Incidence Of Serious Adverse Events Research Articles

#468 Voclosporin-based, triple-immunosuppressive therapy vs high-dose glucocorticoid-based dual-immunotherapy for lupus nephritis: a propensity analysis

Abstract Background and Aims Voclosporin is a second generation calcineurin inhibitor (CNI) approved for the treatment of adults with active lupus nephritis (LN) in combination with immunosuppressive therapy. An integrated analysis of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies concluded that combining voclosporin with lower-dose mycophenolate mofetil (MMF, 2 g/day) and low-dose glucocorticoids (GCs) led to significantly greater and earlier reductions in proteinuria when compared to MMF and GCs alone. This is an important finding as early reduction in proteinuria is associated with improved long-term kidney survival and mortality. Yet, dual-immunosuppressive regimens consisting of high-dose glucocorticoids and either intravenous cyclophosphamide (IVC) or higher doses of MMF (>2 g/day) continue to be frequently used for the initial management of active LN despite their association with incomplete efficacy and dose-dependent toxicities. Method All three studies enrolled participants with active LN. In AURA-LV and AURORA 1, participants received voclosporin 23.7 mg BID in combination with MMF (target 2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (target 3 g/day) or IVC (0.5 to 1.0 g/m2/month × 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate groups of matched participants (ALMS [MMF and IVC] vs. AURA-LV/AURORA 1 [voclosporin]) based on demographic and disease characteristics. Safety and efficacy were assessed at 3 and 6 months. Results Propensity matching identified 179 pairs of participants with similar demographics and baseline disease characteristics. Mean cumulative exposure to GCs was more than 2-fold higher in the IVC and MMF cohorts of ALMS than AURA-LV/AURORA 1 participants over both 3 and 6 months. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants of ALMS, although more participants in AURA-LV and AURORA 1 reported hypertension and anemia (Table 1). Due to the known hemodynamic effects of calcineurin inhibition, there was a small decrease in mean eGFR in the AURA-LV/AURORA 1 participants in the first few weeks of treatment after which mean eGFR remained stable; AURA-LV/AURORA 1 participants also had an increased rate of events of GFR decreased. The incidence of serious AEs was similar across treatments. In the first 3 months of treatment, significantly more AURA-LV/AURORA 1 participants achieved a reduction in UPCR >25% from baseline (91.6% vs 69.3%; odds ratio [OR] 4.75, 95% confidence interval [CI] 2.56, 8.84; p < 0.0001). Over six months of treatment, mean (SD) change from baseline in UPCR was −3.1 (2.9) g/g in voclosporin-treated patients in AURA-LV and AURORA 1 compared to −2.4 (3.3) g/g in IVC- or MMF-treated participants in ALMS (Fig. 1). Conclusion Voclosporin-based, triple immunosuppressive therapy was associated with an improved safety profile as well as greater and earlier reductions in proteinuria compared to more conventional dual immunosuppressive regimens. These data support treatment guidelines for active LN that recommend both minimizing patient exposure to GCs and use of a multi-targeted treatment regimen as initial therapy.

Outcome of Transjugular Intrahepatic Portosystemic Shunt in Patients with Cirrhosis and Refractory Hepatic Hydrothorax: A Systematic Review and Meta-analysis

Abstract Background Around 5% of patients with cirrhosis of the liver develop hepatic hydrothorax (HH). For patients with refractory HH (RHH), transjugular intrahepatic portosystemic shunt (TIPS) has been investigated in small studies. Hence, the present meta-analysis aimed to summarize the current data on the outcome of TIPS in patients with RHH. Methods From inception through June 2023, MEDLINE, Embase, and Scopus were searched for studies analyzing the outcome of TIPS in RHH. Clinical response, adverse events (AEs), mortality, and shunt dysfunction were the primary outcomes assessed. The event rates with their 95% confidence interval were calculated using a random-effects model. Results A total of 12 studies (n = 466) were included in the final analysis. The pooled complete and partial response rates were 47.2% (35.8–58.5%) and 25.5% (16.7–34.3%), respectively. The pooled incidences of serious AEs and post-TIPS liver failure after TIPS in RHH were 5.6% (2.1–9.0%) and 7.6% (3.1–12.1%), respectively. The pooled incidences of overall hepatic encephalopathy (HE) and severe HE nonresponsive to standard treatment after TIPS in RHH were 33.2% (20.0–46.4%) and 3.6% (0.4–6.8%), respectively. The pooled 1-month and 1-year mortality rates were 14.0% (8.3–19.6%) and 42.0% (33.5–50.4%), respectively. The pooled incidence of shunt dysfunction after TIPS in RHH was 24.2% (16.3–32.2%). Conclusion RHH has a modest response to TIPS in patients with cirrhosis, with only half having a complete response. Further studies are required to ascertain whether early TIPS can improve the outcome of patients with cirrhosis and HH.

Intensive Ambulance-Delivered Blood-Pressure Reduction in Hyperacute Stroke.

Treatment of acute stroke, before a distinction can be made between ischemic and hemorrhagic types, is challenging. Whether very early blood-pressure control in the ambulance improves outcomes among patients with undifferentiated acute stroke is uncertain. We randomly assigned patients with suspected acute stroke that caused a motor deficit and with elevated systolic blood pressure (≥150 mm Hg), who were assessed in the ambulance within 2 hours after the onset of symptoms, to receive immediate treatment to lower the systolic blood pressure (target range, 130 to 140 mm Hg) (intervention group) or usual blood-pressure management (usual-care group). The primary efficacy outcome was functional status as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days after randomization. The primary safety outcome was any serious adverse event. A total of 2404 patients (mean age, 70 years) in China underwent randomization and provided consent for the trial: 1205 in the intervention group and 1199 in the usual-care group. The median time between symptom onset and randomization was 61 minutes (interquartile range, 41 to 93), and the mean blood pressure at randomization was 178/98 mm Hg. Stroke was subsequently confirmed by imaging in 2240 patients, of whom 1041 (46.5%) had a hemorrhagic stroke. At the time of patients' arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, as compared with 170 mm Hg in the usual-care group. Overall, there was no difference in functional outcome between the two groups (common odds ratio, 1.00; 95% confidence interval [CI], 0.87 to 1.15), and the incidence of serious adverse events was similar in the two groups. Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common odds ratio, 0.75; 95% CI, 0.60 to 0.92) but an increase among patients with cerebral ischemia (common odds ratio, 1.30; 95% CI, 1.06 to 1.60). In this trial, prehospital blood-pressure reduction did not improve functional outcomes in a cohort of patients with undifferentiated acute stroke, of whom 46.5% subsequently received a diagnosis of hemorrhagic stroke. (Funded by the National Health and Medical Research Council of Australia and others; INTERACT4 ClinicalTrials.gov number, NCT03790800; Chinese Trial Registry number, ChiCTR1900020534.).

Adverse events with endoscopic ultrasound-guided gastroenterostomy for gastric outlet obstruction-A systematic review and meta-analysis.

The technical and clinical effectiveness of endoscopic ultrasonography (EUS)-guided gastroenterostomy (GE) has been reported by several meta-analyses, but few of them have addressed the adverse events (AE). The goal of the current meta-analysis was to analyze the AEs associated with various types of EUS-GE. All relevant studies reporting the AEs with EUS-GE were searched from 2000 to 31st March 2023 in MEDLINE, Embase, and Scopus. The event rates were pooled using a random effects model. A total of 36 studies (n=1846) were included in the meta-analysis. The present meta-analysis reports a pooled technical success rate of 96.9% (95.9-98.0; I2=29.3%) with a pooled clinical success rate of 90.6% (88.5-92.7; I2=60.9%). The pooled incidence of overall AEs with EUS-GE was 13.0% (10.3-15.7; I2=69.7%), with the commonest being maldeployment of the stent, seen in 4.6% (3.2-6.0; I2=50.6%). The pooled incidences of serious AE and procedure-related mortality were 1.2% (0.7-1.8; I2=1.9%) and 0.3% (0.0-0.7; I2=0.0%), respectively. Subgroup analysis of studies using only the free-hand technique showed a significantly lower overall AE and maldeployment but not serious AE and other individual AEs. The pooled incidences of delayed stent migration and stent occlusion were 0.5% (0.0-1.1; I2=0.0%) and 0.8% (0.2-1.3; I2=0.0%), respectively. Despite a technical and clinical success rate of >90%, AEs are seen in around one-seventh of the cases of EUS-GE, maldeployment being the commonest. However, the pooled incidence of serious AE and mortality remains low, which is reassuring.

The Efficacy and Safety of Hyperthermic Intravesical Chemotherapy Compared with Other Instillation Methods in Treating Intermediate- and High-Risk Non-Muscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis

Background. In order to prevent the recurrence and progression of intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT), various bladder instillation therapies have been developed in recent years. Among these, device-assisted Hyperthermic Intravesical Chemotherapy (HIVEC) has received a great deal of attention. Objective. To identify the efficacy and safety of HIVEC, we conducted this meta-analysis. Methods. We identified relevant articles from PubMed, Embase, and Cochrane Library databases. All published randomized controlled trials (RCTs) describing the role of bladder instillation for the treatment of intermediate- and high-risk NMIBC were involved. Outcomes included 1–3 years Recurrence-Free Survival (RFS), 1–3 years Progression-Free Survival (PFS), 5 years Overall Survival (OS), Adverse Events (AEs), and relevant subgroup analyses. Result. Our study involved a total of 10 RCTs and 1360 patients. In subgroup analysis, we found that compared to MMC instillation, HIVEC decreased the 1–3 years RFS (OR = 0.51; p=0.009) while not increasing the incidence of AEs (OR = 0.86; p=0.30). Compared with BCG instillation, HIVEC reduced the incidence of serious AEs (OR = 0.21; p=0.04) while bringing the same efficacy (OR = 0.78; p=0.63). Conclusion. HIVEC combined the advantages of efficacy and safety compared with the two recommended instillation modalities. As a potential alternative therapy, its widespread clinical effect remains to be further evaluated.

Abstract PS15-02: A Phase Ⅰb Study of D-0502 as Monotherapy for Advanced or Metastatic ER-Positive and HER2-Negative Breast Cancer: Results from the Dose-Expansion Stage

Abstract Background: Endocrine therapy is the mainstay treatment for estrogen receptor (ER)-positive advanced breast cancer (BC). D-0502, an orally bioavailable selective estrogen receptor degrader (SERD), has previously demonstrated antitumor activity in various ER-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer cell lines and xenograft models. The phase Ⅰ open-label study (NCT03471663) evaluated the safety, tolerability, pharmacokinetics (PK) and efficacy of D-0502 as monotherapy and in combination with palbociclib in female patients with ER+ and HER2- breast cancer. The dose escalation part of D-0502 monotherapy (phase Ⅰa) has been presented before (SABCS 2021, PS11-26 Abstract #1348). Here, we present the results of D-0502 monotherapy from the dose-expansion stage in phase Ⅰb study. Methods: In the single-agent dose-expansion stage of phase Ⅰb study, patients (n=60) received D-0502 (400 mg QD) in 28-day cycles. Eligible patients included females with confirmed ER+, HER2- locally advanced, or metastatic BC; ECOG 0-1; measurable disease (RECIST v1.1); premenopausal or postmenopausal status; adequate hematologic, hepatic and renal functions. The primary objectives are to characterize the safety of D-0502. The secondary objectives are to evaluate the preliminary anti-tumor activity and the PK characteristic. Results: As of April 07, 2023, 60 female patients were enrolled and treated with 400mg single-agent D-0502. Median age was 57 (range: 32-82) years, 55.0% had an ECOG PS of 1. Disease progression resulting in treatment discontinuation occurred in 66.7% (40/60) of patients, and 6.7% (4/60) of patients discontinued treatment because of AEs. Treatment-related adverse events (TRAEs) were reported in 57 pts (95.0%), most of which were grade 1-2. No grade 4/5 TRAE has been reported. The incidence of serious adverse events was 6.7% (4/60). The most common (≥ 15%) TRAEs included vomiting, dizziness, nausea, increased aspartate aminotransferase and alanine aminotransferase, anaemia, decreased appetite, diarrhoea, and malaise. In the 51 efficacy evaluable patients, 8 patients had partial response (PR) and 27 had stable disease (SD); objective response rate (ORR) and disease control rate (DCR) were 15.7% (8/51) and 68.6% (35/51), respectively. The clinical benefit rate (CBR: CR + PR + SD ≥24 weeks) was 47.1% (24/51). The median PFS was 5.6 months (95% Cl: 2.0, 10.0). Conclusion: D-0502 monotherapy showed promising antitumor activity and tolerable toxicity in female patients with ER+ and HER2- locally advanced or metastatic BC. Currently this treatment is being evaluated in a phase Ⅲ study for patients with ER+ and HER2- locally advanced or metastatic BC in China. Citation Format: Jiayu Wang, Tao Sun, Qingyuan Zhang, Yanxia Shi, Xu Wang, Yiding Chen, Quchang Ouyang, Kunyan Li, Manojkumar Bupathi, w. Jeffery Edenfield, Andrea L.M. Silber, Hong Zong, Erika Hamilton, Dejan Juric, Kate Lathrop, Yihong Zhang, Kathryn Stazzone, Zhe Shi, Yaolin Wang, Ling Zhang, Binghe Xu. A Phase Ⅰb Study of D-0502 as Monotherapy for Advanced or Metastatic ER-Positive and HER2-Negative Breast Cancer: Results from the Dose-Expansion Stage [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS15-02.

Abstract PO5-01-05: An Open-label, Single-center Study Assessing the Efficacy of PH-based Regimen as Neoadjuvant Therapy for HER2-positive Early-stage Breast Cancer: Integrating Genomic Features and Functional Imaging

Abstract Background: Pathological complete response (pCR) has been demonstrated as a surrogate endpoint for disease-free and overall survival in HER2-positive early-stage breast cancer (EBC). Trastuzumab (H) plus pertuzumab (P) improved pCR rates in patients with HER2-positive early-stage breast cancer. Nevertheless, biomarkers to assess the effectiveness of this treatment in the neoadjuvant setting are still unclear. This study aims to evaluate the effectiveness of fluorodeoxyglucose positron emission tomography (18F-FDG-PET) and 68 Ga-Affibody HER2 Imaging PET (HER2-PET) in HER2 EBC neoadjuvant therapy, and to identify novel biomarkers for this regimen. Methods: HER2-positive EBC patients were prospectively recruited at Fudan University Shanghai Cancer Center between April 2020 and March 2022. All patients received the 1 dose of HP, followed by 6 cycles of docetaxel (T), carboplatin (Cb), and HP. We use FoundationOne to evaluate the genomic alterations before treatment. In addition, 18F-FDG-PET and HER2 PET were performed at baseline, after 1 cycle of HP, and after 6 cycles of TCbHP, to assess the effectiveness of these examinations in the prediction of pCR and correlation to disease burden. All patients were received surgery and completed 1 year of HP-based regimen in the adjuvant setting. Results: A total of 61 patients with a median age of 49 years were included. Among them, 93.5% of patients are node positive. 75.8% of the patients reported adverse events (AEs), primarily grade 1 and 2. The incidence of serious AEs was 6.6%. Patients exhibiting a greater than 40% reduction in SUVmax of 18-FDG-PET or HER2-PET scans from baseline to the fifth day after the initial HP treatment were classified as the treatment-sensitive group. The pCR rate for the 18-FDG-PET-sensitive group was 79.3%, while for the insensitive group was 48.1%. For HER2-PET scans, the pCR rate was 70.0% in the sensitive group and 59.3% in the non-sensitive group. To evaluate the potential biomarkers, 25 patients (13 pCR and 12 non-pCR) were evaluated with FoundationOne, with the identification of 1,321 somatic alterations. The most frequently altered genes were ERBB2 (100%), TP53 (96%), CDK12 (76%), MYC (56%), CCND1 (44%), PIK3CA (40%), and SRSF2 (36%). In the pCR group, we found PPM1D (38.5%) and RAD21 (38.5%) were altered more frequently than the non-pCR group. PIK3CA alterations were significantly reduced in pCR group, only 23% of cases are affected compared to 58.3% in non-pCR group. Patients were non-pCR had more MDM4 (41.7%) and ZNF217 (41.7%) alterations than pCR patients. Conclusion: The SUVmax value of 18-FDG-PET and HER2-PET scans are correlated well with the tumor burden and the residual disease in the HER2 EBCs. The reduction of SUVmax could predict pCR but need further exploration. Patients with alterations in PPM1D and RAD21 have a favorable response to the TCbHP regimen. Conversely, alterations in PIK3CA, MDM4, and ZNF217 are associated with treatment resistance. These results indicate the significance of 18-FDG-PET and HER2-PET in monitoring treatment effectiveness. The biomarker analysis in this study will help us understand the mechanism of HER2 positive breast cancer treatment resistance and assisting in tailoring personalized therapy. Clinical trial information: NCT04281641. Citation Format: Ming Chen, Benlong Yang, Sun Yuyun, Linxiaoxi Ma, Song Shaoli, Min He, Zhi-Ming Shao, Bingqiu Xiu, Jiong Wu. An Open-label, Single-center Study Assessing the Efficacy of PH-based Regimen as Neoadjuvant Therapy for HER2-positive Early-stage Breast Cancer: Integrating Genomic Features and Functional Imaging [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-01-05.

Effects of avoidance versus use of neuromuscular blocking agents for facilitation of tracheal intubation in children and infants.

The European Society of Anesthesiology and Intensive Care recommends the use of neuromuscular blocking agents (NMBA) in adults, to facilitate tracheal intubation and reduce its associated complications. Children who undergo tracheal intubation may suffer some of the same complications, however, no consensus exists regarding the use of NMBA for tracheal intubation in the pediatric population. We will explore the existing evidence assessing the effects of avoidance versus the use of NMBA for the facilitation of tracheal intubation in children and infants. This protocol follows the preferred reporting items for systematic reviews and meta-analyses protocols recommendations. We will include all randomized controlled clinical trials assessing the effects of avoidance versus the use of NMBA for facilitation of tracheal intubation (oral or nasal) using direct laryngoscopy or video laryngoscopy in pediatric participants (<18 years). Our primary outcome is incidence of difficult tracheal intubation. Secondary outcomes include incidence of serious adverse events, failed intubation, events of upper airway discomfort or injury, and difficult laryngoscopy. We will conduct a thorough database search to identify relevant trials, including CENTRAL, MEDLINE, EMBASE, BIOSIS, Web of Science, CINAHL, and trial registries. Two review authors will independently handle the screening of literature and data extraction. Each trial will be evaluated for major sources of bias with the "classic risk of bias tool" used in the Cochrane Collaboration tool from 2011. We will use Review manager (RevMan) or R with the meta package to perform the meta-analysis. We will perform a trial sequential analysis on the meta-analysis of our primary outcome, providing an estimate of statistical reliability. Two review authors will independently assess the quality of the body of evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We will use GRADEpro software to conduct the GRADE assessments and to create "Summary of the findings" tables.

A Comparison of the Immunogenicity and Safety of an Additional Heterologous versus Homologous COVID-19 Vaccination among Non-Seroconverted Immunocompromised Patients after a Two-Dose Primary Series of mRNA Vaccination: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aimed to compare the immunogenicity and safety of an additional heterologous (viral vector) versus homologous (mRNA) COVID-19 vaccine dose among non-seroconverted immunocompromised patients after a two-dose primary series of mRNA vaccine. We searched studies published up to 21 June 2023 in PubMed, Scopus, and Embase. The meta-analysis was conducted to compare the seropositivity rates based on anti-SARS-CoV-2 spike protein IgG (anti-S IgG) and SARS-CoV-2-specific T-cell immune response rates, assessed by interferon-γ release assay at 4 weeks, and the incidences of serious adverse events (SAEs) within 28 days between the two vaccine regimens. In four included randomized controlled trials (RCTs), there were no statistically significant differences in the seropositive rate of anti-S IgG (risk ratio [RR]: 0.79, 95% CI: 0.48-1.29) and the concentration of SARS-CoV-2 interferon-γ (RR: 1.19, 95% CI: 0.96-1.48) between heterologous and homologous regimens. The heterologous regimen exhibited a significantly lower incidence of injection pain (RR: 0.55, 95% CI: 0.45-0.69), but a higher incidence of headache (RR: 1.44, 95% CI: 1.02-2.02) compared with the homologous regimen. No vaccine-related SAEs were reported within 28 days following vaccination. An additional heterologous or homologous COVID-19 vaccine dose was well tolerated and demonstrated a comparable vaccine immunogenicity among non-seroconverted immunocompromised patients who were initially vaccinated with a two-dose COVID-19 mRNA vaccine. This finding supports the recommendations of an extended primary series of COVID-19 vaccination in immunocompromised persons.

Efficacy and Safety of PEGylated Interferons for Relapsing-Remitting Multiple Sclerosis in Adult Patients: Results of Matching-Adjusted Indirect Comparison

Introduction. Beta interferons are effective and safe agents for the treatment of relapsing-remitting multiple sclerosis (RRMS). PEGylated interferons have been developed in order to increase patient adherence. Direct comparisons of the efficacy and safety of PEGylated interferons have not yet been conducted.&#x0D; Our objective was to evaluate the efficacy and safety of SamPEG-IFN-β1a versus PEG-IFN-β1a in adult patients with RRMS.&#x0D; Materials and methods. We conducted a systematic search of randomized clinical trials (RCTs) using the PubMed, Embase and eLIBRARY.RU databases. Efficacy was assessed based on the proportion of patients with disease relapses and the annualized relapse rate (ARR) during the 1st and the 2nd years of treatment. Safety was assessed by the number of patients with adverse events (AEs), serious AEs (SAEs), and any AEs that led to the treatment discontinuation. We conducted pairwise matching-adjusted indirect comparison (MAIC) to assess comparative efficacy of PEGylated IFNs. To evaluate the efficacy, hypotheses of non-inferiority of SamPEG-IFN-β1a to PEG-IFN-β1a and superiority of SamPEG-IFN-β1a over PEG-IFN-β1a were tested.&#x0D; Results. Based on results of the systematic review, four articles were selected wherein the results of phase 3 clinical trial of PEG-IFN-β1a and phase 2–3 clinical trial of SamPEG-IFN-β1a were described. In PEG-IFN-β1a group (n = 512) the agent was administered once every 2 weeks, in SamPEGIFN-β1a group (n = 114) the agent was administered at a dose of 240 μg. The analysis results confirmed the hypothesis of SamPEG-IFN-β1a non-inferiority to PEG-IFN-β1a in efficacy, while SamPEG-IFN-β1a superiority over PEG-IFN-β1a in efficacy was not confirmed. The hypothesis of SamPEG-IFN-β1a superiority over PEG-IFN-β1a in safety was also confirmed based on a significantly lower incidence of SAEs and any AEs that led to treatment discontinuation.&#x0D; Conclusions. The proportion of patients with relapses and the ARR in 1 year and in 2 years of therapy indicates that SamPEG-IFN-β1a is non-inferior to PEG-IFN-β1a in efficacy. SamPEG-IFN-B1a demonstrated a more favourable safety profile than PEG-IFN-B1a as showing less odds of SAEs and AEs leading to treatment discontinuation.

Safety and tolerability of OP-724 in patients with haemophilia and liver cirrhosis due to HIV/HCV coinfection: an investigator-initiated, open-label, non-randomised, single-centre, phase I study

ObjectivePatients with haemophilia and HIV who acquire hepatitis C virus (HCV) after receiving contaminated blood products can experience accelerated progression of liver fibrosis and a poor prognosis, making liver disease...

Abstract 3560: Quantified kinematics and wearable sensors to predict serious adverse events in patients undergoing cancer therapy trials

Abstract Background: Serious adverse events (SAEs) are a critical determinant of drug toxicity in clinical trials. However the drivers of toxicity may be related to patient factors as much or more than drug related factors. Prior studies have shown that time in non-sedentary activity predicted toxicity in cancer patients receiving highly emetogenic chemotherapy. SAEs are a critical determinant of drug toxicity in clinical trials. However, predicting SAEs using conventional PS scales measurements, such as ECOG is challenging because measurements can vary among observers. Prior studies have used activity trackers to measure physical activity and showed that time spent in non-sedentary activity predicted toxicity in cancer patients receiving highly emetogenic chemotherapy. Here, we sought to extend these findings to early phase clinical trial participants by examining data collected in two single-arm, observational, prospective studies at USC Keck and MD Anderson centers. We explored the use of out-of-clinic wearable sensors as an objective metric of frailty so as to identify patients at risk for therapy complications. Methods: Adult patients diagnosed with cancer and enrolled in early stage clinical trials across USC Keck and MD Anderson centers were included in parallel single-arm, observational, prospective studies. Patients used a consumer grade wearable activity tracker (Fitbit) and the study examined associations between the number of severe adverse events to activity levels measured by metabolic equivalents (METs) and get-up-go times across the first 30 days. Trends were assessed using t-tests. Results: 36 eligible patients were included in METs activity analysis. There was a total of 16 recorded incidences of SAEs within the first 30 study days, with 10 patients experiencing at least one SAE. The median non-sedentary time for patients with no SAEs was 27.5 hours above 1.5 METs per week, compared to 21.5 hours for those with at least one SAE occurrence (p-value=0.0146, r2=0.1629). The median get-up-go times for those without SAEs was 10.0 seconds (n=26) and with SAEs was 9.8 seconds (n=10), (p-value=0.828, r2=0.0014). Conclusions: Non-sedentary time, as an objective measure of activity, can be used to identify those patients who are at greatest risk for SAEs in clinical trials. Widely available and inexpensive consumer grade sensors can be used as a stratification tool. Findings should be confirmed in larger patient cohorts across a wider variety of trial settings. Figure 1: Weekly non-sedentary hours vs. presence of SAE in first 30 days of trial enrollment Citation Format: Eli Tran, Luciano Nocera, Anand Kolatkar, Anthony El-Khoueiry, Jacob Thomas, Peter Kuhn, Andrew Zeng, Megumi Kai, Meghan Karuturi, Jorge Nieva. Quantified kinematics and wearable sensors to predict serious adverse events in patients undergoing cancer therapy trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3560.

A randomized, blind, parallel controlled phase I clinical trial to evaluate the safety and preliminary immunogenicity of 23-valent pneumococcal polysaccharide vaccine in healthy people aged 2 years and older

BackgroundDespite some progress in pneumococcal immunization, the global burden of pneumococcal infection remains high, and pneumococcal disease remains a public health concern. Studies in China and abroad have found that 23-valent pneumococcal polysaccharide vaccine (PPV23) vaccination can effectively prevent invasive pneumococcal disease. This phase Ⅰ clinical study assessed the safety and immunogenicity of a PPV23 vaccine candidate. MethodsAll subjects were randomly assigned to receive one dose intramuscular injection of experimental vaccine or control vaccine at a ratio of 1:1. The incidence of any adverse events was observed within 30 min, 0–7 days and 8–28 days post vaccination and the incidence of abnormal blood biochemical and blood routine indicators were tested on the 4th day post vaccination, the incidence of serious adverse events (SAEs) at 6 months post vaccination was recorded. Blood samples were collected prior to vaccination and on the 28th day post vaccination, and serum antibodies were detected by enzyme linked immunosorbent assay (ELISA). ResultsThe most common adverse reaction was pain at the injection site, followed by erythema. There was no significant difference of the incidence of systemic adverse reactions between the two vaccine groups. The adverse reactions observed in the trial were all common vaccination-related reactions, and no serious adverse reactions were observed. Compared to pre-vaccination, the (geometric mean concentrations) GMCs of IgG (immunoglobulin G) specific antibody against each serotype were all increased in the experimental group and the control group, there were statistical differences in seroconversion rates of serotypes 4 and 20 between the two vaccine groups. ConclusionThis clinical study showed good safety of the PPV23 vaccine candidate produced by Ab&b Biotechnology Co., Ltd.JS had good safety after vaccination in people aged 2 years and older. At the same time, good immunogenicity was also demonstrated.

Efficacy and safety of the Aria pulmonary endovascular device in pulmonary hypertension.

A common feature of various forms of pulmonary hypertension (PH) is progressive decline of pulmonary arterial compliance (CPA ), which correlates with reduced survival. In this acute study, we evaluated feasibility, safety and haemodynamic performance of the Aria pulmonary endovascular device in patients with PH associated with left heart disease (PH-LHD) and chronic lung disease (PH-CLD). Eight patients with PH-LHD and 10 patients with PH-CLD were included in this study. The device was placed in the main pulmonary artery via the right femoral vein and was connected by a catheter to a gas-filled reservoir outside the body. During systole, gas shifts from the balloon to the reservoir, leading to deflation of the balloon. In diastole, the gas returns from the reservoir to the balloon, leading to balloon inflation and enhancing diastolic blood flow to the distal pulmonary capillary bed. Haemodynamics were assessed at baseline, and again with device off, device on and device off. The primary safety endpoint was the incidence of serious adverse events through 30 days after the procedure. No complications or investigational device-related serious adverse events occurred. Device activation in PH-LHD and PH-CLD patients decreased pulmonary arterial pulse pressure by 5.6 ± 4.2 mmHg (-12%; p = 0.003) and 4.2 ± 2.2 mmHg (-11%; p < 0.001), increased CPA by 0.4 ± 0.2 ml/mmHg (+23%; p = 0.004) and 0.4 ± 0.3 ml/mmHg (+25%; p = 0.001), and increased right ventricular-to-pulmonary vascular (RV-PV) coupling by 0.24 ± 0.18 (+40%; p = 0.012) and 0.11 ± 0.07 (+21%; p = 0.001), respectively. Temporary implantation of the Aria endovascular device was feasible and safe. Device activation resulted in acute improvement of CPA and RV-PV coupling.

Clinico-pathological Outcomes of Muscle Invasive Carcinoma Bladder in Post Neoadjuvant Chemotherapy Radical Cystectomy

Background: Neoadjuvant chemotherapy (NAC) before radical cystectomy is advocated in patients with muscle invasive urothelial carcinoma of the bladder with the goal to improve survival by downstaging the primary tumour and eradicating micro-metastasis. The use of perioperative chemotherapy for bladder cancer, particularly in the neoadjuvant setting, remains limited. This study was designed to evaluate NAC plus RC regarding pathological response, perioperative morbidity and mortality outcomes. Methods: This is a prospective and retro prospective study that was carried out from Jan 2018 to Jan 2020 for patients with muscle invasive bladder carcinoma. All patients having operable muscle invasive bladder carcinoma, Eastern Cooperative Oncology Group (ECOG) performance status 0–1 were included. Patients found to have metastatic disease, recurrent disease, patient not able to tolerate NAC were excluded from the study. Results: Early complications occurred within 30 days after surgery &amp; pathological response rates, perioperative morbidity, and mortality were compared. Conclusions: A short course of neoadjuvant chemotherapy was associated to a low incidence of serious adverse events and did not increase the post-operative morbidity. Results suggest that non-urothelial tumour showed no response to Platinum based combination chemotherapeutic regimens. After NAC, residual local disease, persistent nodal disease and status of surgical margins are the most powerful prognostic factors for patients who underwent RC.

Comparative efficacy and safety of COVID-19 vaccines in phase III trials: a network meta-analysis.

Over a dozen vaccines are in or have completed phase III trials at an unprecedented speed since the World Health Organization (WHO) declared COVID-19 a pandemic. In this review, we aimed to compare and rank these vaccines indirectly in terms of efficacy and safety using a network meta-analysis. We searched Embase, MEDLINE, and the Cochrane Library for phase III randomized controlled trials (RCTs) from their inception to September 30, 2023. Two investigators independently selected articles, extracted data, and assessed the risk of bias. Outcomes included efficacy in preventing symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the incidence of serious adverse events (SAEs) according to vaccine type and individual vaccines in adults and elderly individuals. The risk ratio and mean differences were calculated with 95% confidence intervals using a Bayesian network meta-analysis. A total of 25 RCTs involving 22 vaccines were included in the study. None of vaccines had a higher incidence of SAEs than the placebo. Inactivated virus vaccines might be the safest, with a surface under the cumulative ranking curve (SUCRA) value of 0.16. BIV1-CovIran showed the highest safety index (SUCRA value: 0.13), followed by BBV152, Soberana, Gam-COVID-Vac, and ZF2001. There were no significant differences among the various types of vaccines regarding the efficacy in preventing symptomatic SARS-CoV-2 infection, although there was a trend toward higher efficacy of the mRNA vaccines (SUCRA value: 0.09). BNT162b2 showed the highest efficacy (SUCRA value: 0.02) among the individual vaccines, followed by mRNA-1273, Abdala, Gam-COVID-Vac, and NVX-CoV2373. BNT162b2 had the highest efficacy (SUCRA value: 0.08) in the elderly population, whereas CVnCoV, CoVLP + AS03, and CoronaVac were not significantly different from the placebo. None of the different types of vaccines were significantly superior in terms of efficacy, while mRNA vaccines were significantly inferior in safety to other types. BNT162b2 had the highest efficacy in preventing symptomatic SARS-CoV-2 infection in adults and the elderly, whereas BIV1-CovIran had the lowest incidence of SAEs in adults.

Intraoperative Wound Irrigation for the Prevention of Surgical Site Infection After Laparotomy

Surgical site infections frequently occur after open abdominal surgery. Intraoperative wound irrigation as a preventive measure is a common practice worldwide, although evidence supporting this practice is lacking. To evaluate the preventive effect of intraoperative wound irrigation with polyhexanide solution. The Intraoperative Wound Irrigation to Prevent Surgical Site Infection After Laparotomy (IOWISI) trial was a multicenter, 3-armed, randomized clinical trial. Patients and outcome assessors were blinded to the intervention. The clinical trial was conducted in 12 university and general hospitals in Germany from September 2017 to December 2021 with 30-day follow-up. Adult patients undergoing laparotomy were eligible for inclusion. The main exclusion criteria were clean laparoscopic procedures and the inability to provide consent. Of 11 700 screened, 689 were included and 557 completed the trial; 689 were included in the intention-to-treat and safety analysis. Randomization was performed online (3:3:1 allocation) to polyhexanide 0.04%, saline, or no irrigation (control) of the operative wound before closure. The primary end point was surgical site infection within 30 postoperative days according to the US Centers for Disease Control and Prevention definition. Among the 689 patients included, 402 were male and 287 were female. The median (range) age was 65.9 (18.5-94.9) years. Participants were randomized to either wound irrigation with polyhexanide (n = 292), saline (n = 295), or no irrigation (n = 102). The procedures were classified as clean contaminated in 92 cases (8%). The surgical site infection incidence was 11.8% overall (81 of 689), 10.6% in the polyhexanide arm (31 of 292), 12.5% in the saline arm (37 of 295), and 12.8% in the no irrigation arm (13 of 102). Irrigation with polyhexanide was not statistically superior to no irrigation or saline irrigation (hazard ratio [HR], 1.23; 95% CI, 0.64-2.36 vs HR, 1.19; 95% CI, 0.74-1.94; P = .47). The incidence of serious adverse events did not differ among the 3 groups. In this study, intraoperative wound irrigation with polyhexanide solution did not reduce surgical site infection incidence in clean-contaminated open abdominal surgical procedures compared to saline or no irrigation. More clinical trials are warranted to evaluate the potential benefit in contaminated and septic procedures, including the emergency setting. drks.de Identifier: DRKS00012251.

The value of organ and tissue biovigilance: a cross-sectional analysis

IntroductionBiovigilance (BV) systems aim to improve the quality and safety of tissues and organs for transplantation. This study describes the Catalan BV system and analyzes its utility.MethodsIt is a retrospective analysis of notifications on serious adverse events (SAEs) and reactions (SARs) since the implementation of the BV system (2008 for tissues and 2016 for organs) until 2020. Variables are presented to describe the most common critical steps of the pathway and complications associated with the quality and safety of tissues and organs.ResultsA total of 154 and 125 notifications were reported to the Tissue and the Organ BV systems, respectively. Most SAEs were related to unexpected donor diseases and implemented actions were assured on those deemed preventable. Regarding SARs, donor-transmitted infections and malignancies (only organs) were the most common, followed by graft failure (tissues) and process-related (organs). The incidence of SAEs and SARs related to tissue was 3.44‰ and 0.22‰, respectively. The corresponding figures for organs were 31.48‰ and 8.8‰, respectively.DiscussionThe analysis of the notifications to the Catalan BV systems has provided useful information about existing risks associated with the quality and safety of tissues and organs, and enabled the implementation of actions targeted to diminish risks and mitigate damage.

A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis

BackgroundNonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta–selective agonist in development for the treatment of NASH with liver fibrosis.MethodsWe are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score.ResultsOverall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was −13.6% in the 80-mg resmetirom group and −16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group.ConclusionsBoth the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.)

Effects of Oxygenation Targets on Mortality in Critically Ill Patients in Intensive Care Units: A Systematic Review and Meta-Analysis.

The effects of oxygenation targets (partial pressure of arterial oxygen [Pao2], arterial oxygen saturation [Sao2]/peripheral oxygen saturation [Spo2], or inspiratory oxygen concentration [Fio2] on clinical outcomes in critically ill patients remains controversial. We reviewed the existing literature to assess the effects of lower and higher oxygenation targets on the mortality rates of critically ill intensive care unit (ICU) patients. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science databases were searched from their dates of inception to December 31, 2022, for randomized controlled trials (RCTs) comparing lower and higher oxygenation targets for critically ill patients ≥18 years of age undergoing mechanical ventilation, nasal cannula, oxygen mask, or high-flow oxygen therapy in the ICU. Data extraction was conducted independently, and RoB 2.0 software was used to evaluate the quality of each RCT. A random-effects model was used for the meta-analysis to calculate the relative risk (RR). We used the I2 statistic as a measure of statistical heterogeneity. Certainty of evidence was assessed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. We included 12 studies with a total of 7416 patients participating in RCTs. Oxygenation targets were extremely heterogeneous between studies. The meta-analysis found no differences in mortality between lower and higher oxygenation targets for critically ill ICU patients (relative risk [RR], 1.00; 95% confidence interval [CI], 0.93-1.09; moderate certainty). The incidence of serious adverse events (RR, 0.93; 95% CI, 0.85-1.00; high certainty), mechanical ventilation-free days through day 28 (mean difference [MD], -0.05; 95%CI, -1.23 to 1.13; low certainty), the number of patients requiring renal replacement therapy (RRT) (RR, 0.96; 95% CI, 0.84-1.10; low certainty), and ICU length of stay (MD, 1.05; 95% CI, -0.04 to 2.13; very low certainty) also did not differ among patients with lower or higher oxygenation targets. Critically ill ICU patients ≥18 years of age managed with lower and higher oxygenation targets did not differ in terms of mortality, RRT need, mechanical ventilation-free days through day 28, or ICU length of stay. However, due to considerable heterogeneity between specific targets in individual studies, no conclusion can be drawn regarding the effect of oxygenation targets on ICU outcomes.