Occurrence Of Serious Adverse Events Research Articles

S1067 Endoscopic Sleeve Gastroplasty vs Intragastric Balloon: A Large, Database Analysis of Early Safety and Efficacy

Introduction: Intragastric balloon (IGB) placement and endoscopic sleeve gastroplasty (ESG) are the two most common endoscopic bariatric therapies currently performed in the United States. Procedural selection is often based primarily on patient preference. There is a lack of comparative data to help guide patient discussions regarding these interventions. This study is the largest study to date to directly compare short-term safety and efficacy of IGB to ESG using a large international bariatric database. Methods: All patients undergoing ESG and IGB across 800 hospitals in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database from 2016-2020 were included. All patients undergoing IGB were propensity matched to patients undergoing ESG. We compared occurrences of serious adverse events (SAE), readmissions, re-interventions, and emergency room (ER) visits within 30-days after procedure. Secondary outcomes included procedure time, length of stay (LOS), and total body weight loss (TBWL) measured at 30 days. (Table) Results: A total of 1,996 patients underwent IGB and 6,054 patients underwent ESG. All IGB patients were propensity matched to 1,996 ESG patients, with no differences in baseline characteristics. ESG and IGB had similarly low rates of SAE (p > 0.05). ESG had more readmissions within 30 days (p< 0.05). IGB had more outpatient treatments for dehydration and re-interventions within 30 days (p< 0.05), with 3.7% of patients reporting early balloon removal less than 30 days after implantation. ESG had greater %TBWL at 30 days (p< 0.05). Conclusion: ESG and IGB are both safe procedures with comparably low rates of SAE. ESG is perhaps better tolerated than IGB. Table 1. - ‡ Most common reason for readmission after both procedures was nausea, vomiting, and fluid/electrolyte or nutritional depletion. § Most common type of intervention after IGB was early IGB removal. The most common intervention after ESG was therapeutic endoscopy with stent placement or dilatation Comparing Short Term (30d) Procedural Outcomes of Endoscopic Sleeve Gastroplasty and Intragastric Balloon Placement ESG (n=1998) IGB (n=1998) p Mean BMI (SD) 36.36 (6.19) 36.17 (6.16) 0.316 Mean Change from Pre-Op to Post-Op BMI (SD) -1.51 (2.41) -0.95 (2.83) < 0.001 Mean % Total Body Weight Loss (%TBWL) (SD) 3.8% (7.9%) 2.3% (6.6%) < 0.001 Mean Number of Days from Procedure to Discharge (SD) 0.65 (1.76) 0.04 (0.33) < 0.001 Mean Procedure Length, minutes (SD) 64.97 (45.39) 16.51 (17.12) < 0.001 Serious Adverse Event, n (%) 17 (0.9) 5 (0.3) 0.055 Reoperation, n (%) 22 (1.1) 12 (0.6) 0.121 Readmission, n (%) ‡ 56 (2.8) 29 (1.5) 0.004 Re-Intervention, n (%) § 35 (1.8) 90 (4.5) < 0.001 Received Treatment for Dehydration Outpatient, n (%) 46 (2.3) 89 (4.5) < 0.001 Emergency Department Visit Not Resulting in Admission, n (%) 66 (3.3) 69 (3.5) 0.861

Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care.

Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care.

Efficacy and safety of a quadruple ultra-low-dose treatment for hypertension (QUARTET USA): Rationale and design for a randomized controlled trial

BackgroundOver half of patients with elevated blood pressure require multi-drug treatment to achieve blood pressure control. However, multi-drug treatment may lead to lower adherence and more adverse drug effects compared with monotherapy. ObjectiveThe Quadruple Ultra-low-dose Treatment for Hypertension (QUARTET) USA trial was designed to evaluate whether initiating treatment with ultra-low-dose quadruple-combination therapy will lower office blood pressure more effectively, and with fewer side effects, compared with initiating standard dose monotherapy in treatment naive patients with SBP < 180 and DBP < 110 mm Hg and patients on monotherapy with SBP < 160 and DBP < 100 mm Hg. Methods/DesignQUARTET USA was a prospective, randomized, double-blind trial (ClinicalTrials.gov NCT03640312) conducted in federally qualified health centers in a large city in the US. Patients were randomly assigned (1:1) to either ultra-low-dose quadruple combination therapy or standard dose monotherapy. The primary outcome was mean change from baseline in office systolic blood pressure at 12-weeks, adjusted for baseline values. Secondary outcomes included measures of blood pressure change and variability, medication adherence, and health related quality of life. Safety outcomes included occurrence of serious adverse events, relevant adverse drug effects, and electrolyte abnormalities. A process evaluation aimed to understand provider experiences of implementation and participant experiences around side effects, adherence, and trust with clinical care. DiscussionQUARTET USA was designed to evaluate whether a novel approach to blood pressure control would lower office blood pressure more effectively, and with fewer side effects, compared with standard dose monotherapy. QUARTET USA was conducted within a network of federally qualified healthcare centers with the aim of generating information on the safety and efficacy of ultra-low-dose quadruple-combination therapy in diverse groups that experience a high burden of hypertension.

A Risk-Factor Model for Antineoplastic Drug-Induced Serious Adverse Events in Cancer Inpatients: A Retrospective Study Based on the Global Trigger Tool and Machine Learning.

The objective of this study was to apply a machine learning method to evaluate the risk factors associated with serious adverse events (SAEs) and predict the occurrence of SAEs in cancer inpatients using antineoplastic drugs. A retrospective review of the medical records of 499 patients diagnosed with cancer admitted between January 1 and December 31, 2017, was performed. First, the Global Trigger Tool (GTT) was used to actively monitor adverse drug events (ADEs) and SAEs caused by antineoplastic drugs and take the number of positive triggers as an intermediate variable. Subsequently, risk factors with statistical significance were selected by univariate analysis and least absolute shrinkage and selection operator (LASSO) analysis. Finally, using the risk factors after the LASSO analysis as covariates, a nomogram based on a logistic model, extreme gradient boosting (XGBoost), categorical boosting (CatBoost), adaptive boosting (AdaBoost), light-gradient-boosting machine (LightGBM), random forest (RF), gradient-boosting decision tree (GBDT), decision tree (DT), and ensemble model based on seven algorithms were used to establish the prediction models. A series of indicators such as the area under the ROC curve (AUROC) and the area under the PR curve (AUPR) was used to evaluate the model performance. A total of 94 SAE patients were identified in our samples. Risk factors of SAEs were the number of triggers, length of stay, age, number of combined drugs, ADEs occurred in previous chemotherapy, and sex. In the test cohort, a nomogram based on the logistic model owns the AUROC of 0.799 and owns the AUPR of 0.527. The GBDT has the best predicting abilities (AUROC = 0.832 and AUPR = 0.557) among the eight machine learning models and was better than the nomogram and was chosen to establish the prediction webpage. This study provides a novel method to accurately predict SAE occurrence in cancer inpatients.

Janus kinase inhibitors for the treatment of COVID-19.

Janus kinase inhibitors for the treatment of COVID-19.

Safety and immunogenicity of the FINLAY-FR-1A vaccine in COVID-19 convalescent participants: an open-label phase 2a and double-blind, randomised, placebo-controlled, phase 2b, seamless, clinical trial

BackgroundA phase 1, clinical trial to evaluate FINLAY-FR-1A vaccine in COVID-19 convalescent individuals was completed. Here, we report results of the phase 2, clinical trial.MethodsWe studied 450 convalescent participants with a history of asymptomatic, mild, or moderate COVID-19 at the National Institute of Hematology and Immunology and the National Centre for Sexual Education in Havana, Cuba. The study included adults aged 19–78 years who had recovered from COVID-19 and had had a negative PCR test at least 2 months before the initiation of the study. Phase 2 was done sequentially in two stages. The first stage to assess safety comprised an open, non-controlled phase 2a study in participants aged 60–78 years who received a single dose of the FINLAY-FR-1A vaccine (50 μg of recombinant dimeric receptor binding domain [RBD]). The second stage comprised the placebo-controlled, double-blind, phase 2b trial in participants aged 19–78 years, where participants were randomly assigned (4:1) into two groups: an experimental group vaccinated with a single dose of the FINLAY-FR-1A vaccine, and a control (placebo) group injected with vaccine excipient. The primary outcomes were safety, evaluated 28 days after vaccination by the occurrence of serious adverse events in all participants, and successful immune response, assessed by neutralising antibody ELISA, and defined as half-maximal surrogate virus neutralisation titres of 250 or more. Secondary endpoints included vaccine immunogenicity assessed by ELISA anti-RBD and live-virus neutralisation test. All randomly assigned participants were included in the safety analysis (safety population), and immunogenicity was evaluated in participants without study interruptions (per-protocol population). The trial is registered with the Cuban Public Registry of Clinical Trials, RPCEC00000366-En and WHO-ICTRP and is complete.FindingsFrom April 9, 2021, to April 17, 2021, 663 COVID-19 convalescent participants were enrolled in the study; 213 participants did not meet the selection criteria and 450 volunteers were recruited. 20 participants aged 60–78 years were included in the open, single-group, phase 2a study and 430 participants were randomly assigned to the experimental (n=344) or control groups (n=86) in the phase 2b study of participants aged 19–78 years. 19 (95%) of 20 phase 2a volunteers achieved a successful immune response after vaccination. No vaccine-associated serious adverse events were reported in the whole study population. Minor adverse events were found, the most common being pain at the injection site (105 [29%] of 364 in the intervention group; 13 [15%] of 86 in the placebo group). A successful immune response was found in 289 (81%) of 358 participants 28 days after vaccination. The vaccine elicited a greater than 31-times increase in anti-RBD-IgG antibodies compared with prevaccination rates, and the seroconversion rate was 302 (84%) of 358 on day 28 after vaccination; the geometric mean titres of live-virus neutralisation test increased from 15·4 (95% CI 10·3–23·2) to 400·3 (272·4–588·1) and high response was found against alpha, beta, and delta variants of concern.InterpretationA single dose of the FINLAY-FR-1A vaccine against SARS-CoV-2 strengthened the pre-existing natural immunity, with excellent safety profile.FundingCuba's Ministry of Science, Technology, and Environment.

Universal hepatitis B vaccination in adults aged 19–59 years: Updated recommendations of the advisory committee on immunization practices—United States, 2022

Universal hepatitis B vaccination in adults aged 19–59 years: Updated recommendations of the advisory committee on immunization practices—United States, 2022

Efficacy and Safety of Pathogen-Reduced Platelets Compared with Standard Apheresis Platelets: A Systematic Review of RCTs.

In this systematic review, we evaluate the efficacy and safety of blood components treated with pathogen reduction technologies (PRTs). We searched the Medline, Embase, Scopus, Ovid, and Cochrane Library to identify RCTs evaluating PRTs. Risk of bias assessment and the Mantel–Haenszel method for data synthesis were used. We included in this review 19 RCTs evaluating 4332 patients (mostly oncohematological patients) receiving blood components treated with three different PRTs. Compared with standard platelets (St-PLTs), the treatment with pathogen-reduced platelets (PR-PLTs) does not increase the occurrence of bleeding events, although a slight increase in the occurrence of severe bleeding events was observed in the overall comparison. No between-groups difference in the occurrence of serious adverse events was observed. PR-PLT recipients had a lower 1 and 24 h CI and CCI. The number of patients with platelet refractoriness and alloimmunization was significantly higher in PR-PLT recipients compared with St-PLT recipients. PR-PLT recipients had a higher number of platelet and RBC transfusions compared with St-PLT recipients, with a shorter transfusion time interval. The quality of evidence for these outcomes was from moderate to high. Blood components treated with PRTs are not implicated in serious adverse events, and PR-PLTs do not have a major effect on the increase in bleeding events. However, treatment with PRTs may require a greater number of transfusions in shorter time intervals and may be implicated in an increase in platelet refractoriness and alloimmunization.

Clinical impact of vital sign abnormalities in patients admitted with acute exacerbation of chronic obstructive pulmonary disease: an observational study using continuous wireless monitoring.

Early detection of abnormal vital signs is critical for timely management of acute hospitalised patients and continuous monitoring may improve this. We aimed to assess the association between preceding vital sign abnormalities and serious adverse events (SAE) in patients hospitalised with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Two hundred patients' vital signs were wirelessly and continuously monitored with peripheral oxygen saturation, heart rate, and respiratory rate during the first 4days after admission for AECOPD. Non-invasive blood pressure was also measured every 30-60min. The primary outcome was occurrence of SAE according to international definitions within 30days and physiological data were analysed for preceding vital sign abnormalities. Data were presented as the mean cumulative duration of vital sign abnormalities per 24h and analysed using Wilcoxon rank sum test. SAE during ongoing continuous monitoring occurred in 50 patients (25%). Patients suffering SAE during the monitoring period had on average 455min (SD 413) per 24h of any preceding vital sign abnormality versus 292min (SD 246) in patients without SAE, p = 0.08, mean difference 163min [95% CI 61-265]. Mean duration of bradypnea (respiratory rate < 11min-1) was 48min (SD 173) compared with 30min (SD 84) in patients without SAE, p = 0.01. In conclusion, the duration of physiological abnormalities was substantial in patients with AECOPD. There were no statistically significant differences between patients with and without SAE in the overall duration of preceding physiological abnormalities.Study registration: http://ClinicalTrials.gov (NCT03660501). Date of registration: Sept 6 2018.

Efficacy of pharmacological interventions in COVID-19: A network meta-analysis.

AimsTo perform network meta‐analysis for a head‐to‐head comparison of various interventions used in coronavirus disease 2019 (COVID‐19) on mortality, clinical recovery, time to clinical improvement and the occurrence of serious adverse events.MethodsSystematic search was performed using online databases with suitable MeSH terms including coronavirus, COVID‐19, randomized controlled trial, hydroxychloroquine, lopinavir/ritonavir, tocilizumab, remdesivir, favipiravir, dexamethasone and interferon‐β. Data were independently extracted by 2 study investigators and analysed.ResultsOut of 1225 studies screened, 23 were included for qualitative and quantitative analysis. Among the drugs studied, dexamethasone reduces mortality by 10%, with a relative risk of 0.90 (95% confidence interval [0.82–0.97]) and increases clinical recovery by 6% (relative risk 1.06, 95% confidence interval [1.02–1.10]) compared to standard of care. Similarly, remdesivir administered for 10 days increased clinical recovery by 10%, reduced time to clinical improvement by 4 days and lowered the occurrence of serious adverse events by 27% as compared to standard of care.ConclusionIn comparison to standard of care, dexamethasone was found to increase clinical recovery and lower mortality; remdesivir was significantly associated with a lower risk of mortality as compared to tocilizumab and higher clinical recovery and shorter time to clinical improvement as compared to hydroxychloroquine and tocilizumab; remdesivir followed by tocilizumab were found to have lesser occurrence of serious adverse events in patients with moderate to severe COVID‐19.

Automated virtual reality therapy to treat agoraphobic avoidance and distress in patients with psychosis (gameChange): a multicentre, parallel-group, single-blind, randomised, controlled trial in England with mediation and moderation analyses

SummaryBackgroundAutomated delivery of psychological therapy using immersive technologies such as virtual reality (VR) might greatly increase the availability of effective help for patients. We aimed to evaluate the efficacy of an automated VR cognitive therapy (gameChange) to treat avoidance and distress in patients with psychosis, and to analyse how and in whom it might work.MethodsWe did a parallel-group, single-blind, randomised, controlled trial across nine National Health Service trusts in England. Eligible patients were aged 16 years or older, with a clinical diagnosis of a schizophrenia spectrum disorder or an affective diagnosis with psychotic symptoms, and had self-reported difficulties going outside due to anxiety. Patients were randomly assigned (1:1) to either gameChange VR therapy plus usual care or usual care alone, using a permuted blocks algorithm with randomly varying block size, stratified by study site and service type. gameChange VR therapy was provided in approximately six sessions over 6 weeks. Trial assessors were masked to group allocation. Outcomes were assessed at 0, 6 (primary endpoint), and 26 weeks after randomisation. The primary outcome was avoidance of, and distress in, everyday situations, assessed using the self-reported Oxford Agoraphobic Avoidance Scale (O-AS). Outcome analyses were done in the intention-to-treat population (ie, all participants who were assigned to a study group for whom data were available). We performed planned mediation and moderation analyses to test the effects of gameChange VR therapy when added to usual care. This trial is registered with the ISRCTN registry, 17308399.FindingsBetween July 25, 2019, and May 7, 2021 (with a pause in recruitment from March 16, 2020, to Sept 14, 2020, due to COVID-19 pandemic restrictions), 551 patients were assessed for eligibility and 346 were enrolled. 231 (67%) patients were men and 111 (32%) were women, 294 (85%) were White, and the mean age was 37·2 years (SD 12·5). 174 patients were randomly assigned to the gameChange VR therapy group and 172 to the usual care alone group. Compared with the usual care alone group, the gameChange VR therapy group had significant reductions in agoraphobic avoidance (O-AS adjusted mean difference –0·47, 95% CI –0·88 to –0·06; n=320; Cohen's d –0·18; p=0·026) and distress (–4·33, –7·78 to –0·87; n=322; –0·26; p=0·014) at 6 weeks. Reductions in threat cognitions and within-situation defence behaviours mediated treatment outcomes. The greater the severity of anxious fears and avoidance, the greater the treatment benefits. There was no significant difference in the occurrence of serious adverse events between the gameChange VR therapy group (12 events in nine patients) and the usual care alone group (eight events in seven patients; p=0·37).InterpretationAutomated VR therapy led to significant reductions in anxious avoidance of, and distress in, everyday situations compared with usual care alone. The mediation analysis indicated that the VR therapy worked in accordance with the cognitive model by reducing anxious thoughts and associated protective behaviours. The moderation analysis indicated that the VR therapy particularly benefited patients with severe agoraphobic avoidance, such as not being able to leave the home unaccompanied. gameChange VR therapy has the potential to increase the provision of effective psychological therapy for psychosis, particularly for patients who find it difficult to leave their home, visit local amenities, or use public transport.FundingNational Institute of Health Research Invention for Innovation programme, National Institute of Health Research Oxford Health Biomedical Research Centre.

Challenges and Opportunities of Real-World Data: Statistical Analysis Plan for the Optimise:MS Multicenter Prospective Cohort Pharmacovigilance Study.

IntroductionOptimise:MS is an observational pharmacovigilance study aimed at characterizing the safety profile of disease-modifying therapies (DMTs) for multiple sclerosis (MS) in a real world population. The study will categorize and quantify the occurrence of serious adverse events (SAEs) in a cohort of MS patients recruited from clinical sites around the UK. The study was motivated particularly by a need to establish the safety profile of newer DMTs, but will also gather data on outcomes among treatment-eligible but untreated patients and those receiving established DMTs (interferons and glatiramer acetate). It will also explore the impact of treatment switching.MethodsCausal pathway confounding between treatment selection and outcomes, together with the variety and complexity of treatment and disease patterns observed among MS patients in the real world, present statistical challenges to be addressed in the analysis plan. We developed an approach for analysis of the Optimise:MS data that will include disproportionality-based signal detection methods adapted to the longitudinal structure of the data and a longitudinal time-series analysis of a cohort of participants receiving second-generation DMT for the first time. The time-series analyses will use a number of exposure definitions in order to identify temporal patterns, carryover effects and interactions with prior treatments. Time-dependent confounding will be allowed for via inverse-probability-of-treatment weighting (IPTW). Additional analyses will examine rates and outcomes of pregnancies and explore interactions of these with treatment type and duration.ResultsTo date 14 hospitals have joined the study and over 2,000 participants have been recruited. A statistical analysis plan has been developed and is described here.ConclusionOptimise:MS is expected to be a rich source of data on the outcomes of DMTs in real-world conditions over several years of follow-up in an inclusive sample of UK MS patients. Analysis is complicated by the influence of confounding factors including complex treatment histories and a highly variable disease course, but the statistical analysis plan includes measures to mitigate the biases such factors can introduce. It will enable us to address key questions that are beyond the reach of randomized controlled trials.

Alzheimer's Disease THErapy With NEuroaid (ATHENE): ARandomized Double-Blind Delayed-Start Trial.

Preclinical and clinical studies indicate a role for MLC901 (NeuroAiD II) in Alzheimer's disease (AD). The primary aim was to investigate its safety as add-on therapy to standard treatment and the secondary aims its effect on cognition and slowing disease progression. Randomized double-blind placebo-controlled delayed-start study. Patients with mild to moderate probable AD by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n= 125), were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6months, followed by a further 6months when all patients received MLC901, in a delayed-start design (clinical trial registration: ClinicalTrials.gov, NCT03038035). The primary outcome measure was occurrence of serious adverse events (SAEs) at 6months. Secondary outcomes included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other assessment scales. There was no significant difference in the risk of SAEs between early and delayed starters at month (M) 6 (22.6% vs 27.0%, risk difference-4.4%, 90% CI -16.9% to 8.3%). Similarly, there was no significant difference in the risk of adverse events and the occurrence of stroke or vascular events between early and delayed starters throughout the 12-month study period. Early starters did not differ significantly on ADAS-Cog from delayed starters at M6 [mean difference (MD)-1.0, 95% CI -3.3 to 1.3] and M12 (MD -2.35, 95% CI -5.45 to 0.74) on intention-to-treat analysis. Other cognitive assessment scales did not show significant differences. This study of 125 persons with dementia found no evidence of a significant increase in adverse events between MLC901 and placebo, thus providing support for further studies on both efficacy and safety. Analyses suggest the potential of MLC901 in slowing down AD progression, but this requires further confirmation in larger and longer studies using biomarkers for AD.

Efficacy and Safety of Dapagliflozin in Patients With CKD Across Major Geographic Regions

IntroductionThis study aimed to examine the efficacy and safety of dapagliflozin in the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial (NCT03036150) by geographic region.MethodsAdults with chronic kidney disease (CKD) with or without type 2 diabetes, with estimated glomerular filtration rate (eGFR) 25 to 75 ml/min per 1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 200 to 5000 mg/g were randomized to dapagliflozin (10 mg once daily) or placebo. The primary end point was a composite of a sustained decline in eGFR of ≥50%, end-stage kidney disease or death from kidney or cardiovascular causes. We categorized recruiting countries into 4 broad global regions: Asia, Europe, Latin America, and North America. Of 4304 randomized patients, 1346 (31.3%) were from Asia, 1233 (28.6%) from Europe, 912 (21.2%) from Latin America, and 813 (18.9%) from North America.ResultsThe relative risk of the primary composite end point was lower in patients randomized to dapagliflozin (relative to placebo) in all regions, with hazard ratios (95% CI) of 0.70 (0.48–1.00), 0.60 (0.43–0.85), 0.61 (0.43–0.86), and 0.51 (0.34–0.76) among patients from Asia, Europe, Latin America, and North America, respectively. There was no effect modification by region (interaction P = 0.77). Occurrence of serious adverse events (SAEs) was lower among patients randomized to dapagliflozin versus placebo (21.9% vs. 26.8%, 34.1% vs. 38.6%, 29.8% vs. 31.5%, and 34.9% vs. 41.0% in Asia, Europe, Latin America, and North America, respectively).ConclusionDapagliflozin reduced kidney and cardiovascular events and prolonged survival in patients with CKD, with and without type 2 diabetes, with no apparent effect modification by geographic region.

Safety and preliminary efficacy of allogeneic bone marrow-derived multipotent mesenchymal stromal cells for systemic sclerosis: a single-centre, open-label, dose-escalation, proof-of-concept, phase 1/2 study.

Systemic sclerosis remains an orphan life-threatening autoimmune disease. The unique immunomodulatory, proangiogenic, and antifibrotic properties of mesenchymal stromal cells provide a strong rationale for mesenchymal stromal cell-based therapy for systemic sclerosis, and treatment with mesenchymal stromal cells has shown benefits in preclinical models of this disease. The safety of allogeneic bone marrow-derived mesenchymal stromal cell administration in patients with severe systemic sclerosis has not yet been established. We aimed to test the safety and feasibility of a single intravenous injection of intrafamilial allogeneic bone marrow-derived mesenchymal stromal cells to treat severe diffuse systemic sclerosis. We did an open-label, dose-escalation, proof-of-concept, phase 1/2 study at Saint-Louis-Hospital, Paris, France. Eligible patients were aged 18-70 years with severe diffuse systemic sclerosis, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism systemic sclerosis criteria, had a minimum modified Rodnan skin score of 15 (range 0-51), had severe lung, heart, or kidney involvement, and had inadequate response or contraindications to conventional immunosuppressive therapy or autologous haematopoietic stem cell transplantation. Patients with severe comorbidities were excluded. The first ten recipients were to receive a single intravenous infusion of 1 × 106 bone marrow-derived mesenchymal stromal cells per kg bodyweight, and the subsequent ten recipients were to be infused with a single dose of 3 × 106 bone marrow-derived mesenchymal stromal cells per kg bodyweight. The primary endpoint was immediate tolerance during infusion and within the first 10 days after infusion, measured as the occurrence of serious adverse events (grade 3 or higher) in all infused patients. Safety was assessed in all participants during the 24-month follow-up period. This study is registered with ClinicalTrials.gov, NCT02213705. Between March 24, 2014, and Jan 6, 2020, 20 cisgender individuals (13 women and seven men) with severe diffuse systemic sclerosis were enrolled. All 20 patients were included in the primary outcome analysis. No infusion-related severe adverse events and three infusion-related adverse events occurred in the first 10 days after treatment; one patient had grade 1 flushing and another patient had grade 1 nausea and grade 2 asthenia. After ten days and up to a median follow-up of 24·1 months (IQR 20·8-24·5), 36 non-treatment-related severe adverse events in 14 (70%) patients and no treatment-related adverse event were reported. A single infusion of allogeneic bone marrow-derived mesenchymal stromal cells was safe in patients with severe diffuse systemic sclerosis. Future placebo-controlled trials will help to definitively ascertain the efficacy of mesenchymal stromal cell-based cell therapy from various tissue sources in larger number of patients with systemic sclerosis. French Ministry of Health, Capucine Association, Fonds de Dotation de l'AFER pour la Recherche Médicale, and Agence Nationale de la Recherche (Infrastructure Program Ecell), France.

Abstract WP62: Safety Of Submaximal Aerobic Exercise Testing For People With Subacute Stroke And Comorbidity: A Scoping Review

Introduction: Despite aerobic exercise (AE) testing being a key recommendation for stroke rehabilitation, less than half of physical therapists working with individuals post-stroke perform this practice. Concern for adverse cardiovascular events and inadequate guidance on how to conduct AE testing for individuals with stroke and comorbidity are key barriers. This review aims to describe submaximal AE testing protocols with evidence of safety, defined as less than 11% occurrence of serious adverse events, for people with subacute stroke and comorbidity. Methods: MEDLINE, EMBASE, PsycINFO, CINAHL and SPORTDiscus were searched from inception to October 29, 2020. Published studies that involved submaximal AE testing with individuals with subacute stroke and reported on adverse events during testing were included. Two reviewers independently conducted title and abstract, and full-text screening. One reviewer conducted data extraction, verified by a second reviewer. Results: Sixteen studies involving 595 participants were included. Hypertension (35%), cardiovascular disease (14%) and atrial fibrillation (8%) were the most common cardiovascular comorbidities, while, diabetes (25%), dyslipidemia (23%) and smoking history (11%) were the most common general comorbidities affecting participants with stroke. Evidence of safety for individuals with stroke and comorbidity was found for incremental bicycle (n=5), recumbent stepper (n=3), body weight support treadmill (n=1) and upper extremity ergometer (n=1) protocols; constant load bicycle (n=1) and body weight support treadmill (n=1) protocols; and field (n=10) protocols. Heart rate (95%), blood pressure (82%) and oxygen consumption (72%) monitoring were most frequently done. Test termination criteria based on volition/fatigue (59%) and heart rate (55%) were most commonly reported. Conclusion: A range of submaximal AE testing protocols utilizing diverse exercise modalities can be safely conducted on people with subacute stroke and comorbid conditions that are perceived to increase the risk for serious adverse events. These protocols can be used to guide the development of more specific clinical practice guidelines for conducting AE testing on individuals with stroke and comorbidity.

Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial.

During the first days and weeks after an acute ischemic stroke, patients are prone to complications that can influence further treatment, recovery, and functional outcome. In clinical trials, severe complications are recorded as serious adverse events (SAE). We analyzed the effect of SAE on functional outcome and predictors of SAE in the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke). We performed a post hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled clinical trial of magnetic resonance imaging-guided intravenous thrombolysis with alteplase in patients with acute ischemic stroke and unknown time of onset. Functional outcome was assessed by the modified Rankin Scale 90 days after the stroke. SAE were reported to a central safety desk and recorded and categorized by organ system using Medical Dictionary for Regulatory Activities terminology. We used logistic regression analysis to determine the effect of SAE on functional outcome and linear multiple regression analysis to identify baseline predictors of SAE. Among 503 patients randomized, 199 SAE were reported for n=110 (22%) patients. Of those patients who did suffer a SAE, 20 (10%) had a fatal outcome. Patients suffering from at least one SAE had a lower odds of reaching a favorable outcome (modified Rankin Scale score of 0-1) at 90 days (adjusted odds ratio, 0.36 [95% CI, 0.21-0.61], P<0.001). Higher age (P=0.04) and male sex (P=0.01) were predictors for the occurrence of SAE. SAEs were observed in about one in 5 patients, were more frequent in elderly and male patients and were associated with worse functional outcome. These results may help to assess the risk of SAE in future stroke trials and create awareness for severe complications after stroke in clinical practice. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://eudract.ema.europa.eu; Unique identifier: 2011-005906-32.

Safety and immunogenicity of ChAdOx1 MERS vaccine candidate in healthy Middle Eastern adults (MERS002): an open-label, non-randomised, dose-escalation, phase 1b trial

BackgroundChAdOx1-vectored vaccine candidates against several pathogens have been developed and tested in clinical trials and ChAdOx1 nCoV-19 has now been licensed for emergency use for COVID-19. We assessed the safety and immunogenicity of the ChAdOx1 MERS vaccine in a phase 1b trial in healthy Middle Eastern adults.MethodMERS002 is an open-label, non-randomised, dose-escalation, phase 1b trial. Healthy Middle Eastern adults aged 18–50 years were included in the study. ChAdOx1 MERS was administered as a single intramuscular injection into the deltoid muscle of the non-dominant arm at three different dose groups: 5·0 × 109 viral particles in a low-dose group, 2·5 × 1010 viral particles in an intermediate-dose group, and 5·0 × 1010 viral particles in a high-dose group. The primary objective was to assess the safety and tolerability of ChAdOx1 MERS, measured by the occurrence of solicited and unsolicited adverse events after vaccination for up to 28 days and occurrence of serious adverse events up to 6 months. The study is registered with ClinicalTrials.gov, NCT04170829.FindingsBetween Dec 17, 2019, and June 1, 2020, 24 participants were enrolled (six to the low-dose, nine to the intermediate-dose, and nine to the high-dose group) and received a dose; 23 were available for follow-up at 6 months. The one dose of ChAdOx1 MERS vaccine was well tolerated with no serious adverse event reported during the 6 months of follow-up. Most adverse events were mild (67, 74%) and moderate (17, 19%). Six (7%) severe adverse events were reported by two participants in the intermediate-dose group (two feverish, two headache, one joint pain, and one muscle pain). Pain at the injection site was the most common local and overall adverse event, reported by 15 (63%) of the 24 participants. The most common systemic adverse event was headache, reported by 14 (58%), followed by muscle pain reported by 13 (54%). The vaccine induced both antibody and T cell immune responses in all volunteers; antibodies peaked at day 28 and T cell responses peaked at day 14; and continued until the end of follow-up at 6 months.InterpretationThe acceptable safety and immunogenicity data from this phase 1b trial of ChAdOx1 MERS vaccine candidate in Healthy Middle Eastern adults, combined with previous safety and immunogenicity data from a trial in the UK, support selecting the ChAdOx1 MERS vaccine for advancement into phase 2 clinical evaluation.FundingUK Department of Health and Social Care, using UK Aid funding, managed by the UK National Institute for Health Research; and King Abdullah International Medical Research Center.

Safety and Efficacy of Levamisole in Loiasis: A Randomized, Placebo-controlled, Double-blind Clinical Trial.

BackgroundIndividuals with high microfilarial densities (MFDs) of Loa loa are at risk of developing serious adverse events (SAEs) after ivermectin treatment. Pretreatment with drugs progressively reducing Loa MFDs below the risk threshold might help prevent these SAEs. We assessed the safety and efficacy of levamisole for this purpose.MethodsA double-blind, randomized, placebo-controlled, MFD-ascending trial was conducted in the Republic of the Congo. Participants were treated in 3 cohorts defined by pretreatment MFD and levamisole dose (cohort 1: 1.0kg and 1.5mg/kg; cohorts 2 and 3: 2.5mg/kg). Safety outcomes were occurrence of SAE and adverse event frequency during the first week. The efficacy outcomes were MFD reduction from baseline and proportions of individuals with at least 40% and 80% MFD reduction at day 2 (D2), D7, and D30.ResultsThe 2 lowest doses (1.0mg/kg and 1.5mg/kg) caused no SAEs but were ineffective. Compared with placebo, 2.5mg/kg levamisole caused more mild adverse events (10/85 vs. 3/85, P=.018), a higher median reduction from baseline to D2 (-12.9% vs. +15.5%, P<.001), D7 (-4.9% vs. +18.7%, P<.001), and D30 (-0.5% vs. +13.5%, P=.036) and a higher percentage of participants with >40% MFD reduction at D2 (17.5% vs. 1.2%, P<.001), D7 (11.8% vs. 6.3%, P=.269), and D30 (18.5% vs. 9.6%, P=.107).ConclusionsA single 2.5mg/kg levamisole dose induces a promising transient reduction in Loa loa MFDs and should encourage testing different regimens.

Prevention of pacemaker lead induced tricuspid regurgitAtion by transesophageal eCho guidEd implantation (PLACE Pilot)

Abstract Background Lead-induced tricuspid regurgitation (TR) is a frequent complication after pacemaker- and ICD-implantation that is associated with increased mortality and hospitalizations. Purpose The aim of this pilot study was to investigate if lead implantation guided by transesophageal echocardiography (TEE) is feasible and might be able to reduce lead-associated TR. Methods 21 patients with indication for new pacemaker/ICD including a trans-tricuspid lead implantation and TR &amp;lt; grade 2+ were prospectively enrolled and underwent TEE-guided lead implantation in addition to fluoroscopy. Leads were placed according to a dedicated echo protocol with focus on a transgastric en face view of the tricuspid valve targeting a lead position in a tricuspid valve commissure (preferentially postero-septal) and an apical ventricular lead position. (Figure 1) Transthoracic echocardiography (TTE) was performed before implantation and at discharge. 121 consecutive patients with standard lead implantation guided by fluoroscopy only served as a historical control group. TR was assessed by an experienced cardiologist and graded according to current guidelines. Results Key baseline characteristics of overall 124 patients with a mean age of 74 years didn't differ between groups. Of note, there was no significant difference regarding device type and baseline TR. TEE-guided lead implantation was possible in all 21 patients in the TEE-group in deep conscious sedation without occurrence of serious adverse events. Lead placement in a commissure, mostly postero-septal, was possible in 95.2% of patients without worsening of TR (20/21 pts). Based on TEE-guidance, lead position or length was altered in 52.4% of patients (11/21 pts, 6 pts with lead repositioning, 5 pts with modification of lead length). Compared to baseline, the 21 patients in the TEE-group did not show worsening of TR at discharge. In contrast, TR worsening by one grade occurred in 13.6% of patients (14/103 pts) with new onset of TR ≥2+ in 6.8% of patients (07/103 pts) in the control group (p=0.001). At discharge, lead position was evaluated using 2D and 3D TTE in a subset of patients. In all examined patients (14/14 pts) lead position was unchanged compared to intraprocedural position and stable during inspiration vs. expiration as well as in upright vs. horizontal position. Conclusion TEE-guidance during PM/ICD-implantation was safe and feasible and resulted in steps to optimize lead position in a relevant number of patients. At discharge lead position remained stable and TEE-guided lead implantation was associated with less worsening of TR than standard lead implantation guided by fluoroscopy. Funding Acknowledgement Type of funding sources: None. TEE view with targeted lead position