Serious Adverse Events Research Articles

Serious adverse events reporting in recent randomised clinical trials in intensive care medicine - A methodological study protocol.

Serious adverse events (SAEs) are common in intensive care unit (ICU) patients. Reporting of SAEs in randomised clinical trials (RCTs) varies why underreporting is likely. We aim to describe the reporting of SAEs from 2020 onwards and to illustrate the recent reporting of SAEs published in major medical journals. We will conduct a methodological study assessing pharmacological interventions in RCTs including adult ICU patients. We will search 10 general medical and critical care journals in PubMed. We will include all RCTs published from 2020 onwards. The primary research question is how many RCTs report SAEs in the primary publication. Secondary research questions include how SAEs are reported in the primary publication either as (1) proportion of patients experiencing one or more SAE, (2) all single events occurred, or (3) both strategies combined. We will assess the association between the proportion of patients with reported SAEs and the following trial characteristics: multicentred versus single-centre RCTs, industry-sponsored versus academic-sponsored, published trial protocol versus unpublished work, blinding, trials sample size, and RCTs focusing on COVID-19 patients versus other populations. The outlined methodological study will provide important information on the reporting of SAEs in recent drug trials in adult ICU patients.

Comparative inhibition by oral bilastine, parenteral dexchlorpheniramine, and a new bilastine parenteral (i.v. and i.m.) formulation of histamine-induced wheal and flare response: A randomised phase I trial

BackgroundBilastine is a well-known non-sedating second-generation antihistamine authorised worldwide for the symptomatic treatment of allergic rhinoconjunctivitis (seasonal and perennial) and urticaria with proven efficacy and good safety and tolerability profile. When the oral route is not suitable or a rapid onset of action is preferred, parenteral formulations represent an effective treatment option. However, the parenteral formulations currently available are sedating antihistamines. The objective of this research was to compare the peripheral anti-H1 activity of different bilastine formulations (i.v., i.m. and oral) and dexchlorpheniramine among them also versus placebo. MethodsThis was a single-dose, randomized, crossover, double-blind, placebo-controlled, phase I clinical study performed on 25 adult healthy volunteers that compared the peripheral antihistaminic activity of a single dose of bilastine 12 mg i.v., bilastine 12 mg i.m., bilastine 20 mg oral tablets and dexchlorpheniramine 5 mg i.m. among them and versus placebo by inhibiting the histamine-induced wheal and flare (W&F) response. Pharmacokinetics, safety, and tolerability were also evaluated. ResultsAll bilastine formulations showed a rapid onset of action (15 min for parenteral and 30 min for the oral formulation), and the maximum effect in both wheal (i.v. 74.44 %; i.m.:74.29 %; oral 70,27 %) and flare area reduction (i.v. and i.m. 80.63 %; oral 77.67 %), was significantly larger compared to dexchlorpheniramine i.m. (25.85 % for wheal and 28.65 % for flare) and placebo (1.35 % for wheal and 4.02 % for flare). A more pronounced reduction in itching score was reached for bilastine oral, followed by i.m. and i.v. formulations. No serious adverse events (SAEs) were reported during the study, and 8 treatment-emergent adverse events (TEAEs) were reported by 5 subjects, all resolved without sequelae. For psychomotor assessments, dexchlorpheniramine i.m. showed a fast onset of drowsiness, as well as decreased attention and coordination when compared to all bilastine formulations and placebo. ConclusionsAll bilastine formulations showed a peripheral H1-blocking effect inducing a significantly greater inhibition of the wheal and flare response as compared to dexchlorpheniramine i.m. or placebo and provided a greater reduction of the itching sensation score. This study reconfirmed that bilastine has no sedative effect, even in a parenteral formulation. These results suggest that new bilastine parenteral formulation (i.v. or i.m.) may represent a suitable alternative for patients requiring immediate treatment of histamine-mediated type I hypersensitivity reactions, such as acute urticaria, or in those cases where oral administration is not possible.

Angiotensin-(1–7) infusion in COVID-19 patients admitted to the ICU: a seamless phase 1–2 randomized clinical trial

BackgroundThe coronavirus-related disease (COVID-19) is mainly characterized by a respiratory involvement. The renin-angiotensin system (RAS) has a relevant role in the pathogenesis of COVID-19, as the virus enters host’s cells via the angiotensin-converting enzyme 2 (ACE2).MethodsThis investigator-initiated, seamless phase 1–2 randomized clinical trial was conceived to test the safety and efficacy of continuous short-term (up to 7 days) intravenous administration of Angiotensin-(1–7) in COVID-19 patients admitted to two intensive care units (ICU). In addition to standard of care, intravenous administration of Angiotensin-(1–7) was started at 5 mcg/Kg day and increased to 10 mcg/Kg day after 24 h (Phase 1; open label trial) or given at 10 mcg/Kg day and continued for a maximum of 7 days or until ICU discharge (Phase 2; double-blind randomized controlled trial). The rate of serious adverse events (SAEs) served as the primary outcome of the study for Phase 1, and the number of oxygen free days (OFDs) by day 28 for Phase 2.ResultsBetween August 2020 and July 2021, when the study was prematurely stopped due to low recruitment rate, 28 patients were included in Phase 1 and 79 patients in Phase 2. Of those, 78 were included in the intention to treat analysis, and the primary outcome was available for 77 patients. During Phase 1, one SAE (i.e., bradycardia) was considered possibly related to the infusion, justifying its discontinuation. In Phase 2, OFDs did not differ between groups (median 19 [0–21] vs. 14 [0–18] days; p = 0.15). When patients from both phases were analyzed in a pooled intention to treat approach (Phase 1–2 trial), OFDs were significantly higher in treated patients, when compared to controls (19 [0–21] vs. 14 [0–18] days; absolute difference −5 days, 95% CI [0–7] p = 0.04).ConclusionsThe main findings of our study indicate that continuous intravenous infusion of Angiotensin-(1–7) at 10 mcg/Kg day in COVID-19 patients admitted to the ICU with severe pneumonia is safe. In Phase II intention to treat analysis, there was no significant difference in OFD between groups.Trial Registration ClinicalTrials.gov Identifier: NCT04633772—Registro Brasileiro de Ensaios Clínicos, UTN number: U1111-1255-7167.

Safety, reactogenicity, and immunogenicity of different doses of 10-valent Extraintestinal Pathogenic Escherichia Coli (ExPEC10V) bioconjugate vaccine (VAC52416) in healthy Japanese adults aged 60–85 years in a randomized, double-blind, phase 1 study

AimThis phase 1 study (NCT04306302) evaluated the safety, reactogenicity, and immunogenicity of ExPEC10V (VAC52416) in healthy Japanese adults. MethodThe randomized, double-blind, single-center study included 28-day screening, vaccination (Day 1), 30-day safety and immunogenicity follow-up and 181-day serious adverse events (SAEs) follow-up. Participants (60–85 years) were enrolled in dose-ascending approach and randomized to medium- and high-doses of ExPEC10V (n = 8 in each dose group) and placebo (n = 8). Incidence of adverse events: solicited AEs (until Day 15), unsolicited AEs (until Day 30), SAEs (until Day 181) and immunogenicity (electrochemiluminescent-based assay [ECL] and multiplex opsonophagocytic assay [MOPA]) were assessed on Day 15 and Day 30. ResultsTotal of 24 participants were included (median age, 66.5 years; 50.0 % female). Incidence of solicited AEs was 81.3 % (local) and 18.8 % (systemic) for pooled ExPEC10V group (medium-dose ExPEC10V: 75.0 % [local], 12.5 % [systemic]; high-dose ExPEC10V: 87.5 % [local], 25.0 % [systemic]). One SAE, not vaccine-related, was reported in high-dose ExPEC10V group after Day 30, which was resolved during study. The ECL demonstrated increase in binding antibody titers, which was maintained from Day 15 to Day 30. For all serotypes, the geometric mean fold increases from baseline on Day 15 ranged from 2.51 to 10.60 and 1.97–5.23 for medium- and high-dose groups, respectively. The MOPA demonstrated increase in functional antibody responses for all serotypes (except O8) at Day 15 which was maintained from Day 15 to Day 30. ConclusionsExPEC10V medium- and high-doses were well tolerated with an acceptable safety profile without any significant safety issues in healthy Japanese participants.

295. SAFETY OF SURVEILLANCE GASTROSCOPY AND ENDOSCOPIC ULTRASONOGRAPHY IN THE OESOPHAGUS AFTER NEOADJUVANT CHEMORADIOTHERAPY: RESULTS FROM THE SANO COHORT

Abstract Background An organ sparing strategy has been proposed for patients with oesophageal cancer and a clinically complete response after neoadjuvant chemoradiotherapy (nCRT). This active surveillance strategy involves (repeated) oesophagogastroduodenoscopy (OGD) with bite-on-bite biopsies and endoscopic ultrasonography (EUS). The preSANO trial and preliminary results of the SANO trial concluded that these procedures are safe to identify those with a clinically complete response. However, the safety of these procedures beyond that timeframe remains unknown. The aim of this study is to assess the safety of endoscopic procedures after nCRT, extending beyond three months. Methods This is a retrospective multicentre cohort study. All patients who participated in the pre-SANO and SANO studies were included. All were treated with CROSS nCRT for oesophageal cancer and underwent (repeated) endoscopic response evaluations (OGD with bite-on-bite biopsies and/or EUS with fine needle aspiration, as indicated). Primary outcome was serious adverse events (SAE) as defined by Central Committee on Research Involving Human Subjects (CCMO) associated with endoscopic procedures which include (but are not limited to) bleeding, infection and perforation. Secondary outcome included mechanical injury. Results A total of 919 patients underwent at least one endoscopic response evaluation. Some 2355 endoscopic procedures (61% OGD with EUS combined, 33% OGD and 6% EUS) were performed. Of these, 819 (35%) were performed more than three months after nCRT. SAEs were reported for five endoscopic procedures (0.2%) and included three cases of gastrointestinal bleeding after OGD with biopsies and two cases with infection secondary to the endoscopic procedures. No significant difference in SAEs was found between the procedures conducted before and more than three months after nCRT (2 vs. 3, OR 2.8, 95% CI, 0.3 – 33.7, P = 0.35). Conclusion OGD with biopsies and EUS are both procedures which can be safely performed after nCRT during an active surveillance strategy.

Duodeno-ileal diversion with self-forming magnets in a sutureless neodymium anastomosis procedure (SNAP) for weight recidivism after sleeve gastrectomy: feasibility and 9-month results.

The sleeve gastrectomy (SG) has become the most common bariatric procedure worldwide. However, insufficient weight loss or weight recidivism is frequent, which may require effective and safe revisional procedures. To determine the technical feasibility and safety of a minimally invasive, duodeno-ileal side-to-side anastomosis using a Sutureless Neodymium Anastomosis Procedure (SNAP) for patients with weight recidivism or inadequate weight loss following SG. This is a prospective, single-arm, open-label pilot study that enrolled patients with obesity to assist in weight reduction following an SG performed > 12months prior. For the SNAP, self-assembling magnets were deployed into the ileum (laparoscopically) and duodenum (per-oral endoscopy). Magnets were coupled under laparoscopic and fluoroscopic guidance to create a compression anastomosis. The primary endpoints were technical feasibility, weight loss, and rate of serious adverse events (SAEs). Successful duodeno-ileal diversions were created with SNAP in 27 participants (mean age: 50.6 ± 9.1, mean BMI: 38.1 ± 4.6kg/m2) with no device-related serious adverse events. Upper endoscopy at 3months confirmed patent, healthy anastomoses in all patients. At 9months, patients (n = 24) experienced 11.9 ± 6.2%, 14.5 ± 10.8%, and 17.0 ± 13.9% TBWL at 3, 6, and 9months, respectively. There were no device-related SAEs. The SNAP is technically feasible and relatively safe, with all patients presenting widely patent anastomosis at 3months. Patients experienced a progressive, clinically meaningful weight loss. Further studies are needed to confirm our findings.

Abstract P340: Efficacy and safety of a novel single-pill combination (SPC) of allisartan isoproxil and sustained-release indapamide for uncontrolled hypertension by allisartan isoproxil monotherapy: a multicenter, randomized, double-blind, parallel-group phase III study

Introduction: SAL0108 by Shenzhen Salubris Pharmaceuticals Co., Ltd is a novel SPC containing 240mg of allisartan isoproxil (AI) and 1.5 mg of sustained-release (SR) indapamide. AI is a novel angiotensin receptor blocke available in China for over ten years and has the same active compound EXP3174 with losartan, while indapamide SR is a long-standing thiazide-type diuretic. Hypothesis: We assessed the hypothesis that SAL0108 is more effective than AI monotherapy. Methods: Patients with uncontrolled HTN after AI monotherapy for a minimum duration of 4 weeks were enrolled and randomized 2:1 to receive SAL0108 or continue AI treatment for a 12-week duration (double-blinded phase). Subsequently, all participants receive SAL0108 treatment until week 52 (extended period). The primary endpoint was the change in mean seated systolic blood pressure (msSBP) from baseline to week 12, assessed utilizing a treatment policy estimand within the full analysis set. Results: A total of 366 patients were enrolled, with 243 randomized to SAL0108 cohort and 123 to AI cohort. The mean age was 58.7 years, with 50.3% of patients being female. Baseline characteristics were comparable between the two cohorts. After 12 weeks of treatment, the mean change in msSBP from baseline was -15.48±17.96 mmHg in SAL0108 cohort, and -10.19±17.93 mmHg in AI cohort. SAL0108 demonstrated a significantly greater reduction in msSBP compared to AI, showing a mean difference of -5.29 mmHg (95% CI: -9.24 to -1.33; P=0.009). The achievement of msSBP/diastolic blood pressure of < 130/80 mmHg at week 12 was observed in 15.3% and 6.3% of patients in SAL0108 and AI cohorts, respectively (proportion difference 8.9%; P=0.016). Throughout the double-blinded phase, adverse events were observed in 56.8% of patients in SAL0108 cohort (most commonly being hyperuricemia, hyperlipidemia and COVID-19 infection) and 45.5% in AI cohort. Serious adverse events (SAEs) occurred in 1.7% and 4.1% of patients receiving SAL0108 and AI, respectively, and were deemed unrelated to the study drugs. Hypokalemia was infrequent, noted in 4.1% of SAL0108 recipients and 1.6% of AI recipients. During extended period, SAEs were observed in 3.9% of patients and were unrelated to SAL0108. No deaths related to the study drugs were reported. Conclusions: In conclusion, SAL0108 exhibits better efficacy in reducing blood pressure compared to AI monotherapy. The results also highlight the favorable safety profile of SAL0108 for long-term HTN management.

A randomized, double-blind, placebo-controlled trial of weight loss using liraglutide 3.0 mg for weight recurrence after Roux-en-Y gastric bypass

BackgroundBariatric surgery, such as Roux-en-Y gastric bypass (RYGB) remains the gold standard for treating obesity. Most people regain weight from postsurgery nadir. ObjectivesLiraglutide 3.0 mg is approved for weight management. This study will examine the effects on liraglutide 3.0 mg on weight regain post-RYGB. SettingUniversity Hospital, United States. MethodsA 56-week, double-blind, placebo-controlled study was conducted in 132 subjects, who achieved ≥25% total body weight loss (TBWL) status-post-RYGB and regained ≥10% TBWL after reaching nadir weight (NW). Subjects 18–120 months post-RYGB were randomized to receive liraglutide 3.0 mg/d (n = 89) or placebo (n = 43) with lifestyle counseling regularly for 56 weeks. The co-primary endpoints were the proportion of subjects losing at least 5%, 10%, and 15% TBWL and achieving weight lower than their NW. Results53.4% of the placebo group and 65% of the liraglutide group completed the trial due to Severe acute respiratory syndrome coronavirus 2 pandemic. The change in %TBWL from baseline to 56-weeks was −8.8 (8.5, −29.2 to 9.7) and 1.1 (3.5, −7.9 to 5.99) in the liraglutide and placebo groups, respectively. 76% and 17% of subjects achieved ≥5% TBWL at 56 weeks in the liraglutide and placebo groups, respectively; 51% and 26.0% of the liraglutide group achieved ≥10% and ≥15% TBWL, respectively. None of the placebo group lost ≥10% TBWL. Twenty-one percent of subjects receiving liraglutide surpassed postoperative NW. No subjects on placebo met this goal. Nonserious adverse events occurred in 41.6% of subjects on liraglutide. Serious adverse events (SAE) occurred less often on liraglutide. ConclusionsLiraglutide was significantly more effective than placebo in treating weight regain that occurs post-RYGB without increased SAE.

Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial.

Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use. Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507. In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs. ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947.

Three months of weekly rifapentine plus isoniazid for TB prevention among people with HIV

&lt;sec&gt;&lt;title&gt;BACKGROUND&lt;/title&gt;Evidence on implementation of three months of weekly isoniazid (H, INH) and rifapentine (P, RPT) (3HP) as a TB preventive therapy (TPT) for at-risk groups in Indian programmatic conditions is limited.&lt;/sec&gt;&lt;sec&gt;&lt;title&gt;METHODS&lt;/title&gt;A prospective demonstration study assessing scale-up, safety, and effectiveness of 3HP TPT among people living with HIV (PLHIV) in Indian programmatic settings was conducted.&lt;/sec&gt;&lt;sec&gt;&lt;title&gt;RESULTS&lt;/title&gt;Of 656 screened PLHIV, 502 (77%) received 3HP. Of these, 20 (4%) discontinued TPT due to toxicity,17 (3.8%) lost to follow-up, one (0.2%) had breakthrough rifampicin-sensitive TB, and 464 (92%) completed 3 HP TPT. Of 288 (57%) overall adverse events (AEs), 46 (9%) had Grade 2 or above AEs. The median time to AE was 14 days (IQR 7–42). Serious adverse events (SAEs) were reported in 9 (2%) participants; of these, 7 (78%) were not related to 3HP. No TB episodes occurred during the 1-year follow-up period.&lt;/sec&gt;&lt;sec&gt;&lt;title&gt;CONCLUSION&lt;/title&gt;3HP TPT completion rate of 92%, with few adverse events leading to 3HP discontinuation, providing evidence of the scalability and safety of 3HP TPT among PLHIV in Indian health program settings.&lt;/sec&gt;

Catamaran SI Joint Fusion System(R) MAINSAILTM Study: a prospective, single-arm, multi-center, post-market study of six-month clinical outcomes and twelve-month radiographic findings

ABSTRACT Background Minimally invasive surgical techniques for sacroiliac joint (SIJ) fixation have the potential to reduce risk and improve patient outcomes, but evidence remains limited. This interim analysis presents initial findings from an ongoing prospective study evaluating the safety and efficacy of the Catamaran System. Methods The primary endpoint of success at 6 months was defined as a ≥20 mm improvement in SIJ pain (Visual Analog Scale, VAS), no neurologic worsening, absence of device-related serious adverse events (SAEs), and no surgical reintervention. Secondary endpoints included 6 month evaluation of the Oswestry Disability Index (ODI), patient satisfaction, and 12 month radiographic CT fusion, performed by an indpendent radiologist. Results Thirty-three consecutive patients (mean age: 58.9 years; %-females: 76%; Body Mass Index: 30.5) were treated across six U.S. clinical sites. At the primary endpoint of 6 months, 80% of patients met the criteria for success, with no device-related SAEs and no surgical reintervention reported. VASSIJ-Pain significantly decreased from preoperative levels (mean: 80.9 mm) to 6 months postoperatively (31.1 mm; p < 0.001). Mean ODI scores also showed a significant improvement from preoperative values (51.9%) to 6 months postoperatively (29.6%, p < 0.01). Patients reported high satisfaction rates throughout all follow-ups, with 93.3% of patients being satisfied at 6 months. Conclusion In patients diagnosed with chronic SIJ pain, minimally invasive inferior-posterior delivery of the Catamaran implant was safe and effective in relieving pain and reducing disability.

Drug-induced liver injury associated with atypical generation antipsychotics from the FDA Adverse Event Reporting System (FAERS)

BackgroundRecent studies have shown that liver enzyme abnormalities were not only seen with typical antipsychotics (APs) but also with atypical antipsychotics (AAPs). During the last 20 years, the hepatotoxicity of various antipsychotics received much attention. However, systematic evaluations of hepatotoxicity associated with APs are limited.MethodsAll drug related hepatic disorders cases were retrieved from the FDA Adverse Event Reporting System (FAERS) database using standardized MedDRA queries (SMQ) from the first quarter of 2017 to the first quarter of 2022. Patient characteristics and prognosis were assessed. In this study, a case/non-case approach was used to calculate reporting odds ratio (RORs) and 95% confidence intervals (CIs). We calculated the drug-induced liver injury (DILI) RORs for each AAPs.ResultsA total of 408 DILI cases were attributed to AAPs during the study period. 18.6% of these were designated as serious adverse event (SAE), which include death (19.74%), hospitalization (68.42%), disability (2.63%), and life-threatening (9.21%) outcomes. The RORs values in descending order were: quetiapine (ROR = 0.782), clozapine (ROR = 0.665), aripiprazole (ROR = 0.507), amisulpride (ROR = 0.308), paliperidone (ROR = 0.212), risperidone (ROR = 0.198), ziprasidone (0.131).ConclusionThe result found in our study was that all AAPs didn’t have a significant correlation with increased hepatotoxicity. Future analysis of the FAERS database in conjunction with other data sources will be essential for continuous monitoring of DILI.

Prognostic significance and treatment strategies for IKZF1 deletion in pediatric B-cell precursor acute lymphoblastic leukemia

BackgroundThe predictive importance of IKZF1del in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has shown variability across different studies. Thus, the optimal treatment approach for children with IKZF1del BCP-ALL remains contentious, with the ongoing debate surrounding the use of IKZF1del-based high-risk stratification versus a minimal residual disease (MRD)-guided protocol.MethodsIKZF1 status was reliably determined in 804 patients using multiplex ligation-dependent probe amplification (MLPA) data obtained from four hospitals in Fujian, a province of China. In the Chinese Children Leukemia Group (CCLG)-ALL 2008 cohort, IKZF1 status was included in the risk assignment, with all IKZF1del patients receiving a high-risk regimen. Conversely, in the Chinese Children’s Cancer Group (CCCG)-ALL 2015 cohort, IKZF1del was not incorporated into the risk assignment, and patients were treated based on an MRD-guided risk stratification protocol.ResultsIKZF1del was found in 86 patients (86/804, 10.7%) overall and in 30 (30/46, 65.2%) BCR::ABL1-positive patients. Overall, IKZF1del was a poor prognostic predictor for patients, though the significance diminished upon age adjustment, white blood cell (WBC) count at diagnosis, treatment group, and MRD status. In the CCLG-ALL 2008 cohort, IKZF1del conferred a notably lower 5-year overall survival (OS) and event-free survival (EFS) and a significantly higher 5-year cumulative incidence of relapse (CIR) than IKZF1wt. In the CCLG-ALL 2015 cohort, IKZF1del conferred a lower 5-year OS and EFS and a higher 5-year CIR than IKZF1wt, but the differences were insignificant. The IKZF1del patients treated with higher intensity chemotherapy (CCLG-ALL 2008 high-risk regimen) had a markedly lower 5-year OS and EFS compared with those treated with the MRD-guided protocol (CCCG-ALL 2015 protocol). Furthermore, patients treated with the CCLG-ALL 2008 high-risk regimen experienced a higher frequency of serious adverse events (SAEs), especially infection-related SAEs, compared with those treated with the CCCG-ALL 2015 MRD-guided protocol.ConclusionsThe prognostic effect of IKZF1del may vary in different protocols. Compared with higher intensity chemotherapy, the MRD-guided protocol may be a more effective approach to treating BCP-ALL with IKZF1del in children.

Immunogenicity and Safety of Chikungunya Vaccines: A Systematic Review and Meta-Analysis.

Several vaccines against chikungunya fever have been developed and tested, and one has been recently licensed. We performed a meta-analysis to estimate the immunogenicity and safety of all chikungunya vaccines that have been progressed to clinical trial evaluation (VLA1553; mRNA-1388/VAL-181388; PXVX0317/VRC-CHKVLP059-00-VP; ChAdOx1 Chik; MV-CHIK). We included trials retrieved from MedLine, Scopus, and ClinicalTrials.gov. The outcomes were the rates of seroconversion/seroresponse and serious adverse events (SAEs) after the primary immunization course. We retrieved a total of 14 datasets, including >4000 participants. All candidate chikungunya vaccines were able to elicit an immunogenic response in ≥96% of vaccinated subjects, regardless of the vaccination schedule and platform used, and the seroconversion/seroresponse rates remained high 6 to 12 months after vaccination for most vaccines. Four of the five candidate vaccines showed a good overall safety profile (no data were available for ChAdOx1 Chik), with no significant increase in the risk of SAEs among the vaccinated, and a low absolute risk of product-related SAEs. Overall, the present findings support the potential use of the candidate vaccines for the prevention of chikungunya and the current indication for use in adult travelers to endemic regions of the licensed VLA 1553 vaccine. In order to extend chikungunya vaccination to a wider audience, further studies are needed on individuals from endemic countries and frail populations.

Discrepancies in the results reported for multiple sclerosis clinical trials: A comparison between ClinicalTrials.gov and peer-reviewed journals.

We aimed to compare the results of phase III and IV clinical trials examining drugs to treat multiple sclerosis (MS) registered at ClinicalTrials.gov to those published in peer-reviewed journals. After identifying trials registered at ClinicalTrials.gov, consecutive searches were conducted in PubMed, EMBASE and Google Scholar for matching publications. Information regarding participants and efficacy and safety results was extracted and compared. The degree of consistency was classified as 'concordant', 'discrepant' or 'not comparable'. The Kaplan-Meier method was used to model time to reporting. In total, 65 trials were appraised. The median time from completion to reporting was shorter for ClinicalTrials.gov (16.4 vs 27.3 months; p = 0.010). Information availability was generally higher in journals except for serious adverse events (SAEs) (86.2% vs 100.0%, p = 0.029) and their description (78.2% vs 100.0%, p < 0.001). However, 45 trials had at least one reporting discrepancy (69.2%). Three studies omitted one or more primary outcomes in the matching journal publication. Regarding safety results, the lowest consistencies were found for causes of death (60.0%) and description of SAEs (27.9%). Consulting both ClinicalTrials.gov and journals increases the accessibility to MS clinical trial results. Some data were frequently missing or disagreed between sources, raising concerns about transparency and generalizability of results.

Long-term outcomes of infliximab treatment in neuro-Behcet syndrome: A single-center retrospective study.

Behcet's syndrome is a rare inflammatory disorder characterized by oral and genital ulcers, skin lesions, and uveitis. It exhibits a higher prevalence along the historic Silk Road. Neuro-Behcet syndrome (NBS) affects the central nervous system and poses significant morbidity and mortality risks. Infliximab, a TNF-alpha antagonist, has shown potential in NBS management, although the current evidence is mainly derived from case series due to the lack of randomized controlled trials. This retrospective study aimed to evaluate the disease outcomes during the first and second years following infliximab treatment in NBS patients experiencing attacks despite prior conventional immunosuppressive therapy. The study also sought to investigate the safety profile and adverse effects associated with infliximab. Fifty-three NBS patients were examined, with 22 receiving infliximab as either monotherapy or in combination with other therapies. Retrospective analysis was conducted on demographic data, clinical characteristics, and treatment responses. Treatment efficacy was measured using the Expanded Disability Status Scale (EDSS) modified for NBS. The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist guidelines. Among the study cohort, 60.4% had parenchymal NBS, and 39.6% had nonparenchymal NBS. Treatment with infliximab resulted in remission or disease stabilization in 95% of patients after one year and 68.7% after 2years. Relapse rates were 4.5% at 1year and 18.7% at 2years, with disease progression observed in two cases. Adverse effects were primarily mild to moderate, with no reports of serious adverse events. Infliximab exhibited efficacy in achieving remission or stabilization in NBS patients, maintaining a favorable safety profile. The timing of infliximab treatment may prevent the accumulation of disability and hinder disease progression. Nonetheless, future prospective studies are necessary to confirm these findings and refine treatment strategies for this complex condition.

Development and application of a serious adverse events risk model for concurrent chemoradiotherapy in patients with nasopharyngeal carcinoma.

The objective of this study was to construct a concise prediction model for serious adverse events (SAEs) in order to assess the likelihood of SAE occurrence among hospitalized patients undergoing concurrent chemoradiotherapy. An electronic database of a Cancer Centre was utilized to conduct a cross-sectional review survey. Our research involved the recruitment of 239 patients who were undergoing concurrent chemoradiotherapy in the Department of Nasopharynx and Radiotherapy. The clinical prediction rule was derived using logistic regression analysis, with SAE serving as the primary outcome. Internal verification was conducted. The occurrence rate of SAE in the derivation cohort was 59.4%. The ultimate model used had 3 variables, namely cystatin C, C-reactive protein, and serum amyloid A. The model exhibited an area under the curve of 0.626 (95% CI: 0.555-0.696; P < .001). The model accurately predicts the occurrence of SAE, and the variable data can be easily obtained, and the assessment technique is straightforward.

Immunogenicity and Safety of SARS-CoV-2 Protein Subunit Recombinant Vaccine (IndoVac®) as a Heterologous Booster Dose against COVID-19 in Indonesian Adolescents.

Adolescents are vulnerable to Coronavirus disease 2019 (COVID-19) infections; thus, their antibodies should be maintained above the protective value. This study aimed to evaluate the immune response and safety to the SARS-CoV-2 protein subunit recombinant vaccine (IndoVac®) as a heterologous booster dose against COVID-19 in Indonesian adolescents. This open-label prospective intervention study enrolled 150 clinically healthy adolescents aged 12-17 years who had received complete primary doses of the CoronaVac® vaccine from Garuda Primary Care Centres in Bandung City. The result of immunogenicity was presented with a 95% confidence interval (CI) and analyzed with t-tests from 14 days and 3, 6, and 12 months. The neutralizing antibody geometric mean titers (GMTs) (IU/mL) at baseline and 14 days after booster dose were 303.26 and 2661.2, respectively. The geometric mean fold rises (GMFR) at 3, 6, and 12 months after booster dose were 6.67 (5.217-8.536), 3.87 (3.068-4.886), and 2.87 (2.232-3.685), respectively. Both the neutralizing antibody and IgG antibody were markedly higher in the adolescents than in the adults at every timepoint. The incidence rate of adverse effects (AEs) until 28 days after booster dose was 82.7%, with a higher number of local events reported. Most reported solicited AEs were local pain followed by myalgia with mild intensity. Unsolicited AEs varied with each of the incidence rates < 10%, mostly with mild intensity. Adverse events of special interest (AESI) were not observed. At the 12-month follow-up after the booster dose, four serious adverse events (SAEs) not related to investigational products and research procedures were noted. This study showed that IndoVac® has a favorable immunogenicity and safety profile as a booster in adolescents and that the antibody titer decreases over time.

Equivalence of freeze-dried and liquid-frozen formulations of MVA-BN as smallpox and mpox vaccine

ABSTRACT Modified Vaccinia Ankara Bavarian Nordic (MVA-BN) as a smallpox and mpox vaccine has been approved in its liquid-frozen (LF) formulation in the US, Canada, and EU. A freeze-dried (FD) formulation may offer additional benefits, such as a longer shelf life and reduced dependence on cold chain storage and transport. In a phase 2 clinical trial, 651 vaccinia-naïve participants were vaccinated with two doses of MVA-BN LF or FD, 4 weeks apart. The objectives were to compare MVA-BN FD with LF in terms of vaccine-induced immune responses, safety, and reactogenicity. Non-inferiority of the immune response was assessed by the 95% CI of the geometric mean ratios. Both formulations induced robust vaccinia-specific humoral and cellular immune responses. At peak humoral responses (Week 6), geometric means of total antibody titers were 1096 (95% CI 1013, 1186) from the FD group and 877 (95% CI 804, 956) from the LF group, achieving the primary endpoint of non-inferiority of MVA-BN FD compared to MVA-BN LF. At peak cellular responses (Week 2), geometric means of T cell spot forming units were 449 (95% CI 341, 590) from the FD group and 316 (95% CI 234, 427) from the LF group. Both formulations of MVA-BN were well tolerated, with similar unsolicited AEs and solicited systemic reactions in both groups but slightly more local reactions in the FD group. No vaccine-related serious adverse events (SAEs) or vaccine-related AE of special interest were reported. The FD formulation of MVA-BN was shown to be equivalent to MVA-BN LF.

Safety and effectiveness of tofacitinib in Korean adult patients with ulcerative colitis: post-marketing surveillance study

BackgroundTofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to identify the safety and effectiveness of tofacitinib in patients with UC in routine clinical settings in Korea.MethodsThis open-label, observational, prospective, post-marketing surveillance study was conducted at 22 hospitals in the Republic of Korea. Patients with moderate to severe active UC who received tofacitinib were included and followed up for up to 52 weeks. Tofacitinib was administered at a dosage of 10 mg twice daily for at least 8 weeks, followed by 5 or 10 mg twice daily at the investigator’s discretion based on clinical evaluation according to the approved Korean label. Safety including adverse events (AEs) and effectiveness including clinical remission, clinical response, and endoscopic mucosal healing were evaluated. Safety analysis set was defined as all patients registered for this study who received at least one dose of tofacitinib according to the approved Korean label and followed up for safety data. Effectiveness analysis set included patients in the safety analysis set who were evaluated for overall effectiveness assessment and excluded patients who had received tofacitinib less than 8 weeks.ResultsA total of 110 patients were enrolled, of whom 106 patients were included in the safety population. The median duration of treatment was 370 days and the treatment duration ranged from 16 to 684 days for the safety population. AEs occurred in 42 patients (39.6%). Serious AEs (SAEs) occurred in 7 patients (6.6%) and of them, there were 2 cases of serious infections. These serious infections were reported as Adverse Event of Special Interest (AESI) in this study and no other AESI were reported. There were no cases of death during the study period. Clinical remission rates were 40.0%, 46.7%, 57.6%, and 55.1% at 8, 16, 24, and 52 weeks, and clinical response rates were 77.8%, 87.9%, 56.6%, and 81.4% at each visit, respectively. Endoscopic mucosal healing rates were 58.7% at 16 weeks and 46.2% at 52 weeks.ConclusionTofacitinib was effective in Korean patients with moderate to severe active UC and the safety findings were consistent with the known safety profile of tofacitinib.SummaryThis study confirmed the safety and effectiveness of tofacitinib in Korean patients with moderate to severe active UC in routine clinical settings.Trial registrationThis study is registered in the ClinicalTrials.gov under the identifier NCT04071405, registered on 28 August 2019.