and VD cohorts, the median age was 30.0 and 29.0 years; 490 (17.6%) and 145 patients (18.2%) were adolescents, and 143 (5.1%) and 30 patients (3.8%) were aged ≥65 years at screening, respectively. Incidence rates (IRs; unique patients with events per 100 patient-years) of serious adverse events (SAEs), deaths, and treatment-emergent adverse events of special interest are shown in Table 1. IRs for SAEs were consistent across abrocitinib doses but were higher in patients aged ≥65 years vs. younger patients. Serious infections were the most frequent SAEs; frequency was not dose related. Herpes zoster (HZ), herpes simplex and pneumonia were the most frequent serious infections. From a Cox regression analysis, potential risk factors for treatment-emergent HZ included abrocitinib dose, baseline age, medical history of HZ, absolute lymphocyte count &amp;lt;1000 mm−3 prior to infection and region. Most (95%) adjudicated opportunistic HZ infections were cutaneous; 2 (5%) were extracutaneous (one serious disseminated varicella-zoster virus infection, one serious HZ meningitis). IRs for nonmelanoma skin cancer, malignancy (excluding nonmelanoma skin cancer), thrombocytopenia and lymphopenia were higher in patients aged ≥65 years vs. younger patients but were not dose related. Abrocitinib has an acceptable long-term safety profile in this large analysis of patients with moderate-to-severe AD. Risk of SAEs, HZ infection, malignancies and hematologic abnormalities increased with older age; HZ risk was also related to dose and prior HZ infection.

Atezolizumab plus bevacizumab in patients with child-Pugh B advanced hepatocellular carcinoma.

Atezolizumab plus bevacizumab (Ate/Bev) demonstrated promising efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the phase III IMbrave150 trial. However, patients with Child-Pugh B HCC were excluded in the abovementioned prospective trial. Therefore, we aimed to investigate the efficacy and safety of Ate/Bev in patients with Child-Pugh B HCC. This multicenter retrospective study included 36 patients with Child-Pugh B advanced HCC who received Ate/Bev at four cancer referral centers between May 2020 and August 2021. Comparative analyses were performed with an independent cohort of patients with Child-Pugh A HCC from the same registry (n = 133). All patients received Ate/Bev as first-line systemic treatment for advanced HCC. The objective response and disease control rates of patients in the Child-Pugh groups B and A were 11.1% and 58.3% and 34.6% and 76.7%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.0 months [95% confidence interval (CI), 1.7-4.3) and 7.7 months (95% CI, 4.8-10.6) in the Child-Pugh B group, whereas the median PFS and OS were 9.6 months (95% CI, 5.1-14.2) and not reached (95% CI, not available) in the Child-Pugh A group, respectively. Compared to the Child-Pugh A group, grade 3-4 adverse events (AEs) were more common in the Child-Pugh B group (44.4% versus 15.8, p < 0.001), with the most frequent grade 3-4 AEs being gastrointestinal bleeding (n = 6, 16.7%), neutropenia (n = 5, 13.9%), and thrombocytopenia (n = 4, 11.1%). In the Child-Pugh B subgroup of patients with advanced HCC, Ate/Bev treatment showed modest clinical activity. However, due to the increased frequency of serious AEs, careful evaluation of treatment response and AE management is required in this subgroup of patients.

Common Data Elements Analysis of Mechanical Thrombectomy Clinical Trials for Acute Ischemic Stroke with Large Core Infarct.

Clinical trials addressing large core acute ischemic stroke (AIS) are ongoing across multiple international groups. Future development of clinical guidelines depends on meta-analyses of these trials calling for adegree of homogeneity of elements across the studies. This common data element study aims to provide an overview of key features of pertinent large core infarct trials. PubMed and ClinicalTrials.gov databases were screened for published and ongoing clinical trials assessing mechanical thrombectomy in patients with AIS with large core infarct. Nested Knowledge AutoLit living review platform was utilized to categorize primary and secondary outcomes as well as inclusion and exclusion criteria for patient selection in the trials. The most reported data element was ASPECTS score but with varied definitions of what constitutes large core. Non-utility-weighted modified Rankin score (mRS) was reported in 6/7studies as the primary outcome, while the utility-weighted mRS was the outcome of interest in the TESLA trial, all of them at the 3 months mark, with only LASTE looking for mRS shift at the 6 months mark. Secondary outcomes had more variations. Mortality is reported separately only in 4/7trials, all at the 3‑month mark. Additionally, the TENSION trial reported the frequency of serious adverse events, including mortality, at the 1‑week and 12-month mark. Overall, in large core trials there is alarge degree of heterogeneity in the collected data elements. Differences in definition and timepoints render reaching aunified standard difficult, which hinders high quality meta-analyses and cohesive evidence-driven synthesis.