Serious Adverse Events In Patients Research Articles

Real-world effectiveness and safety of direct-acting antivirals in patients with cirrhosis and history of hepatic decompensation: Epi-Ter2 Study.

The aim of this study was to assess the real-life effectiveness and safety of direct acting antivirals (DAAs) in patients with cirrhosis and history of hepatic decompensation compared to those with compensated cirrhosis. Data of patients treated with DAAs and included in the EpiTer-2 database (N=10152) were collected retrospectively. The primary endpoint was sustained viral response (SVR) at 12weeks posttreatment. Patients were also evaluated in terms of liver-related adverse events and treatment modification/discontinuation. The overall SVR rate was 91.4% in the intent to treat (ITT) analysis and 95.2% in the per-protocol (PP) analysis (P<.001). Patients with decompensated cirrhosis had lower SVR rates compared to those with compensated cirrhosis in ITT analysis (86.4% vs 92.0%, P<.001), while not in PP analysis (92.9% vs 95.5%, P>.05). Adverse events (AE) occurred 45.6% and 29.3% of patients with decompensated and compensated cirrhosis (P<.001). Patients with decompensated cirrhosis were at higher risk of death (5.4% vs 0.9%; P<.0001) or liver decompensation (21.5% vs 1.3%; P<.0001). Treatment with protease inhibitors was not associated with hepatic decompensation (P=.3). Only 82.6% of patients with decompensated cirrhosis completed DAA treatment (vs 92.8% in compensated cirrhotics; P<.0001). Despite higher frequency of AE and treatment modifications, once completed, DAAs yield comparable results for patients with decompensated and compensated cirrhosis. High rate of serious adverse events in patients with advanced liver disease treated with PI may not be related to the detrimental effect of the medications, but rather to the disease itself.

Enhanced detection of cardiac arrhythmias utilizing 14-day continuous ECG patch monitoring

BackgroundTo evaluate the performance of a single‑lead, 14-day continuous electrocardiogram (ECG) patch for the detection of arrhythmias compared to conventional 24-h monitoring. MethodsThis prospective clinical trial enrolled patients suspected of arrhythmias but not diagnosed by 12‑lead ECGs. Each patient underwent a 24-h Holter and 14-day ECG patch simultaneously. Seven types of arrhythmias were classified: supraventricular tachycardia (SVT, repetitive atrial beats >4 beats), irregular SVT without P wave (>4 beats), AF/AFL (irregular SVT without P wave ≥30 s), pause ≥3 s, atrioventricular block (AVB; Mobitz type II, third-degree, two to one or high degree AVB), ventricular tachycardia (VT), and polymorphic VT. ResultsA total of 158 patients were recruited (mean wear time:12.3 ± 3.2 days). The overall arrhythmia detection rate was higher with 14-day ECG patches (59.5%) compared to 24-h Holter (19.0%, P < 0.001). Up to 87.2% of arrhythmias recorded with 14-day ECG patches were not associated with symptoms. The 14-day ECG patch was associated with higher detection rates compared to the 24-h Holter in patients with SVT (52.5% versus 15.8%, P < 0.001), irregular SVT without P wave (12.7% versus 4.4%, P = 0.002), AF/AFL (9.5% versus 3.8%, P = 0.042), and critical arrhythmias (pause ≥3 s, AVB, VT, polymorphic VT) (16.5% versus 2.5%, P < 0.001). The 14-day ECG patch detected more than 2 types of arrhythmias in 5.1% of patients. No serious adverse events in patients wearing the 14-day ECG patch were reported. ConclusionsThe 14-day ECG patch outperformed 24-h Holter to detect overall, asymptomatic, critical and multiple arrhythmias. It is safe and has the potential to identify individuals with hidden arrhythmias, especially those with critical arrhythmias.

Adverse events associated with bone-directed therapies in patients with cancer.

Bone metastatic disease may lead to serious adverse events in patients with cancer. Bone-directed therapies, including bisphosphonates such as pamidronate and zoledronic acid and the human monoclonal antibody denosumab, are currently approved for the prevention of bone-related adverse events. However, despite the benefits of these drugs, they may cause side effects that are mostly associated with dosages and treatment durations. These side effects range from more frequent, mostly mild, and generally self-limited side effects-such as fever, myalgias, arthralgias, and electrolyte imbalances-to less frequent and more severe side effects such as medication-related osteonecrosis of the jaw and atypical femoral fractures. The purpose of this review is to familiarize clinicians with the literature regarding adverse events associated with bone-directed therapies in patients with cancer. It is important to be aware of these possible adverse events and to educate patients about the predisposing factors associated with side effects from bone-directed therapies and the preventive measures necessary to decrease the risk of occurrence.

Safety and Efficacy of PD-1/PD-L1 inhibitors combined with radiotherapy in patients with non-small-cell lung cancer: a systematic review and meta-analysis.

BackgroundA combination of programmed cell death protein‐1 (PD‐1)/programmed cell death ligand‐1 (PD‐L1) inhibitors and radiotherapy (RT) is increasingly being used to treat non‐small‐cell lung cancer (NSCLC). However, the safety and efficacy of this approach remains controversial. We performed a systematic review and meta‐analysis to summarize the related research.MethodsWe searched the China Biology Medicine, EMBASE, Cochrane Library, and PubMed databases for all the relevant studies. The Stata software, version 12.0 was used for the meta‐analysis.ResultsThe study included 20 clinical trials that enrolled 2027 patients with NSCLC. Compared with non‐combination therapy, combination therapy using PD‐1/PD‐L1 inhibitors and RT was associated with prolonged overall survival (OS) (1‐year OS: odds ratio [OR] 1.77, 95% confidence interval [CI] 1.35–2.33, p = 0.000; 2‐year OS: OR 1.77, 95% CI 1.35–2.33, p = 0.000) and progression‐free survival (PFS) (0.5‐year PFS: OR 1.83, 95% CI 1.13–2.98, p = 0.014; 1‐year PFS: OR 2.09, 95% CI 1.29–3.38, p = 0.003; 2‐year PFS: OR 2.47, 95% CI 1.13–5.37, p = 0.023). Combination therapy also improved the objective response rate (OR 2.76, 95% CI 1.06–7.19, p = 0.038) and disease control rate (OR 1.80, 95% CI 1.21–2.68, p = 0.004). This meta‐analysis showed that compared with non‐combination therapy, combination therapy using PD‐1/PD‐L1 inhibitors and RT did not increase the serious adverse event rates (≥grade 3); however, this approach increased the rate of grade 1–2 immune‐related or radiation pneumonitis. Subgroup analyses revealed that the sequence of PD‐1/PD‐L1 inhibitors followed RT outperformed in which concurrent PD‐1/PD‐L1 inhibitor and RT followed PD‐1/PD‐L1 inhibitor. Combination of stereotactic body RT or stereotactic radiosurgery with PD‐1/PD‐L1 inhibitors may be more effective than a combination of conventional RT with PD‐1/PD‐L1 inhibitors in patients with advanced NSCLC.ConclusionCombination therapy using PD‐1/PD‐L1 inhibitors and RT may improve OS, PFS, and tumor response rates without an increase in serious adverse events in patients with advanced NSCLC. However, combination therapy was shown to increase the incidence of mild pneumonitis.

Retrospective analyzes of adverse events during biologic agents in children with juvenile idiopathic arthritis from a single center in Turkey.

ObjectivesJuvenile idiopathic arthritis is the most common rheumatic disease in childhood. Biologic agents have changed the course of juvenile idiopathic arthritis. However, there are concerns regarding the occurrence of serious adverse events in patients receiving biologic agents. The aim of this study was to evaluate adverse events in children with juvenile idiopathic arthritis receiving biologic agents.Material and methodsThis retrospective study includes juvenile idiopathic arthritis patients receiving biologic agents. Demographic features and adverse events during biologic agents were collected from medical files. Adverse events that either resulted in death, were life-threatening, required inpatient hospitalization, or resulted in persistent or significant disability/incapacity were considered as serious adverse events.ResultsIn total, 162 juvenile idiopathic arthritis patients (55.6% female) receiving biologic agents were enrolled: 101 (62.3%) patients treated with etanercept, 27 (16.7) with tocilizumab, 14 (8.6%) with adalimumab, 15 (9.2%) with anti-interleukin 1 agents (13 canakinumab, 2 anakinra), and 5 (3.1%) with infliximab. 75.9% of the patients received concomitantly disease-modifying anti-rheumatic drugs, and 20.4% received disease-modifying anti-rheumatic drugs plus corticosteroid. The mean age at initiation of the biologic agent was 10.5 ±4.3 years. The mean age at the study enrolment was 12.1 ±4.5 years. The mean follow-up duration was 19.7 ±2.1 months. The most frequent adverse event was upper respiratory tract infections (54.3%) followed by urinary tract infections (21%). Anaphylaxis occurred in 3 patients (1.9%): 2 with tocilizumab and one with infliximab. Macrophage activation syndrome occurred in 1 patient (0.6%) receiving tocilizumab. Lung tuberculosis developed in 2 patients (1.2%) receiving canakinumab. The frequency of serious adverse events in total was 6.7%.ConclusionsWhile the most frequent adverse events during biologic agents was upper respiratory tract infections, the frequency of serious adverse events was 6.7%; therefore, juvenile idiopathic arthritis patients receiving biologic agents should be carefully evaluated for these adverse events in clinical practice.

Optimal treatment strategy of fremanezumab in migraine prevention: a systematic review with network meta-analysis of randomized clinical trials

Identifying the optimal fremanezumab treatment strategy is crucial in treating patients with migraines. The optimal strategy was investigated by assessing the cumulative 50% reduction rate (50%CRR), cumulative 75% reduction rate (75%CRR), reduction in the number of migraine days, treatment-related adverse events, and serious adverse events in patients treated with fremanezumab 225 mg monthly (225 mg), 675 mg monthly (675 mg), 900 mg monthly (900 mg), a single high dose of 675 mg (S675mg), 675 mg at baseline with 225 mg monthly (675/225 mg), and placebo. Biomedical databases were searched for randomized controlled trials on this topic, and data were individually extracted. Risk ratios and mean differences were used to present the pooled results. The surface under the cumulative ranking curve (SUCRA) was used to determine the effects of the medication strategies of fremanezumab. Five trials (n = 3404) were used to form a six-node network meta-analysis. All fremanezumab medication strategies displayed significantly higher cumulative 50% reduction rates than the placebo. The SUCRA revealed that treatment with 675 mg yielded the highest 50%CRR value (mean rank = 2.5). S675 mg was the only treatment with significantly higher 75%CRR reduction rate than placebo, whereas the SUCRA for 225 mg displayed the highest mean rank (2.2). Moreover, 225 mg (mean rank = 2.2) and S675 mg (mean rank = 2.2) presented lower probabilities of serious adverse events. Collectively, S675mg and 225 mg exhibited the optimal balance between efficacy and safety within three months. Long-term efficacy and safety remain unclear, and future studies should further evaluate the long-term outcomes.

A predictive model for serious adverse events in adults with acute poisoning in prehospital and hospital care

ObjectiveThe objective of this study was to design a risk model with variables determined before hospital arrival to predict the risk of serious adverse events in patients with acute poisoning. MethodsA preliminary prospective, multicentre cohort study of adults with prehospital diagnosis of acute intoxication was conducted. The study was carried out in the Public Health System of the Community of Castilla-Leon (Spain), including seven advanced life support units and five hospitals, between April 1, 2018, and June 30, 2019. People aged >18 years with a main prehospital diagnosis of acute poisoning admitted to a referral hospital on advanced life support were included. The main outcome measure was prehospital and hospital serious adverse events in patients with acute poisoning. ResultsWe included 221 patients, with a median age of 47 years (interquartile range: 33–61). The most frequent cause of poisoning was psychopharmaceuticals (111 cases, 49.8%): 38 (17.2%) patients had a serious adverse event, with a hospital mortality of 4.1% (nine cases) in the 30 days after the index event. The final model included age ≥65 years (odds ratio [OR]: 9.59, 95% confidence interval [CI]: 3.48–26.45; p < 0.001), oxygen saturation/fraction of inspired oxygen index ≤300 (OR: 15.03, 95% CI: 5.74–39.33; p < 0.001), and point-of-care lactate ≥4 mmol/L (OR: 7.68, 95% CI: 2.88–20.45; p < 0.001). The poisoning Early Warning Score was constructed from these three variables, and 1 point was assigned to each variable. The area under the curve of the score was 0.896 (95% CI: 0.82–0.96; p < 0.001). ConclusionsThe poisoning Early Warning Score may help in decision-making and promote early identification of high-risk patients with acute poisoning in the prehospital context.

Results of direct comparison of the clinical efficacy of ixekizumab and adalimumab: data from the SPIRIT H2H study

Objective: to analyze the data available in the literature on the efficacy and safety of ixekizumab (IXE) and adalimumab (ADA) via their direct comparisons in the treatment of psoriatic arthritis (PsA).Patients and methods. The results of the SPIRIT H2H study were analyzed, the aim of which was to investigate the potential superiority of IXE to ADA for arthritis and skin manifestations in a group of patients with active PsA, stable plaque psoriasis with an inadequate response to synthetic disease-modifying antirheumatic drugs (sDMARDs) who had not previously received biological agents (BAs).Design: a 52-week multicenter, randomized, parallel-group study. The patients were randomized 1:1 to open IXE or ADA administration groups for 52 weeks. This review presents the data obtained at 24-week follow-up.Of the 684 screened patients, 566 (82.7%) were included in the study; moreover, the distribution of the patients was equal between the ADA (n=283) and IXE (n=283) groups. At 6 months, 269 (95%) patients in the ADA group and 262 (93%) in the IXE one continued to participate in the study. Efficacy analysis was made based on the achievement of the primary endpoint that was considered to be related to the relative number of patients, who had simultaneously achieved improvements in the joints and skin according to the ACR50 and PASI100 criteria.Results and discussion. At 24 weeks, the proportion of patients who had simultaneously achieved ACR50 and PASI100 responses was significantly higher in the IXE group (36%) than in the ADA one (28%) (p=0.036). It was found that the IXE group was not inferior to the ADA one in terms of ACR50 response rates (in 51% (IXE) and 47% (ADA) patients) and was superior in achieving PASI100 response rates (in 60% (IXE) and 47% (ADA) patients) (p=0.001). The IXE group was recorded to have a higher response than the ADA group and in terms of other manifestations of the disease: the severity of skin and nail psoriasis, enthesitis, remission achievement, minimal and very low disease activity, and improved quality of life. Comparable effectiveness was noted for the effect of the drugs on dactylitis, as well as for the simultaneous achievement of remission and low disease activity in psoriatic arthritis according DAPSA. Serious adverse events (SAEs) were recorded in 8.5% (ADA) and 3.5% (IXE) patients.The safety and tolerability of both BAs corresponded to their previously presented safety profile. The findings were also confirmed at 52-week follow-up, presented at the Meetings of the American College of Rheumatology in November 2019 and the European League Against Rheumatism in June 2020, and published in the leading journals of rheumatology.Conclusion. The first randomized placebo-controlled study (SPIRIT H2H) directly comparing the two BAs with different mechanisms of action demonstrated the advantage of IXE over ADA in simultaneously reducing the activity of arthritis and psoriasis and showed their comparable efficacy comparable efficacy regarding joint symptoms. The use of IXE versus ADA was accompanied by the more frequent achievement of a combined endpoint related to the signs of joint and skin damages in patients with PSA, as well as by the quantitatively lower frequency of SAEs in patients with active PSA who had failed previous sDMARD therapy. The findings are of great importance for clinical practice from the point of view of the reasonable choice of a treatment strategy in these patients.

Educational interventions to improve outcomes in patients with atrial fibrillation-a systematic review.

Atrial fibrillation (AF) is an emerging epidemic associated with poor mental health and quality of life, as well as morbidity and mortality. Whilst other cardiovascular conditions have demonstrated positive outcomes from educational programmes, this approach is not well integrated in clinical practice in patients with AF. Though evidence in this area is mounting, a thorough overview seems to be lacking. To assess benefits and harms of educational interventions compared with no intervention in adults with AF. A systematic review and meta-analysis were performed including the outcomes: Serious adverse events (mortality and readmission), mental health (anxiety and depression), physical capacity, quality of life and self-reported incidence of symptoms of AF. PubMed, Embase, CINAHL, Cochrane Library and PsycINFO were searched between June and august 2018. Data extraction and quality assessment were performed independently by two reviewers. The Cochrane Risk of Bias tool was applied for the randomised controlled trials and the Amstar Checklist for the systematic reviews. Eight randomised controlled trials and one non-randomised interventional study were included, with a total of 2388 patients. Comparing with controls patient education was associated with a reduction in: Serious adverse events (Risk Ratio 0.78, CI 95% 0.63-0.97), anxiety with a mean difference of -0.62 (CI 95% -1.21, -0.04) and depression with a mean difference of -0.74 (CI 95% -1.34, -0.14). Health-related quality of life and physical capacity was found to increase after patient education, yet, only one study found statistically significant differences between groups. No differences were observed with regards to self-reported incidence of symptoms of AF. Educational interventions significantly decrease the number of serious adverse events in patients with AF and seem to have a positive impact on mental health and self-reported quality of life. However, the evidence is limited, and more studies are warranted.

Seasonal Variations in the Incidence of Ischemic Stroke, Extracranial and Intracranial Hemorrhage in Atrial Fibrillation Patients.

Ischemic stroke (IS) and major bleeding, which are serious adverse events in patients with atrial fibrillation (AF), could have seasonal variations, but there are few reports. In the Shinken Database 2004-2016 (n=22,018), 3,581 AF patients (average age, 63.5 years; 2,656 men, 74.2%; 1,388 persistent AF, 38.8%) were identified. Median CHADS2and HAS-BLED scores were both 1 point. Oral anticoagulants were prescribed for 2,082 (58.1%) patients (warfarin, 1,214; direct oral anticoagulants [DOACs], 868). Incidence and observation period (maximum 3 years) of IS, extracranial hemorrhage (ECH), and intracranial hemorrhage (ICH) were counted separately for the northern hemisphere seasons. During the mean follow-up period of 2.4 years, there were totals of 90 IS, 73 ECH, and 33 ICH cases. The respective incidence rates per 1,000 patient-years in spring, summer, autumn, and winter were 8.5, 8.8, 7.5, and 16.8 for IS, 7.2, 9.7, 3.8, and 13.1 for ECH, and 2.7, 1.9, 3.8, and 7.0 for ICH. The number of patients with DOACs relatively increased among those with ECH in summer. Significant seasonal variations were observed for IS, ECH, and ICH events in AF patients, and were consistently the highest in winter. A small peak of ECH was observed in summer, which seemed, in part, to be related to increased DOAC use.

Serum high-mobility group box 1 as a predictive marker for cytotoxic chemotherapy-induced lung injury in patients with lung cancer and interstitial lung disease

BackgroundHigh-mobility group box 1 (HMGB1) is a pro-inflammatory protein, that is associated with tumorigenesis, interstitial lung disease (ILD), and acute lung injury. Chemotherapy-induced lung injury is a common and serious adverse event in patients with lung cancer and ILD, but its pathogenesis and predictive biomarkers are not known. This study aimed to investigate the predictive potential of serum HMGB1 levels for cytotoxic chemotherapy-induced lung injury in these patients. MethodsFrom 743 patients with advanced lung cancer, we enrolled 83 consecutive patients with ILD and background-matched 83 patients without ILD. Additionally, 83 healthy subjects were included. After measuring baseline levels of serum HMGB1 in three groups, we evaluated the predictive values of baseline HMGB1 levels for cytotoxic chemotherapy-induced lung injury in patients with lung cancer and ILD. ResultsHigher levels of serum HMGB1 were independently associated with higher tumor burden, as assessed by total tumor size, and the presence of ILD. Twenty-five (30.1%) of patients with lung cancer and ILD experienced cytotoxic chemotherapy-induced lung injury within one year. Univariate Cox proportional hazards model showed that higher levels of HMGB1 and higher tumor burden were associated with disease onset. Moreover, multivariate analysis revealed that only HMGB1 was independently associated with this severe complication in patients with lung cancer and ILD. ConclusionsHMGB1 is a potential predictive blood biomarker for cytotoxic chemotherapy-induced lung injury in patients with lung cancer and ILD. This study also suggests a potential pathogenesis of this serious adverse event that tumor- and ILD-derived HMGB1 accelerates lung injury.

Interferon β-1b in treatment of severe COVID-19: A randomized clinical trial

In this study, efficacy and safety of interferon (IFN) β-1b in the treatment of patients with severe COVID-19 were evaluated.Among an open-label, randomized clinical trial, adult patients (≥18 years old) with severe COVID-19 were randomly assigned (1:1) to the IFN group or the control group. Patients in the IFN group received IFN β-1b (250 mcg subcutaneously every other day for two consecutive weeks) along with the national protocol medications while in the control group, patients received only the national protocol medications (lopinavir/ritonavir or atazanavir/ritonavir plus hydroxychloroquine for 7–10 days). The primary outcome of the study was time to clinical improvement. Secondary outcomes were in-hospital complications and 28-daymortality.Between April 20 and May 20, 2020, 80 patients were enrolled and finally 33 patients in each group completed the study. Time to clinical improvment in the IFN group was significantly shorter than the control group ([9(6–10) vs. 11(9–15) days respectively, p = 0.002, HR = 2.30; 95% CI: 1.33–3.39]). At day 14, the percentage of discharged patients was 78.79% and 54.55% in the IFN and control groups respectively (OR = 3.09; 95% CI: 1.05–9.11, p = 0.03). ICU admission rate in the control group was significantly higher than the IFN group (66.66% vs. 42.42%, p = 0.04). The duration of hospitalization and ICU stay were not significantly different between the groups All-cause 28-day mortality was 6.06% and 18.18% in the IFN and control groups respectively (p = 0.12).IFN β-1b was effective in shortening the time to clinical improvement without serious adverse events in patients with severe COVID-19. Furthermore, admission in ICU and need for invasive mechanical ventilation decreased following administration of IFN β-1b. Although 28-day mortality was lower in the IFN group, further randomized clinical trials with large sample size are needed for exact estimation of survival benefit of IFN β-1b.

The effectiveness and harms of bortezomib in combination with chemotherapy for mantle cell lymphoma: A protocol for systematic review and meta-analysis.

Background:Chemotherapy with or without consolidation followed by autologous hematopoietic stem cell transplantation is the first-line treatment for mantle cell lymphoma. However, the effectiveness and safety of bortezomib-based chemotherapy for patients with mantle cell lymphoma is still uncertain.Methods:In this systematic review, the electronic databases of Cochrane Central Register of Controlled Trials, EMBASE, and PUBMED will be searched from inception to May 1, 2020. Randomized controlled trials that assessed the effectiveness and safety of bortezomib in combination with chemotherapy for patients with mantle cell lymphoma will be included. The patient's important outcomes include overall survival, progression-free survival, overall response rate, quality of life, and serious adverse events (eg, grade III-IV peripheral neuropathy, neutropenia, and infection). All process of the study selection, data extraction, and methodology evaluation will be carried out by 2 authors independently. RevMan 5.3 software will be utilized for statistical analysis.Results:This study will provide a detailed summary of latest evidence related to the effectiveness and safety of bortezomib in combination with chemotherapy in overall survival, progression-free survival, overall response rate, quality of life, and serious adverse events for patients with mantle cell lymphomaConclusion:The findings of this study may provide possible guidance for bortezomib in combination with chemotherapy for patients with mantle cell lymphoma.Systematic review registration:PROSPERO CRD 42020154938.

Physical activity and serious adverse events in patients with atrial fibrillation and/or atrial flutter treated with catheter ablation

BackgroundAtrial fibrillation (AF) and atrial flutter (AFL) are cardiac arrhythmias associated with cardiovascular morbidity. Physical activity (PA) can trigger AF and AFL recurrence, but can also improve physical functional capacity in this patient group. Guidelines do not include concrete recommendations regarding PA for this patient group. ObjectiveTo assess the impact of the level of PA on risk of serious adverse events (SAEs) in patients with AF and/or AFL treated with catheter ablation. MethodsA prospective cohort study including 462 patients with AF and/or AFL treated with catheter ablation from the CopenHeart Survey. The International Physical Activity Questionnaire (IPAQ) was used to explore patients’ self-reported level of PA. SAEs were identified in the Danish National Patient Register and the Danish Civil Registration System one year after study onset. Cox regression analysis was carried out to assess the risks of SAE. ResultsDuring the one-year follow-up period, 98 patients (21.8%) experienced at least one SAE. Patients with a moderate-high PA level had a 36% lower risk of experiencing SAEs during the follow-up period, compared to patients in the low PA group, after adjusting for confounders. ConclusionA moderate-high vs. low level of PA was found to be associated with a lower incidence of SAEs in patients undergoing AF and/or AFL ablation.

Efficacy and safety of evogliptin treatment in patients with type 2 diabetes: A multicentre, active-controlled, randomized, double-blind study with open-label extension (the EVERGREEN study).

AimTo investigate the efficacy and safety of evogliptin compared with linagliptin in patients with type 2 diabetes.Materials and MethodsIn this 12‐week, multicentre, randomized, double‐blind, active‐controlled, and 12‐week open‐label extension study, a total of 207 patients with type 2 diabetes who had HbA1c levels of 7.0%‐10.0% were randomized 1:1 to receive evogliptin 5 mg (n = 102) or linagliptin 5 mg (n = 105) daily for 12 weeks. The primary efficacy endpoint was the change from baseline HbA1c at week 12. The secondary endpoint was the change in the mean amplitude of glycaemic excursion (MAGE) assessed by continuous glucose monitoring. In the extension study conducted during the following 12 weeks, evogliptin 5 mg daily was administered to both groups: evogliptin/evogliptin group (n = 95) and linagliptin/evogliptin group (n = 92).ResultsAfter 12 weeks of treatment, the mean change in HbA1c in the evogliptin group and in the linagliptin group was −0.85% and −0.75%, respectively. The between‐group difference was −0.10% (95% CI: −0.32 to 0.11), showing non‐inferiority based on a non‐inferiority margin of 0.4%. The change in MAGE was −24.6 mg/dL in the evogliptin group and −16.7 mg/dL in the linagliptin group. These values were significantly lower than the baseline values in both groups. However, they did not differ significantly between the two groups. In the evogliptin/evogliptin group at week 24, HbA1c decreased by −0.94%, with HbA1c values of <7.0% in 80.2% of the patients. The incidence and types of adverse events were comparable between the two groups for 24 weeks.ConclusionIn this study, the glucose‐lowering efficacy of evogliptin was non‐inferior to linagliptin. It was maintained at week 24 with a 0.94% reduction in HbA1c. Evogliptin therapy improved glycaemic variability without causing any serious adverse events in patients with type 2 diabetes.

Remdesivir in Treatment of COVID-19: A Systematic Benefit–Risk Assessment

IntroductionThere is a need to identify effective, safe treatments for COVID-19 (coronavirus disease) rapidly, given the current, ongoing pandemic. A systematic benefit–risk assessment was designed and conducted to examine the benefit–risk profile of remdesivir in COVID-19 patients compared with standard of care, placebo or other treatments. A key objective of this study was to provide a platform for a dynamic systematic benefit–risk evaluation, which starts with inevitably limited information (to meet the urgent unmet public health need worldwide), then update the benefit–risk evaluation as more data become available.MethodsThe Benefit–Risk Action Team (BRAT) framework was used to assess the overall benefit–risk of the use of remdesivir as a treatment for COVID-19 compared with standard of care, placebo or other treatments. We searched PubMed, Google Scholar and government agency websites to identify literature reporting clinical outcomes in patients taking remdesivir for COVID-19. A value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance.ResultsUsing the BRAT method, several key benefits and risks for use of remdesivir in COVID-19 compared with placebo have been identified. In one trial, the benefit of time to clinical improvement was not statistically significant (21 vs 23 days, HR 1.23, 95% CI 0.87–1.75), although the study was underpowered. In another trial, a shorter time to recovery in patients treated with remdesivir was observed (11 vs 15 days), with non-significant reduced mortality risk (8% vs 12%). Risk data were only available from one trial. This trial reported fewer serious adverse events in patients taking remdesivir (18%) compared with the placebo group (26%); however, more patients in the remdesivir group discontinued treatment as a result of an adverse event compared with those patients receiving placebo (12% vs 5%).ConclusionsPreliminary clinical trial results suggest that there may be a favourable benefit–risk profile for remdesivir compared with placebo in severe COVID-19 infection and further data on benefits would strengthen this evaluation. There is limited safety data for remdesivir, which should be obtained in further studies. The current framework summarises the key anticipated benefits and risks for which further data are needed. Ongoing clinical trial data can be incorporated into the framework when available to provide an updated benefit–risk assessment.

Endotoxin quality control testing for CAR T-cell manufacturing: validation considerations for Endosafe portable testing system

Background & Aim Background Adoptive cell therapies have emerged as promising treatments for cancer patients. The manufacture of clinical-grade Chimeric Antigen Receptor (CAR) T-cells therapies encompass multiple complex processes under the code of good manufacturing practice (cGMP) to ensure high-quality and safe products. Endotoxins are lipo-polysaccharides from gram-negative bacteria that cause serious adverse events in patients. For this reason, it is important that CAR T-cells are tested for endotoxin content. The limulus amoebocyte lysate (LAL) test is FDA approved and allows sensitive detection of bacterial endotoxins. The Endosafe Portable Testing System (PTS) is a rapid, FDA approved testing system manufactured by Charles River that uses disposable cartridges for accurate real-time endotoxin testing, However, a number of important parameters need to be considered when establishing Endosafe-PTS testing for CAR T-cells products. Aim To determine endotoxin limits, maximum valid dilution of samples and reproducibility of the Endosafe-PTS test. Methods, Results & Conclusion Methods Inhibition and enhancement screening cartridges were used initially to establish maximum valid dilution and investigate potential inhibition of the test. CAR T-cells were manufactured from three individuals and analysed for endotoxins on the Endosafe-PTS using cartridges with a sensitivity of 5-0.05 EU/mL and spike recovery 50-200% according to manufacturer's protocol. Three replicates of each sample were tested. Results The optimal dilution of CAR T-cell product was determined at 1:20 with the spike recovery of 84% to 130%. No inhibition was detected at the 1:20 dilution for all three samples. The upper limit of acceptance criteria for endotoxin was determined on the basis of dose and FDA guidelines to be 5 EU/kg body weight/hour of intended product administration. Conclusion The Endosafe-PTS provides an accurate, reproducible and rapid method for Endotoxin detection which is crucial in quality control release testing and administration of time-sensitive CAR T-cell products. It is important to validate inhibition and enhancement screening for each CAR T-cell product and determine the optimal sample dilution before implementation of the Endosafe-PTS for product release testing.

P179 Glucocorticoid exposure and link to serious adverse events in patients with ANCA-associated vasculitis

Abstract Background Remission induction in ANCA-associated vasculitis (AAV) is with high dose glucocorticoids (GC) and immunosuppressants. Patients are exposed to high GC dose and/or prolonged low dose. EULAR/EDTA guidelines target 7.5-10mg at 3 months but acknowledge this is often achieved later. This study used UK real world practice data to examine the scale of GC exposure and associated clinical risks in AAV. Methods The study utilised the Clinical Practice Research Datalink (CPRD) - Hospital Episode Statistics (HES) linked database. AAV patients were identified using specific READ and ICD codes and followed between 01/01/1997 and 01/01/2018. GP prescriptions were used to describe periods of continuous GC use, stop and restart and when high dose (&amp;gt; 30mg/day) and low dose (&amp;lt;30mg/day) was prescribed. Diagnostic codes indicative of infections and adverse events linked to GCs were used to estimate rates in the AAV population using a generalized linear model with a Poisson distribution. Results 450 AAV patients with at least one GC prescription were analysed. The median dose decreased to 9.3 mg (IQR 5.0 - 17.0) at 6 months and 5.1 mg (0.00 - 10.0) at 12 months,50% patients were taking &amp;gt; 10mg at 5 months and 25% were still &amp;gt; 10mg at 12 months. However, within 6 months of achieving 10mg/day, 50% relapse to needing dose &amp;gt;10mg, 75% within 2 years and 90% within 6 years. In adjusted Poisson model (age, gender, year of diagnosis before/after 2013) the rate of infection in AAV patients taking high dose was 2.59 times (CI95 1.95, 3.45) that of those on low dose and lower in those not taking GCs (IRR 0.27 (0.22-0.34)). Increased risk of new onset cardiovascular disease (IRR 2.55 (0.92, 7.04)) and new onset renal disease (IRR 3.4 (1.29-8.96)) were higher in patients receiving high dose. Conclusion AAV patients have significant exposure to high dose GCs and in real world practice, GC dose remains higher than recommended in current clinical guidelines. High dose GCs are associated with high risk of infection and new cardiovascular disease and renal disease. This creates a significant patient burden and has implications for healthcare resource use. Disclosures P. Spearpoint: Corporate appointments; Employee of Vifor Pharma. C. Sammon: Corporate appointments; Employee of PHMR. A. Ramirez de Arellano Serna: Corporate appointments; Employee of Vifor Pharma. P. Rutherford: Corporate appointments; Employee of Vifor Pharma. Shareholder/stock ownership; Vifor Pharma.

Early Detection of Pump Thrombosis in Patients With Left Ventricular Assist Device.

Pump thrombosis (PT) is a serious adverse event in patients receiving left ventricular assist devices (LVAD). The study aims to determine whether pump parameters and clinical data may enable early detection of PT. This retrospective study included 88 patients who received an LVAD between 2012 and 2015 among which those with intra-PT were identified. In a propensity score-matched control group observation, time periods were matched with time before thrombosis. International normalized ratio (INR) time in therapeutic range (TTR) and lactate dehydrogenase (LDH) were analyzed for 60 days preceding PT. Furthermore, pump data (power, flow, and speed) in HeartWare ventricular assist devices (HVAD) patients were analyzed 7 days before PT using a mixed-design analysis of variance to investigate temporal changes in pump data. Pump thrombosis occurred in 15 patients (13 males, age 58 ± 10 years, 7 HeartMate II and 8 HVAD). International normalized ratio therapeutic range (2.0-3.0) and acetylsalicylic acid daily doses (100-200 mg) were similar for both groups, but patients with PT had lower TTR (36% vs. 65%; p = 0.025). No significant difference in LVAD power between groups was seen at baseline (p = 0.31), and power did not change in the control group over time (p > 0.99). Lactate dehydrogenase increased already 1 week prior PT and power from 4.4 ± 0.8 W at baseline to 4.9 ± 0.8 W (p = 0.007) 2 days before readmission and to 6.5 ± 1.8 W (p = 0.015) at readmission. Pump thrombosis is associated with a lower percentage of INR TTR and elevated LDH before the event. A better monitoring of pump parameters would enable PT detection already up to 2 days in advance.

Identification of Serious Adverse Events in Patients with Traumatic Brain Injuries, from Prehospital Care to Intensive-Care Unit, Using Early Warning Scores.

Traumatic brain injuries are complex situations in which the emergency medical services must quickly determine the risk of deterioration using minimal diagnostic methods. The aim of this study is to analyze whether the use of early warning scores can help with decision-making in these dynamic situations by determining the patients who need the intensive care unit. A prospective, multicentric cohort study without intervention was carried out on traumatic brain injury patients aged over 18 given advanced life support and taken to the hospital. Our study included a total of 209 cases. The total number of intensive-care unit admissions was 50 cases (23.9%). Of the scores analyzed, the National Early Warning Score2 was the best result presented with an area under the curve of 0.888 (0.81–0.94; p < 0.001) and an odds ratio of 25.4 (95% confidence interval (CI):11.2–57.5). The use of early warning scores (and specifically National Early Warning Score2) can help the emergency medical services to differentiate traumatic brain injury patients with a high risk of deterioration. The emergency medical services should use the early warning scores routinely in all cases for the early detection of high-risk situations.