Frequency Of Serious Adverse Events Research Articles

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

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

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

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

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

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

Retrospective Observational Study of the Long-Term Safety and Efficacy Outcomes of Rituximab Biosimilar: Partial Data of RTXM83-AC-01-11 Subanalysis Study

Introduction Rituximab is a chimeric monoclonal antibody designed against the CD20 receptor displayed on the surface of B cells and used to treat nearly all B-cell non-Hodgkin lymphomas (NHLs). It was the first monoclonal antibody approved in oncology and it has improved outcomes in all B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. In recent years, the approval of several rituximab biosimilar molecules worldwide has further improved the patients' access to this drug, promoting cost-effective treatment. Biosimilar molecules are defined by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a biological molecule product highly similar to the approved reference product with no clinically meaningful differences. The multicentric double-blind international prospective pivotal study RTXM83-AC-01-11 led to the approval of rituximab biosimilar RTXM83. The study evaluated the efficacy, pharmacokinetics (PK)/pharmacodynamics (PD), safety, and immunogenicity profile of RTXM83 (rituximab biosimilar) vs reference rituximab (Mabthera®), both with CHOP, as first-line treatment of Diffuse-Large-B-Cell-Lymphoma (DLBCL). Participants from both arms received 6 cycles of R-CHOP followed by a 9-month follow-up (Candelaria et al., 2019). Data regarding long-term efficacy and safety events are of great relevance to demonstrate the strength of the clinical response and deepen the confidence in the use of biosimilar molecules. Here, we present a partial data analysis regarding the long-term safety of 11 patients included in this retrospective observational study. Aim This national retrospective observational study aimed to collect long-term data regarding safety e efficacy outcomes from Brazilian participants of the pivotal study RTXM83-AC-01-11 which led to the approval of biosimilar rituximab (Vivaxxia®) in Brazil. Methods All 28 Brazilian participants that were randomized and completed the phase III study RTXM83-AC-01-11 were eligible for this observational, retrospective LB2002 study (Clinical trial information: NCT04928573). Participants were invited to sign the consent form and share the disease history collected since their randomization on the RTXM83-AC-01-11 study. This partial analysis shows the participants' demographic and baseline characteristics, baseline disease characteristics, and the long-term safety data collected and monitored until July 1st, 2022. The long-term safety endpoint was the frequency of serious adverse events of interest, and we considered in this analysis the time between the end of the RTXM83-AC-01-11 study and the consent date of the LB2002 study. Results The intention to treat (ITT) and Safety populations comprised the partial analysis of the same 11 participants, 7 of them (63.6%) treated with biosimilar RTXM83 plus CHOP and 4 (36.4%) with Mabthera® plus CHOP. The median study follow-up time was 73.3 months, considered in this analysis as the time between the randomization of RTXM83-AC-01-11 study participants and the consent date of the LB2002 study. Overall, participants' median age was 55 years old, 63.6% were white, 54.5% were female, 18.8% were active smokers and the body mass index (BMI) ranged from 20 to 35.7 Kg/m² (Table 1). Regarding disease characteristics, 9,1% of the overall participants were classified as stage I DLBCL, 45.5% stage II and IV at the time of diagnosis. Of all 11 participants, 72.7% displayed extranodal lesions, and 18.2% had bulky lesions with a median body surface area (BSA) of 1.8 m2 (Table 1). As for prognostic factor and performance status, participants were classified with IPI 1 (45.5%) and 2 (54.5%), ECOG 1 (72.7%) and 2 (18.3%). The long-term safety analysis from the 11 participants revealed that 2 participants (18.2%) suffered from serious adverse events (SAE) among those of interest listed in Table 2. One participant of the RTXM83-CHOP arm had a SAE classified as severe infection related to rituximab (hypogammaglobulinemia). From the R-CHOP/MabThera® 1 participant displayed 1 SAE (secondary neoplasm) with a possible relationship to rituximab. Conclusion The partial analysis of the LB2002 has demonstrated thus far the safety profile of the biosimilar RTXM83 (Vivaxxia®) in the Brazilian population is consistent with the known safety profile of rituximab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Procedural Pain and Serious Adverse Events Following Bone Marrow Aspiration and Biopsy: Analysis from an Academic Center in India

Background: The Bone Marrow Aspiration and Biopsy (BMAB) is an important and frequent investigative procedure for hematological diseases. Although thought to be safe and well tolerated; data is limited on the complications and degree of pain experienced by patients undergoing BMAB. Further scarce is data from India and other regions from the developing world especially given the evidence that cultural factors that could shape pain perception. Adverse events following bone marrow biopsy are rare but poorly documented. Aims: To estimate the level of pain and frequency of serious adverse events experienced by patients undergoing BMAB at our center. We also attempted to identify factors associated with increased pain perception. Study Setting: This study was conducted at a tertiary level teaching hospital, the Christian Medical College &amp; Hospital, Ludhiana. Ethics approval was obtained from the Institutional research committee (CMC/1495). Study Period: 01 April 2015 through 30 Nov 2019 Study Design: This is a comparative cross sectional study where comparison of those with relatively more pain to those with less was done to elicit the factors associated with pain perception. Results: A total of 942 BMAB procedures were performed in this period (Table 1). The major serious adverse event was hemorrhage, which comprised 2 of the 9 serious adverse events. Those with prior BMAB had very low odds of pain (OR (95% CI): 0.23 (0.15–0.37)). However, when more than one attempt of biopsy was made the odds of pain was much higher (OR (95% CI): 1.62 (1.29–2.05)).

Indirect Comparison of Glucocorticoid-Sparing Agents for Remission Maintenance in Giant Cell Arteritis: A Network Meta-analysis

ObjectiveTo compare and rank the effect of glucocorticoid-sparing agents in giant cell arteritis (GCA), for which several drugs have been evaluated but with a benefit-risk balance that remains uncertain. MethodsThe MEDLINE and Clinical Trials databases were searched up to November 2021; all randomized controlled trials investigating glucocorticoids in GCA were included. The glucocorticoid regimen was dichotomized into short (≤6 months) or prolonged (>6 months) use. Risk of relapse and safety were estimated using network meta-analysis with frequentist random effects models. ResultsOf the 96 records screened, 8 trials were included (572 patients). The trials compared glucocorticoids and a sparing agent: tocilizumab (2 trials), oral methotrexate (3 trials), infliximab (1 trial), etanercept (1 trial), and adalimumab (1 trial). The pooled prevalence of GCA relapse was 52.6% (95% CI, 38.1 to 66.9). The risk of relapse was significantly lower with tocilizumab compared with methotrexate (relative risk [RR], 0.41; 95% CI, 0.17 to 0.97) and prolonged (RR, 0.41; 95% CI, 0.20 to 0.83) and short (RR, 0.32; 95% CI, 0.16 to 0.66) glucocorticoid use. The risk of relapse was not significantly different with methotrexate compared with short (RR, 0.79; 95% CI, 0.48 to 1.31) and prolonged (RR, 0.95; 95% CI, 0.31 to 2.89) glucocorticoid use. The frequency of serious adverse events and serious infection was comparable between the different drugs. The certainty of the evidence was low to very low. ConclusionThis meta-analysis suggests that tocilizumab may be superior to other sparing agents to prevent GCA relapse, but with a low to very low certainty of evidence, and that safety is comparable to the other drugs. RegistrationThe protocol of the meta-analysis is registered in the international prospective register of systematic reviews PROSPERO (https://www.crd.york.ac.uk/prospero/; registration CRD42020112387).

Safety and immunogenicity of anti-SARS-CoV-2 heterologous scheme with SOBERANA 02 and SOBERANA Plus vaccines: Phase IIb clinical trial in adults

BackgroundSOBERANA 02 has been evaluated in phase I and IIa studies comparing homologous versus heterologous schedule (this one, including SOBERANA Plus). Here, we report results of immunogenicity, safety, and reactogenicity of SOBERANA 02 in a two- or three-dose heterologous scheme in adults.MethodPhase IIb was a parallel, multicenter, adaptive, double-blind, randomized, and placebo-controlled trial. Subjects (n = 810) aged 19–80 years were randomized to receive two doses of SARS-CoV-2 RBD conjugated to tetanus toxoid (SOBERANA 02) and a third dose of dimeric RBD (SOBERANA Plus) 28 days apart; two production batches of active ingredients of SOBERANA 02 were evaluated. Primary outcome was the percentage of seroconverted subjects with ≥4-fold the anti-RBD immunoglobulin G (IgG) concentration. Secondary outcomes were safety, reactogenicity, and neutralizing antibodies.FindingsSeroconversion rate in vaccinees was 76.3% after two doses and 96.8% after the third dose of SOBERANA Plus (7.3% in the placebo group). Neutralizing IgG antibodies were detected against D614G and variants of concern (VOCs) Alpha, Beta, Delta, and Omicron. Specific, functional antibodies were detected 7–8 months after the third dose. The frequency of serious adverse events (AEs) associated with vaccination was very low (0.1%). Local pain was the most frequent AE.ConclusionsTwo doses of SOBERANA 02 were safe and immunogenic in adults. The heterologous combination with SOBERANA Plus increased neutralizing antibodies, detectable 7–8 months after the third dose.Trial registryhttps://rpcec.sld.cu/trials/RPCEC00000347FundingThis work was supported by Finlay Vaccine Institute, BioCubaFarma, and the Fondo Nacional de Ciencia y Técnica (FONCI-CITMA-Cuba, contract 2020-20).

Effectiveness and toxicity of metronomic oral cyclophosphamide for recurrent or platinum-refractory ovarian cancer: A meta-analysis

PurposeTo systematically assess the effectiveness and toxicity of metronomic oral cyclophosphamide (MOC) on recurrent or platinum-refractory ovarian cancer. MethodsWe searched the Cochrane Library, Embase, PubMed, CNKI, Weipu, and Wanfang databases for eligible studies. A descriptive statistical method was used to analyze the pooled results. Ratios and means were merged to analyze the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the rate of serious adverse events (SAEs). Subgroup analysis, sensitivity analysis, and examination of publication bias were conducted for heterogeneity test and quality assurance of the results. ResultsThe ORR and DCR by MOC were 25% (95% CI 12–41) and 61% (95% CI 43–77), respectively. The median PFS and OS were 4.29 months (95% CI 2.62–5.97) and 11.26 months (95% CI 8.13–14.39), respectively. The rate of SAEs was 41% (95% CI 30–52). The most frequent SAEs were gastrointestinal toxicity 6% (95% CI 1–12), lymphopenia 6% (95% CI 1–13), and neutropenia 5% (95% CI 2–9). In the subgroup analysis, the ORR and DCR in the subgroup of MOC combined with bevacizumab/pazopanib were 42% (95% CI 26–58) and 82% (95% CI 63–95), respectively. The median PFS and OS were 7.32 months (95% CI 5.93–8.70) and 17.35 months (95% CI 12.89–21.82), respectively. ConclusionMOC has a certain effect in clinical response on patients with recurrent or platinum-refractory ovarian cancers, especially when MOC combined with bevacizumab/pazopanib. However, there is a high risk of SAEs.

Adjunctive Recombinant Human Plasma Gelsolin for Severe Coronavirus Disease 2019 Pneumonia.

BackgroundExcessive inflammation contributes to the morbidity and mortality of severe coronavirus disease 2019 (COVID-19) pneumonia. Recombinant human plasma gelsolin (rhu-pGSN) improves disease outcomes in diverse experimental models of infectious and noninfectious inflammation.MethodsIn a blinded, randomized study, 61 subjects with documented COVID-19 pneumonia having a World Health Organization (WHO) Severity Score of 4 to 6 and evidence of a hyperinflammatory state were treated with standard care and either adjunctive rhu-pGSN 12 mg/kg or an equal volume of saline placebo given intravenously at entry, 12 hours, and 36 hours. The prespecified coprimary outcomes were survival without major respiratory, hemodynamic, or renal support on Day 14 and the incidence of serious adverse events (SAEs) during the 90-day study period.ResultsAll subjects receiving ≥1 dose of study drug were analyzed. Fifty-four of 61 subjects (88.5%) were WHO severity level 4 at entry. The proportions of subjects alive without support on Day 14 were 25 of 30 rhu-pGSN recipients (83.3%) and 27 of 31 placebo recipients (87.1%). Over the duration of the study, WHO Severity Scores improved similarly in both treatment groups. No statistically significant differences were observed between treatment groups at any time point examined. Two subjects died in each group. Numerically fewer subjects in the rhu-pGSN group had SAEs (5 subjects; 16.7%) or ≥ Grade 3 adverse events (5 subjects; 16.7%) than in the placebo group (8 subjects [25.8%] and 9 subjects [29.0%], respectively), mostly involving the lungs. Three rhu-pGSN recipients (10.0%) were intubated compared to 6 placebo recipients (19.4%).ConclusionsOverall, subjects in this study did well irrespective of treatment arm. When added to dexamethasone and remdesivir, no definitive benefit was demonstrated for rhu-pGSN relative to placebo. Safety signals were not identified after the administration of 3 doses of 12 mg/kg rhu-pGSN over 36 hours. The frequencies of SAEs and intubation were numerically fewer in the rhu-pGSN group compared with placebo.

Efficacy and safety of vector vaccines for the prevention of new coronavirus infection

The review article discusses vaccines against SARS-CoV 2 based on adenovirus vectors currently used in the world. The concept of creating vector vaccines is described. The data of clinical studies on the efficacy and safety of registered adenovirus-vector vaccines for the prevention of new coronavirus infection are presented. The frequency of serious adverse events after their use is described in detail. In addition, the clinical efficacy of vector vaccines for changing genotypes of the Covid 19 virus has been determined.The review analyzes literature data on the safety and efficacy of vector vaccines against coronavirus infection.The vector vaccines currently used against the new coronavirus infection are quite safe and effective even in relation to the new genotypes of the SARS-CoV 2 virus.

Potential Drawbacks of ICS/LABA/LAMA Triple Fixed-Dose Combination Therapy in the Treatment of Asthma: A Quantitative Synthesis of Safety Profile

IntroductionInhaled corticosteroid/long-acting β2-adrenoceptor agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) fixed-dose combination (FDC) is currently recommended as controller option at asthma Step 4 and as preferred treatment at asthma Step 5, but no research investigated the potential drawbacks of this therapeutic option in a large asthmatic population. Thus, the aim of this study was to quantify the potential drawbacks of triple FDC therapy in asthma.MethodsA pairwise meta-analysis was performed according to PRISMA-P guidelines to assess the risk of overall serious adverse events (SAEs), cardiovascular SAEs, and pneumonia reported as SAE in asthmatic patients treated with ICS/LABA/LAMA FDC vs ICS/LABA FDC. A pooled analysis was performed to calculate the frequency of SAEs.ResultsData from 7204 asthmatic patients were extracted from the CAPTAIN, IRIDIUM, TRIMARAN, and TRIGGER studies. Triple FDC vs ICS/LABA FDC did not increase the risk of total SAEs (RR 0.99 95% CI 0.83–1.18) and cardiac SAEs (RR 0.74 95% CI 0.39–1.40), whereas the sensitivity analysis performed to resolve heterogeneity resulted in increased risk of vascular SAEs (RR 3.23 95% CI 1.05–9.90, P<0.05). The level of ICS dose did not modulate the risk of pneumonia, in any case pneumonia was the most frequent SAE (0.57%). These results were not affected by significant risk of bias.ConclusionTriple FDC is a safe pharmacological therapy in severe asthmatic patients; it is characterized by a favourable safety profile and few potential drawbacks, namely, the increased risk of vascular SAEs, that certainly are worthy of future investigations.

Inflammatory Bowel Disease Patients' Treatment Preferences Using a Discrete Choice Experiment Technique: The InPuT Study.

IntroductionThe aim of this study was to investigate patients’ preferences regarding the evolving treatment landscape in Crohn’s disease (CD) and ulcerative colitis (UC) based on a discrete choice experiment.MethodsEligible patients (aged 18 years or older) had a confirmed diagnosis of CD or UC and were willing and able to participate in telephone interviews. The survey design is based on a prior literature review, a pilot study, and clinical expert discussions. Preferences related to clinical and practical features of advanced therapies, like tumor necrosis factor alpha inhibitors, anti-integrins, anti-interleukins, and Janus kinase inhibitors, were assessed. Patients were asked to choose between two different hypothetical treatment alternatives visualized in up to 11 choice scenarios. Based on these choices, the relative importance of treatment characteristics was derived from regression coefficients estimated by a conditional logit model.ResultsOf the 291 patients included, 219 (75%) were eligible for this analysis. Among the evaluated attributes in CD, 1-year remission rate was ranked highest, with 42.3% relevance for the overall decision. The second most important attribute was the frequency of serious adverse events (AE) (25.1%), followed by sustained remission over 2 years (17.8%). Lower importance was assigned to the administration mode (14.6%) and none to the frequency of non-serious AE (0.1%). In UC, preferences were driven by efficacy (25.3% for mucosal healing; 23.4% for corticosteroid-free remission) and the frequency of serious AE (18.3%), followed by the administration mode (18.1%). Also, non-serious AE were classified as relevant factors for decision-making (10.7%), while maintaining remission for at least 2 years showed no significant impact (4.4%).ConclusionFor both indications, efficacy outcomes were rated most important, followed by the frequency of serious AE. Variations were mainly found in the evaluation of non-serious AE and sustained remission. Considering patient preferences may improve the effectiveness of available therapies for moderate to severe CD and UC.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02143-z.

Clinical efficacy and safety of interleukin-6 receptor antagonists (tocilizumab and sarilumab) in patients with COVID-19: a systematic review and meta-analysis

ABSTRACT This study investigated the efficacy and safety of interleukin-6 (IL-6) receptor antagonists with standard care treatment in patients with coronavirus disease 2019 (COVID-19). The randomized controlled trials were identified through systematic searches of electronic databases through February 10, 2022. In total, 17 trials comprising 8,614 patients were included. Compared with exclusive standard care or placebo, IL-6 receptor antagonists with standard of care treatment were associated with a significantly reduced all-cause mortality at 28 days (pooled risk ratios [RR], 0.88; 95% confidence interval (CI), 0.82–0.95; 17 studies) and progression to invasive mechanical ventilation (RR, 0.79; 95% CI, 0.71–0.88; nine studies). Particularly, the subgroup of patients with moderate-to-severe COVID-19 showed a significant mortality benefit (RR, 0.89; 95% CI, 0.81–0.96; four studies) and a reduced risk for mechanical ventilation (RR, 0.80; 95% CI, 0.70–0.91; three studies) with tocilizumab treatment. The frequency of serious adverse events was lower in the tocilizumab treatment group than in the standard of care treatment group (RR, 0.83; 95% CI, 0.71–0.97; 11 studies), with no significant difference in the sarilumab treatment group (RR, 1.12; 95% CI, 0.89–1.40; four studies). Our meta-analysis demonstrated that tocilizumab treatment showed promising results in reducing 28-day mortality and progression to mechanical ventilation in patients with moderate-to-severe COVID-19, without the burden of serious adverse events. Trial registration: PROSPERO: registration number CRD42021294120.

Analysis of serious adverse events in a pediatric community-acquired pneumonia randomized clinical trial in Malawi

Amoxicillin is recommended as first-line antibiotic treatment for community-acquired pneumonia, the leading infectious cause of mortality in children aged less than 5 years. We conducted a double-blind, randomized controlled non-inferiority trial comparing 3- to 5-day amoxicillin treatment for non-severe chest-indrawing pneumonia in HIV-negative children aged 2 to 59 months in Malawi. In a secondary analysis, we assessed the frequency of serious adverse events (SAEs) during the trial to evaluate the safety of treatment with amoxicillin. Enrolled children with non-severe chest-indrawing pneumonia were randomized to either 3- or 5-day amoxicillin and followed for 14 days to track clinical outcomes. In addition to evaluation for treatment failure (primary endpoint, day 6), relapse, and study drug adherence, children were assessed for adverse events, including SAEs, which were managed per local standard clinical practice until resolution or stabilization. Between March 2016 and April 2019, 3000 children were enrolled, with male and younger children (aged less than 24 months) demonstrating more SAEs (10.3% for males vs 8.1% for females, p = 0.04; 10.0% for 2–6 months, 10.8% for 7–11 months, 9.7% for 12–23 months and 5.6% for 24–59 months, p = 0.01). The most common SAEs were progression of or recurrent pneumonia (220 SAEs in 217 children), acute gastroenteritis (14 SAEs in 14 children), and fever (8 SAEs in 8 children); however, there were no significant or substantive differences in the percentage of children with pneumonia-related, acute gastroenteritis, or fever SAEs noted between the 3- versus 5-day amoxicillin treatment groups. In our pediatric community-acquired pneumonia trial evaluating amoxicillin treatment, there were relatively few SAEs overall and very few attributed to amoxicillin. Duration of amoxicillin treatment did not impact the frequency of SAEs. We found male and younger children appear to be more vulnerable to SAEs in our trial; however, our data support previous data demonstrating the safety of amoxicillin use in children with pneumonia.Clinical trial registration: ClinicalTrials.gov (NCT02678195).

Are Cell-Based Therapies Safe and Effective in the Treatment of Neurodegenerative Diseases? A Systematic Review with Meta-Analysis.

Over the past two decades, significant advances have been made in the field of regenerative medicine. However, despite being of the utmost clinical urgency, there remains a paucity of therapeutic strategies for conditions with substantial neurodegeneration such as (progressive) multiple sclerosis (MS), spinal cord injury (SCI), Parkinson’s disease (PD) and Alzheimer’s disease (AD). Different cell types, such as mesenchymal stromal cells (MSC), neuronal stem cells (NSC), olfactory ensheathing cells (OEC), neurons and a variety of others, already demonstrated safety and regenerative or neuroprotective properties in the central nervous system during the preclinical phase. As a result of these promising findings, in recent years, these necessary types of cell therapies have been intensively tested in clinical trials to establish whether these results could be confirmed in patients. However, extensive research is still needed regarding elucidating the exact mechanism of action, possible immune rejection, functionality and survival of the administered cells, dose, frequency and administration route. To summarize the current state of knowledge, we conducted a systematic review with meta-analysis. A total of 27,043 records were reviewed by two independent assessors and 71 records were included in the final quantitative analysis. These results show that the overall frequency of serious adverse events was low: 0.03 (95% CI: 0.01–0.08). In addition, several trials in MS and SCI reported efficacy data, demonstrating some promising results on clinical outcomes. All randomized controlled studies were at a low risk of bias due to appropriate blinding of the treatment, including assessors and patients. In conclusion, cell-based therapies in neurodegenerative disease are safe and feasible while showing promising clinical improvements. Nevertheless, given their high heterogeneity, the results require a cautious approach. We advocate for the harmonization of study protocols of trials investigating cell-based therapies in neurodegenerative diseases, adverse event reporting and investigation of clinical outcomes.

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

397 Background: Atezolizumab plus bevacizumab (Ate/Bev) demonstrated promising efficacy and safety in patients with advanced hepatocellular carcinoma (aHCC) in the phase III IMbrave 150 trial. However, despite the high unmet need in Child-Pugh B patients, this subgroup of patients was not included in this study. Therefore, we aimed to investigate the efficacy and safety of Ate/Bev in Child-Pugh B HCC patients. Methods: This multicenter retrospective study included 27 HCC patients classified as Child-Pugh B who received Ate/Bev at four cancer referral centers between May 2020 and August 2021. Comparative analyses were performed with an independent cohort of Child-Pugh A patients from the same registry (n=130). Results: All patients received Ate/Bev as first-line systemic treatment for aHCC. The objective response rates of patients in Child-Pugh groups B and A were 14.8% and 32.3%, and the disease control rates were 55.5% and 76.1%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.0 months (95% CI, 1.6-4.3) and 6.0 months (95% CI, 4.9-7.0) in Child-Pugh B patients, while the median PFS was 6.0 months (95% CI, 4.6-13.4) and the median OS was not-reached (95% CI not available) in Child-Pugh A group. Compared to Child-Pugh A group, grade 3-4 adverse events (AEs) were more common in the Child-Pugh B group (48.1% vs 17.7%, p=0.001), with the most frequent grade 3-4 AEs being thrombocytopenia (11.1%) and AST elevation (11.1%). The rate of treatment discontinuation due to AEs was higher in the Child-Pugh B group (14.8% vs 3.1%, p=0.030), and the reasons for discontinuation were gastrointestinal (GI) bleeding (n=2), GI perforation (n=1) and interstitial pneumonitis (n=1). Conclusions: In the Child-Pugh B subgroup of patients with aHCC, Ate/Bev treatment showed modest clinical activity. However, due to the increased frequency of serious AEs, careful evaluation of treatment response and AE management is required in this subgroup patients. [Table: see text]

Plasma exchange and infliximab as a third‐line therapy for refractory infantile Kawasaki disease

The treatment for Kawasaki disease (KD) patients refractory to intravenous immunoglobulin (IVIG) therapy is still controversial, and the efficacy of plasma exchange (PE) and infliximab (IFX) therapy for infantile KD is unknown. A total of 22 infantile KD patients refractory to initial and additional IVIG, who received either PE or IFX as third-line therapy from October 2008 to February 2020 were examined retrospectively. The patients' sex, age, days of first IVIG, days of PE or IFX therapy, laboratory data preceding PE or IFX therapy, coronary artery lesions (CALs), and adverse effects were investigated. Thirteen patients received PE and nine patients received IFX as the third-line therapy. For the median age at onset, the median days of first IVIG and PE or IFX, and pre-PE or IFX therapy blood test results, there were no significant between-group differences. At admission, and before and after the third-line therapy, there were also no significant differences in occurrence of CALs. The frequency of serious adverse events was significantly higher in the PE group than in the IFX group. Although there were no significant differences in patient background, blood test results, or frequency of CALs, the frequency of adverse events was significantly higher in the PE group. With the trend of expansion of IFX therapy for KD patients refractory to IVIG, the role of PE as the additional therapy may become more limited.

Effectiveness of an Annular Closure Device to Prevent Recurrent Lumbar Disc Herniation

Patients with large annular defects following lumbar microdiscectomy for disc herniation are at increased risk for symptomatic recurrence and reoperation.To determine whether a bone-anchored annular closure device in addition to lumbar microdiscectomy resulted in lower reherniation and reoperation rates vs lumbar microdiscectomy alone.This secondary analysis of a multicenter randomized clinical trial reports 5-year follow-up for enrolled patients between December 2010 and October 2014 at 21 clinical sites. Patients in this study had a large annular defect (6-10 mm width) following lumbar microdiscectomy for treatment of lumbar disc herniation. Statistical analysis was performed from November to December 2020.Lumbar microdiscectomy with additional bone-anchored annular closure device (device group) or lumbar microdiscectomy only (control group).The incidence of symptomatic reherniation, reoperation, and adverse events as well as changes in leg pain, Oswestry Disability Index, and health-related quality of life when comparing the device and control groups over 5 years of follow-up.Among 554 randomized participants (mean [SD] age: 43 [11] years; 327 [59%] were men), 550 were included in the modified intent-to-treat efficacy population (device group: n = 272; 270 [99%] were White); control group: n = 278; 273 [98%] were White) and 550 were included in the as-treated safety population (device group: n = 267; control group: n = 283). The risk of symptomatic reherniation (18.8% [SE, 2.5%] vs 31.6% [SE, 2.9%]; P < .001) and reoperation (16.0% [SE, 2.3%] vs 22.6% [SE, 2.6%]; P = .03) was lower in the device group. There were 53 reoperations in 40 patients in the device group and 82 reoperations in 58 patients in the control group. Scores for leg pain severity, Oswestry Disability Index, and health-related quality of life significantly improved over 5 years of follow-up with no clinically relevant differences between groups. The frequency of serious adverse events was comparable between the treatment groups. Serious adverse events associated with the device or procedure were less frequent in the device group (12.0% vs 20.5%; difference, -8.5%; 95% CI, -14.6% to -2.3%; P = .008).In patients who are at high risk of recurrent herniation following lumbar microdiscectomy owing to a large defect in the annulus fibrosus, this study's findings suggest that annular closure with a bone-anchored implant lowers the risk of symptomatic recurrence and reoperation over 5 years of follow-up.ClinicalTrials.gov Identifier: NCT01283438.

Intravenous immunoglobulins in patients with COVID-19-associated moderate-to-severe acute respiratory distress syndrome (ICAR): multicentre, double-blind, placebo-controlled, phase 3 trial

BackgroundAcute respiratory distress syndrome (ARDS) is a major complication of COVID-19 and is associated with high mortality and morbidity. We aimed to assess whether intravenous immunoglobulins (IVIG) could improve outcomes by reducing inflammation-mediated lung injury.MethodsIn this multicentre, double-blind, placebo-controlled trial, done at 43 centres in France, we randomly assigned patients (1:1) receiving invasive mechanical ventilation for up to 72 h with PCR confirmed COVID-19 and associated moderate-to-severe ARDS to receive either IVIG (2 g/kg over 4 days) or placebo. Random assignment was done with a web-based system and was stratified according to the participating centre and the duration of invasive mechanical ventilation before inclusion in the trial (<12 h, 12–24 h, and >24–72 h), and treatment was administered within the first 96 h of invasive mechanical ventilation. To minimise the risk of adverse events, the IVIG administration was divided into four perfusions of 0·5 g/kg each administered over at least 8 hours. Patients in the placebo group received an equivalent volume of sodium chloride 0·9% (10 mL/kg) over the same period. The primary outcome was the number of ventilation-free days by day 28, assessed according to the intention-to-treat principle. This trial was registered on ClinicalTrials.gov, NCT04350580.FindingsBetween April 3, and October 20, 2020, 146 patients (43 [29%] women) were eligible for inclusion and randomly assigned: 69 (47%) patients to the IVIG group and 77 (53%) to the placebo group. The intention-to-treat analysis showed no statistical difference in the median number of ventilation-free days at day 28 between the IVIG group (0·0 [IQR 0·0–8·0]) and the placebo group (0·0 [0·0–6·0]; difference estimate 0·0 [0·0–0·0]; p=0·21). Serious adverse events were more frequent in the IVIG group (78 events in 22 [32%] patients) than in the placebo group (47 events in 15 [20%] patients; p=0·089).InterpretationIn patients with COVID-19 who received invasive mechanical ventilation for moderate-to-severe ARDS, IVIG did not improve clinical outcomes at day 28 and tended to be associated with an increased frequency of serious adverse events, although not significant. The effect of IVIGs on earlier disease stages of COVID-19 should be assessed in future trials.FundingProgramme Hospitalier de Recherche Clinique.

Intravenous immunoglobulin therapy for COVID-19 ARDS

Intravenous immunoglobulin therapy for COVID-19 ARDS