Subjective Adverse Events Research Articles

CTIM-14. EARLY SAFETY DATA FROM A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PHASE 2B STUDY OF IGV-001, AN AUTOLOGOUS CELL IMMUNOTHERAPY, VERSUS PLACEBO, IN NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)

Abstract Standard of care (SOC) for ndGBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. IGV-001 is an autologous biologic-device combination immunotherapy for the treatment of ndGBM that consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA, irradiated and administered via biodiffusion chambers implanted in the abdomen. In a phase 1b study, IGV-001 was well tolerated without unexpected adverse events in subjects with ndGBM. Multiple efficacy signals were observed, including significant improvements in progression-free survival (PFS), overall survival (OS), radiographic evidence of tumor response, and changes in immune response biomarkers. Here, we present early safety data from the phase 2b randomized, multicenter, double-blind, placebo-controlled study (NCT04485949) designed to assess efficacy and safety of IGV-001 in subjects with ndGBM across 20 sites in the United States. After surgical resection, subjects were randomized 2:1 and treated with IGV-001 or placebo followed by SOC. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include OS, defined as the time from randomization to death due to any cause, and safety. As of May 22, 2024, 99 subjects were randomized and 95 implanted with IGV-001 or placebo plus SOC. A total of 39/45 (86.7%) subjects had sufficient follow-up time after initiated treatment with concurrent radiation and temozolomide. Nine of 72 randomized (12.5%) discontinued treatment, including 7 who stopped during the SOC treatment period. None ceased treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized subjects discontinued the study after randomization. A review of blinded safety data did not show any emerging risk and supports no change to the benefit-risk profile of IGV-001 versus placebo. Updated data will be presented.

Efficacy and safety of oral semaglutide in older patients with type 2 diabetes: a retrospective observational study (the OTARU-SEMA study)

BackgroundOral semaglutide in older subjects with type 2 diabetes was as effective as in younger subjects, according to phase 3 clinical trials. However, its efficacy can be limited in very aged population, due to the presence of impaired cognitive function and the complex instructions for its use. Here, we investigated its efficacy and safety by further age bracket in older subjects in real-world.MethodsWe retrospectively studied subjects > 65 years of age with type 2 diabetes who started oral semaglutide treatment. The primary outcome was the change in glycated hemoglobin (HbA1c) over 6 months. Adverse events and cognitive function were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) and the Hasegawa Dementia Rating Scale-revised (HDS-R). The achievement rate of glycemic targets was evaluated based on the age, health status of subjects and their use of anti-diabetic agents which can cause hypoglycemia, with additional analysis between two subgroups; early (65–74) versus late (≥ 75) older. Furthermore, we evaluated the relationships between their improvements in HbA1c and the baseline characteristics of the subjects, including their cognitive function and insulin secretory capacity.ResultsWe studied the efficacy of the drug in 24 subjects. Their HbA1c and body weight significantly decreased (− 13.1 ± 7.5 mmol/mol and − 3.0 ± 2.4 kg, respectively; P < 0.01). Although cognitive function was lower in the late older group (r = −0.57, P < 0.01), changes in HbA1c showed no difference between the two subgroups (P = 0.66) and it correlated with the insulin secretory capacity rather than cognitive function (r = −0.49, P < 0.05). Glycemic targets were more likely to be achieved (P < 0.01), but HbA1c excessively decreased in late older subjects who were also using insulin or an insulin secretagogue. The frequency of adverse events was similar to that in the clinical trial, whereas discontinuation of medication were more frequent among the late older subjects (Early; n = 2, Late; n = 4).ConclusionsOral semaglutide improves the glycemic control of older subjects, but it might be a risk for potential hypoglycemia and discontinuation because of adverse events in subjects of ≥ 75 years. Attention should be paid to insulin secretory capacity and concomitant medications rather than concern about adherence.

Efficacy and safety of the Valsalva maneuver in relieving venipuncture pain in children and adults: A systematic review and meta-analysis.

Venipuncture is a common invasive clinical procedure, and pain management during puncture has been of interest to healthcare professionals. The purpose of this systematic review and meta-analysis was to evaluate the efficacy and safety of the Valsalva maneuver (VM) for the relief of venipuncture pain in children and adults. PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang, VIP database, and CBM were searched from inception to December 2023 for all available randomized controlled trials (RCTs) that evaluated the impact of VM on venipuncture. Two reviewers independently performed study selection, data extraction, and risk of bias assessment. Continuous variables were analyzed by mean differences (MD) or standardized mean differences (SMD), whereas dichotomous variables were analyzed by risk ratios (RR). A total of 22 studies involving 1740 participants were included. The pooled results showed that VM relieved pain intensity during venipuncture in children (SMD = -0.89, 95% CI = -1.47 to -0.30, p = 0.003) and adults (SMD = -1.11, 95% CI = -1.46 to -0.77, p < 0.00001), reduced anxiety intensity (SMD = -1.07, 95% CI = -1.68 to -0.47, p = 0.0005), and shortened puncture time (MD = -13.52, 95% CI = -21.14 to -5.90, p = 0.0005). There was no significant difference in the success rate of venous cannulation, MAP, HR, or incidence of adverse events in subjects who performed VM compared to controls. VM was an effective and safe method of pain management that reduced pain intensity during venipuncture in children and adults without significant adverse effects. The results of this meta-analysis need to be further validated by more rigorous and larger RCTs.

P034 A common IL2RA polymorphism alters natural killer cell immunophenotype and function in Crohn’s disease, with implications for IL-2 based therapy

Abstract Background The single nucleotide polymorphism (SNP) rs61839660 lies within the IL2RA (CD25) intronic enhancer and has been identified as a causal variant in Crohn’s disease (CD), with a heterozygote frequency of 16.8% in a European population. CD25 is the high-affinity receptor for IL-2, and is constitutively expressed on regulatory T cells (Tregs). Low-dose IL-2 (LD-IL2) is under investigation in IBD, under the premise that it will expand a group of tolerising Tregs. However, finding a therapeutic dose which activates Tregs without activating effector T cells (Teffs) has proved challenging and activation of CD56dim NK cells has been linked to adverse events in trial subjects. We have demonstrated that the rs61839660 risk (T) allele carriers exhibit higher CD4+ T cell CD25 expression, enhanced pSTAT5 activation on stimulation with IL-2, and greater Teff release of pro-inflammatory cytokines. We sought to understand the impact of the risk allele on NK cell immunophenotype and function. Methods We recruited CD patients homozygous major allele (CC), or heterozygous (CT) at the rs61839660 locus. We extracted peripheral blood mononuclear cells and flow-sorted CD56dim (cytotoxic) and CD56bright (regulatory) NK subsets. Cells were stimulated with IL-2, then stained for intracellular pSTAT5. To assess cytotoxicity, NK cells were rested in media either with or without IL-2, before plating with CFSE-labelled K562 target cells. The proportion of K562 cells positive for dead cell marker was assessed for each condition. Results There was no difference in CD phenotype or severity between groups, in terms of age at diagnosis, sex distribution, presence of perianal disease or the proportion requiring surgery. CD25 expression was significantly enhanced on CD56Bright NK cells in CT subjects compared to CC subjects (1b). Enhanced CD25 expression was also seen in CD56Dim NK cells, though this did not reach statistical significance (1a). The concentration of IL-2 required to activate 50% intracellular STAT5 was lower in CT subjects’ CD56Bright NK cells compared to those from CC subjects (21.5IU/ml vs. 132.4IU/ml, p=0.039). The cytotoxicity of CT subjects’ CD56dim NK cells was significantly enhanced following exposure to IL-2, compared to CC subjects (1c). Conclusion Our findings suggest that risk (T) allele carriers have enhanced responsiveness to IL-2 signalling in NK cells, mediated by increased expression of CD25. We hypothesise that these subjects would be at greater risk of adverse events on exposure to LD-IL2, through enhanced CD56Dim NK cytotoxicity. Our results suggest that screening of subjects entering trials of IL-2-based therapy for the rs61839660 risk variant should be considered, as the threshold for adverse events in these subjects may be lower.

Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the pharmacokinetics and demonstrating the safety and selectivity of the aldosterone synthase inhibitor baxdrostat in healthy volunteers

Baxdrostat is a selective inhibitor of aldosterone synthase designed for the treatment of disorders associated with elevated aldosterone. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of baxdrostat in healthy volunteers. Subjects were randomized to receive oral baxdrostat (0.5, 1.5, 2.5, or 5.0 mg) or placebo once daily for 10 days and were placed on either a low-salt or normal-salt diet for the duration of the study. Blood samples were collected before and after dosing on days 1 and 10 to characterize pharmacokinetics and pharmacodynamics. Safety was assessed by adverse events, physical examinations, electrocardiograms, orthostatic vital signs, and clinical laboratory evaluations. Fifty-four subjects completed the study. There were no deaths or serious adverse events, and all treatment-emergent adverse events in subjects receiving baxdrostat were mild in severity. Plasma levels of baxdrostat increased proportionally with ascending doses, with peak concentrations observed within 4 h after dosing and a mean half-life of 26 to 31 h. A dose-dependent reduction of plasma aldosterone occurred with baxdrostat doses ≥1.5 mg, regardless of diet. Decreases in plasma aldosterone were sustained, with levels reduced by approximately 51 to 73% on day 10. Baxdrostat had no meaningful impact on plasma cortisol levels and resulted in mild dose-dependent decreases in plasma sodium levels and increases in potassium levels. Baxdrostat was safe and well tolerated with a half-life that supports once-daily dosing. The dose-dependent reduction in plasma aldosterone and lack of effect on cortisol demonstrate the selective blockade of aldosterone synthase.

Association of Catechol-O-Methyltransferase Gene Polymorphisms and Haplotypes in the Levodopa-Induced Adverse Events in Subjects with Parkinson's Disease.

The presence of dyskinesia is the most common side effect of chronic administration of levodopa in Parkinson's disease (PD) subjects. Genetic polymorphisms in levodopa metabolizing gene, catechol-O-methyl transferase (COMT), is shown to influence the inter-individual variability in drug response and adverse events. In the present study, the association of COMT rs6269, rs4633, rs4818, and rs4680 polymorphisms and haplotypes on pharmacokinetics and adverse events with levodopa was investigated in 150 PD patients. The age of onset of PD was 58.00 ± 10 yrs. The most common side effect faced by 78% of the subjects was dyskinesia. The AUC of levodopa was found to be significantly higher in subjects with dyskinesia (1695 ± 113ng/ml/hr, p < 0.0001) than those without dyskinesia (1550 ± 122ng/ml/hr). We found that the frequency of subjects presenting dyskinesia was significantly higher in subjects carrying variant genotype of COMT rs6269, rs4633, and rs4680 than that with wild genotype and these subjects presented higher AUC of levodopa. In addition, in subjects with dyskinesia, the AUC of levodopa was found to be significantly higher with low COMT (ACCG) haplotype. The association of COMT rs6269, COMT rs4633, COMT rs4818, and COMT rs4680 variant genotypes with the risk of dyskinesia due to levodopa therapy showed an ROC AUC of 0.67 indicating the moderate prediction of dyskinesia (p = 0.0021) with these COMT variants. In conclusion, PD subjects carrying the variant genotypes of COMT strongly influence high levodopa-induced dyskinesia. Hence the genotyping of COMT before the levodopa therapy will be useful to reduce the adverse events associated with the chronic levodopa treatment.

Efficacy Results of a Phase 2 Trial Evaluating Idelalisib Plus Ofatumumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia

Efficacy Results of a Phase 2 Trial Evaluating Idelalisib Plus Ofatumumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia

OP0124 EFFECTS OF NINTEDANIB IN PATIENTS WITH PROGRESSIVE FIBROSING INTERSTITIAL LUNG DISEASE ASSOCIATED WITH RHEUMATOID ARTHRITIS (RA-ILD) IN THE INBUILD TRIAL

Background:In the INBUILD trial in subjects with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF), nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 57% compared with placebo.Objectives:To assess the rate of decline in FVC in subjects with RA-ILD in the INBUILD trial.Methods:Subjects in the INBUILD trial had a chronic fibrosing ILD other than IPF, reticular abnormality with traction bronchiectasis (with or without honeycombing) of &gt;10% extent on high-resolution computed tomography (HRCT), forced vital capacity (FVC) ≥45% predicted, diffusing capacity of the lungs for carbon monoxide ≥30%–&lt;80% predicted, and met criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Patients taking stable doses of approved medications to treat RA or connective tissue disease could participate, except that the protocol excluded those taking azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, rituximab, cyclophosphamide, or oral glucocorticoids &gt;20 mg/day. We analysed the rate of decline in FVC (mL/year) over 52 weeks and adverse events in subjects with RA-ILD.Results:Of 663 subjects who received trial medication, 89 had RA-ILD (42 nintedanib, 47 placebo), of whom 60.7% were male, 64.0% were current or former smokers, 86.5% had a usual interstitial pneumonia (UIP)-like pattern on HRCT; 93.3% had received confirmation of their RA diagnosis from a rheumatologist. At baseline, 21.3% of subjects were taking biologic disease-modifying anti-rheumatic drugs (DMARDs), 53.9% were taking non-biologic DMARDs and 73.0% were taking glucocorticoids (≤20 mg/day prednisone or equivalent). At baseline, mean (SD) age was 66.9 (9.6) years, time since RA diagnosis was 9.9 (9.4) years, time since ILD diagnosis was 3.6 (3.2) years, FVC was 71.5 (16.2) % predicted and C-reactive protein was 13.7 (22.5) mg/L. The adjusted mean (SE) rate of decline in FVC over 52 weeks was -82.6 (41.3) mL/year in the nintedanib group versus -199.3 (36.2) mL/year in the placebo group (difference 116.7 mL/year [95% CI 7.4, 226.1]; nominal p=0.037), consistent with findings in the overall trial population (Figure). As in the overall trial population, the most common adverse event in subjects with RA-ILD was diarrhoea (reported in 54.8% of the nintedanib group and 25.5% of the placebo group). Adverse events led to permanent discontinuation of trial drug in 19.0% of subjects in the nintedanib group and 12.8% of subjects in the placebo group.Conclusion:In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing RA-ILD, with adverse events that were manageable for most patients. The efficacy and safety of nintedanib in subjects with RA-ILD were consistent with those observed in the overall trial population.Acknowledgements:The INBUILD trial was funded by Boehringer Ingelheim. Medical writing support was provided by Fleishman Hillard Fishburn, London, UK. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE).Disclosure of Interests:Clive Kelly Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Eric Matteson Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim and Gilead Sciences, Grant/research support from: Sun Pharmaceuticals and Pfizer, Martin Aringer Speakers bureau: AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Gilead, GlaxoSmithKline, HEXAL, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi and UCB, Consultant of: AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Lilly, Merck Sharp &amp; Dohme, Novartis, Pfizer, Roche, Sanofi and UCB, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Lilly, Merck Sharp &amp; Dohme, Pfizer, Roche and Sanofi, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Lilly, Merck Sharp &amp; Dohme, Pfizer, Roche and Sanofi, Heiko Mueller Employee of: Currently an employee of Boehringer Ingelheim, Lizette Moros Employee of: Currently an employee of Boehringer Ingelheim, Klaus Rohr Employee of: Currently an employee of Boehringer Ingelheim, Martin Kolb Consultant of: Algernon, Boehringer Ingelheim, Pieris Pharmaceuticals and Roche, Grant/research support from: Boehringer Ingelheim, Pieris Pharmaceuticals and Prometic

Individual risk of post-ivermectin serious adverse events in subjects infected with Loa loa

BackgroundImplementation of onchocerciasis elimination programmes has been delayed in Central Africa because of the risk of ivermectin-related serious adverse events (SAEs) in individuals with high Loa loa microfilarial densities (MFD). We developed the first statistical models enabling prediction of SAE risk in individuals with a given MFD.MethodsWe used individual participant data from two trials conducted in loiasis-onchocerciasis co-endemic areas in Cameroon. among the 10 506 ivermectin-treated subjects included in the analysis, 38 (0·36%) developed an ivermectin-related SAE. To predict individual-level risk of SAE, we developed mixed multivariate logistic models including subjects’ sex, age, pre-treatment L loa and Mansonella perstans MFDs, and study region.FindingsThe models predicted that regardless of sex, about 1% of people with 20 000 L loa microfilariae per millilitre of blood (mf/mL), 10% of people with 50 000 mf/mL and about one third of those with 100 000 mf/mL will develop an SAE. For a given MFD, males have a three-fold higher risk of developing an SAE than females.InterpretationBy enabling the prediction of post-ivermectin SAE risk in communities with known distribution of L loa MFDs, our results can guide decisions on the choice of ivermectin-based treatment strategies. They also predict that 37 SAEs were prevented in 2015 by using a Test-and-Treat strategy in the Okola District of Cameroon.FundingUNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases; Institut de Recherche pour le Développement; Mectizan Donation Program; Bill & Melinda Gates Foundation.

Systematic review with meta-analysis: the efficacy and safety of direct-acting antivirals in children and adolescents with chronic hepatitis C virus infection.

The effect of direct-acting anti-virals (DAAs) in children and adolescents with chronic hepatitis C virus (HCV) infection is difficult to determine, since few, aged between 3 and 18years, have been enrolled in clinical trials, and some data come from observational studies. To summarise the evidence on efficacy and safety of DAAs in children and adolescents with chronic HCV infection. We performed a systematic review and meta-analysis of prospective studies on the efficacy and safety of DAAs in subjects <18years of age. We considered the sustained virological response at post-treatment week 12 as efficacy outcome and adverse events as safety outcome. We considered intervention effect for each study arm by calculating the proportion of sustained virologic response at post-treatment week 12 in subjects receiving all doses of treatment and proportion of adverse events in subjects receiving at least one dose of treatment. Pooled proportions were calculated using the Freeman-Tukey double arcsine transformation. Random effects model was used for all analyses. Among 39 included studies (1796 subjects), the pooled proportion among those receiving all doses of treatment and reaching sustained virologic response at post-treatment week 12 was 100% (95% confidence interval: 100-100). Considering subjects receiving at least one dose of treatment, lowest estimates were reported among children with cirrhosis (83%). Headache and fatigue were the most common adverse events. Serious adverse events were uncommon. Children and adolescents with chronic HCV infection can be safely treated with DAAs with similar efficacy as reported in adults.

Prebiotic UG1601 mitigates constipation-related events in association with gut microbiota: A randomized placebo-controlled intervention study.

BACKGROUNDConstipation is a common functional gastrointestinal disorder and its etiology is multifactorial. Growing evidence suggests that intestinal dysbiosis is associated with the development of constipation. Prebiotics are subjected to bacterial fermentation in the gut to produce short-chain fatty acids (SCFAs), which can help relieve constipation symptoms. The prebiotic UG1601 consists of inulin, lactitol, and aloe vera gel, which are known laxatives, but randomized, controlled clinical trials that examine the effects of this supplement on gut microbiota composition are lacking.AIMTo assess the efficacy of the prebiotic UG1601 in suppressing constipation-related adverse events in subjects with mild constipation.METHODSAdults with a stool frequency of less than thrice a week were randomized to receive either prebiotics or a placebo supplement for 4 wk. All participants provided their fecal and blood samples at baseline and at the end of intervention. Gastrointestinal symptoms and stool frequency were evaluated. The concentrations of serum endotoxemia markers and fecal SCFAs were determined. The relative abundance of SCFA-producing bacteria and the gut microbial community in the responders and non-responders in the prebiotics supplementation group were evaluated.RESULTSThere were no significant differences in gastrointestinal symptoms between groups, although the prebiotic group showed greater symptom improvement. However, after prebiotic usage, serum cluster of differentiation (CD) 14 and lipopolysaccharide (LPS) concentrations were significantly decreased (CD14, P = 0.012; LPS, P < 0.001). The change in LPS concentration was significantly larger in the prebiotic group than in the placebo group (P < 0.001). Fecal SCFAs concentrations did not differ between groups, while the relative abundance of Roseburia hominis, a major butyrate producer, was significantly increased in the prebiotic group (P = 0.045). The abundances of the phylum Firmicutes and the family Lachnospiraceae (phylum Firmicutes, class Clostridia) (P = 0.009) were decreased in the responders within the prebiotic group. In addition, the proportions of the phylum Firmicutes, the class Clostridia, and the order Clostridiales were inversely correlated with several fecal SCFAs (P < 0.05).CONCLUSIONAlterations in gut microbiota composition, including a decrease in the phylum Firmicutes and an increase in butyrate-producing bacteria, following prebiotic UG1601 supplementation might help alleviate symptom scores and endotoxemia.

The effects of a CCR3 inhibitor, AXP1275, on allergen‐induced airway responses in adults with mild‐to‐moderate atopic asthma

CCR3 is the cognate receptor for major human eosinophil chemoattractants from the eotaxin family of proteins that are elevated in asthma and correlate with disease severity. This proof-of-mechanism study examined the effect of AXP1275, an oral, small-molecule inhibitor of CCR3, on airway responses to inhaled allergen challenge. Twenty-one subjects with mild atopic asthma and documented early and late asthmatic responses to an inhaled aeroallergen completed a randomized double-blind cross-over study to compare early and late allergen-induced asthmatic responses, methacholine PC20 , blood and sputum eosinophils and exhaled nitric oxide after 2weeks of treatment with once-daily doses of AXP1275 (50mg) or placebo. There was a significant increase in methacholine PC20 after 12days of AXP1275 treatment compared to placebo (increase of 0.92 doubling doses versus 0.17 doubling doses, P=.01), but this protection was lost post-allergen challenge. There was no effect of AXP1275 on allergen-induced late asthmatic responses, or eosinophils in blood and sputum. The early asthmatic response and exhaled nitric oxide levels were slightly lower with AXP1275, but this did not reach statistical significance. The number of subjects who experienced treatment-emergent adverse events while receiving AXP1275 was comparable placebo. AXP1275 50mg administered daily was safe and well tolerated, and there was no difference in the type, severity or frequency of treatment-emergent adverse events in subjects while receiving AXP1275 compared to placebo. AXP1275 increased the methacholine PC20 ; however, the low and variable exposure to APX1275 over a short treatment period may have contributed to poor efficacy on other outcomes.

Multicenter Trial of the VenaTech Convertible Vena Cava Filter

PurposeTo demonstrate rates of successful filter conversion and 6-month major device-related adverse events in subjects with converted caval filters. Materials and MethodsAn investigational device exemption multicenter, prospective, single-arm study was performed at 11 sites enrolling 149 patients. The VenaTech Convertible Vena Cava Filter (B. Braun Interventional Systems, Inc, Bethlehem, Pennsylvania) was implanted in 149 patients with venous thromboembolism and contraindication to or failure of anticoagulation (n = 119), with high-risk trauma (n = 14), and for surgical prophylaxis (n = 16). When the patient was no longer at risk for pulmonary embolism as determined by clinical assessment, an attempt at filter conversion was made. Follow-up of converted patients (n = 93) was conducted at 30 days, 3 months, and 6 months after conversion. Patients who did not undergo a conversion attempt (n = 53) had follow-up at 6 months after implant. ResultsAll implants were successful. One 7-day migration to the right atrium required surgical removal. Technical success rate for filter conversion was 92.7% (89/96). Mean time from placement to conversion was 130.7 days (range, 15–391 d). No major conversion-related events were reported. The mean conversion procedure time was 30.7 minutes (range, 7–135 min). There were 89 converted and 32 unconverted patients who completed 6-month follow-up with no delayed complications. ConclusionsThe VenaTech Convertible filter has a high conversion rate and low 6-month device-related adverse event rate. Further studies are necessary to determine long-term safety and efficacy in both converted and unconverted patients.

Safety and tolerability of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil fumarate in a real life setting: Data from surveillance cohort long-term toxicity antiretrovirals/antivirals (SCOLTA) project.

ObjectivesThe study aim was to evaluate the impact on Liver and Kidney toxicity of the single tablet regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate (EVG/COBI/FTC/TDF) on Antiretroviral Therapy (ART) experienced or naïve patients.MethodsPatients initiating EVG/COBI/FTC/TDF were enrolled in the SCOLTA project, a multicenter observational study reporting grade 3–4 Adverse Events in subjects beginning new antiretroviral drug regimens. In this analysis, patients were evaluated at T0 (baseline), T1 (six months) and at T2 (twelve months).ResultsA total of 329 patients were enrolled, and 280 (85.1%) of these had at least one follow-up visit. Median observation time was 11 months (IQR 7.0–15.5). Two hundred and two patients (72.1%) were ART experienced and 78 (27.9%) ART naive. Prevalence of HCV-co-infection was 21.4%. At T1, we observed a significant decline in estimated glomerular filtration rate (eGFR), both in experienced and naive patients (mean change from T0–7.5 ± 12.8 ml/min, -15.5 ± 17.8 ml/min, respectively, p = 0.0005), which was confirmed at T2 (mean change from T0–8.2 ± 15.8 ml/min, -17.6 ± 19.4 ml/min, respectively, p = 0.001). Regarding aspartate aminotransferase (AST) and alanine transaminase (ALT) grade 1–2 modifications, no significant differences were observed between experienced and naïve subjects, but an increased prevalence of abnormal liver function test was observed in patients with chronic HCV infection (p<0.001).ConclusionsA significant decline in eGFR was observed in patients initiating EVG/COBI/FTC/TDF in the first 6 months, with no significant worsening occurring at 12 months vs. 6 months of therapy. Patients with chronic HCV infection were at higher risk to develop abnormal liver tests.

Vaccination of active component US military personnel against Salmonella Typhi

IntroductionVaccination against Salmonella Typhi is one of the leading public health interventions reducing the risk of typhoid fever. There are two available licensed vaccines, Vivotif, oral live-attenuated, and Typhim Vi, intramuscular Vi capsular polysaccharide. The US military is a high risk travel population commonly vaccinated for S. Typhi. We describe the use of S. Typhi vaccination in this population and the acute reactogenicity profile of these vaccines. MethodsData were obtained from the Defense Medical Surveillance System and vaccination identified between 1998 and 2011 from vaccination codes. Clinical outcomes were assessed for four weeks post vaccination. Adverse event rates and odds ratios were estimated across the two vaccine types. ResultsA total of 1.9million predominately male military personnel received 3.6 million S. Typhi vaccinations with 94.3% of vaccinees receiving the Vi capsule vaccine though variability in the vaccine administered was observed. Receipt of other vaccinations in the 6months surrounding the S. Typhi vaccine was common. Rates of nausea (195 per 100,000 vaccinations), headache (13 per 100,000 vaccinations) and fever (40 per 100,000 vaccinations) were significantly higher following Vi capsule vaccination compared to receipt of Vivotif (130, 2, 10 per 100,000 vaccinations, respectively). In contrast the rates of rash and non-infectious diarrhea (186 and 426 per 100,000 vaccinations, respectively) were increased in those receiving Vivotif compared to the Vi capsule vaccine. DiscussionThe US military is a major consumer of S. Typhi vaccines. The parenterally administered vaccine appears to be more amenable, though we were limited in our ability to assess the reasons for its higher usage. While we observed a higher rate of several adverse events in subjects receiving the intramuscular vaccination, the overall rate of these events was low. Future studies assessing more long-term health outcomes are warranted.

Efficacy and Safety of Evacetrapib for Modifying Plasma Lipids: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Evacetrapib, a new cholesteryl ester transfer protein inhibitor, is being investigated as a potential therapeutic option for reducing cardiovascular events through increasing high-density lipoprotein cholesterol (HDL-C) concentrations. How evacetrapib affects other lipid parameters is less certain. The present study aimed to estimate the effect of evacetrapib on plasma lipid concentrations and to assess its safety through a systematic review and meta-analysis of randomized controlled trials. SCOPUS, Medline, and Google Scholar were searched to identify randomized controlled trials investigating the impact of evacetrapib on blood lipid concentrations published before December 29, 2014. A random-effects model (using the DerSimonian-Laird method) and the generic inverse variance method were used to examine the effect of evacetrapib on plasma lipid concentrations. The safety of evacetrapib was assessed by comparing the pooled incidence of adverse events (total adverse events, adverse events leading to study discontinuation, elevations in hepatic and muscular enzymes and blood pressure) between treatment and placebo groups. Sensitivity analyses were conducted using the one study remove approach. Meta-regression was performed to evaluate the association between changes plasma lipid concentrations and administered doses of evacetrapib. Meta-analysis of 14 randomized treatment arms over a mean of 2 months suggested that evacetrapib significantly reduces low-density lipoprotein cholesterol (LDL-C) (weighted mean difference [WMD]: -21.11%, 95% confidence interval (CI): -24.89, -17.33, p<0.001) and elevated HDL-C (WMD: +86.00%, 95% CI: +67.63, +104.37, p<0.001) concentrations following treatment with evacetrapib. Evacetrapib had no significant effect on plasma triglycerides (WMD: -2.97%, 95% CI: -8.63, +2.69, p = 0.303) concentrations. The effects of evacetrapib on all three lipid indices (LDL-C, HDL-C and triglycerides) did not differ between subsets of trials administering evacetrapib as monotherapy or as add-on to statin therapy. Meta-regression suggested a dose-dependent effect of evacetrapib on plasma LDL-C and HDL-C, but not triglycerides concentrations. Meta-analysis suggested equivalent rates of adverse events in subjects receiving evacetrapib and placebo. Results of this meta-analysis suggested that evacetrapib, either as monotherapy or in combination with a statin, reduces LDL-C and increases HDL-C levels but has no effect on triglyceride concentrations. Adverse events appeared to be similar in subjects receiving evacetrapib and placebo in short-term follow-ups.

The impact of two semiannual treatments with albendazole alone on lymphatic filariasis and soil-transmitted helminth infections: a community-based study in the Republic of Congo.

Implementation of mass drug administration (MDA) with ivermectin plus albendazole (ALB) for lymphatic filariasis (LF) has been delayed in central Africa because of the risk of serious adverse events in subjects with high Loa loa microfilaremia. We conducted a community trial to assess the impact of semiannual MDA with ALB (400 mg) alone on LF and soil-transmitted helminth (STH) infections in the Republic of Congo. Evaluation at 12 months showed that ALB MDA had not significantly reduced Wuchereria bancrofti antigenemia or microfilaria (mf) rates in the community (from 17.3% to 16.6% and from 5.3% to 4.2%, respectively). However, the geometric mean mf count in mf-positive subjects was reduced from 202.2 to 80.9 mf/mL (60% reduction, P = 0.01). The effect of ALB was impressive in 38 subjects who were mf-positive at baseline and retested at 12 months: 37% had total mf clearance, and individual mf densities were reduced by 73.0%. MDA also dramatically reduced the hookworm infection rate in the community from 6.5% to 0.6% (91% reduction), with less impressive effects on Ascaris and Trichuris. These preliminary results suggest that semiannual community MDA with ALB is a promising strategy for controlling LF and STH in areas with coendemic loiasis.

Symptoms of nicotine toxicity in subjects achieving high cotinine levels during nicotine replacement therapy.

Nicotine replacement therapy (NRT) aids smoking reduction and cessation. Although NRT is effective and safe, some smokers may achieve high nicotine levels. The purpose of this study was to determine the incidence and severity of nicotine-related adverse events in subjects with levels of cotinine, a metabolite of nicotine, that increased by >50% compared with baseline smoking in controlled clinical trials of NRT. Data from participants in randomized, double-blind, controlled trials of various formulations of NRT (Nicorette®), including patch, gum, oral inhaler, sublingual tablet, nasal spray, mouth spray, and combinations, were extracted from a clinical database. Eligible studies were performed between 1989 and 2010. In addition to baseline, at least 1 subsequent plasma or salivary cotinine concentration was measured, and adverse events were recorded simultaneously. Of 28 eligible studies, 24 were smoking cessation studies and 4 were smoking reduction studies. Cotinine levels that increased by >50% above baseline were recorded during treatment in 746 of 7,120 subjects (10.5%). Nausea was reported in 16 subjects (0.2% of the total, upper 99% confidence limit [CL] 0.4%), vomiting in 2 subjects (0.0%, upper 99% CL 0.1%), palpitations in 5 subjects (0.1%, upper 99% CL 0.2%), dizziness in 11 subjects (0.2%; upper 99% CL 0.3%), and headache in 35 subjects (0.5%, upper 99% CL 0.7%). Typical symptoms indicating nicotine overdose together with high cotinine levels were rare during treatment with NRT. These findings support the safety of NRT for smoking cessation or reduction.

Incidence and Influence of Hospitalization for Recurrent Syncope and Its Effect on Short- and Long-Term All-Cause and Cardiovascular Mortality

Recurrence of syncope is a common event, but the influence of recurrent syncope on the risk of death has not previously been investigated on a large scale. We examined the prognostic impact of recurrent syncope in a nationwide cohort of patients with syncope. All patients (n = 70,819) hospitalized from 2001 to 2009 in Denmark with a first-time diagnosis of syncope aged from 15 to 90 years were identified from national registries. Recurrence of syncope was incorporated as a time-dependent variable in multivariable-adjusted Cox models on the outcomes of 30-day, 1-year, and long-term all-cause mortality and cardiovascular death. During a mean follow-up of 3.9 ± 2.6 years, a total of 11,621 patients (16.4%) had at least 1 hospitalization for recurrent syncope, with a median time to recurrence of 251 days (33 to 364). A total of 14,270 patients died, and 3,204 deaths were preceded by a hospitalization for recurrent syncope. The long-term risk of all-cause death was significantly associated with recurrent syncope (hazard ratio 2.64, 95% confidence interval 2.54 to 2.75) compared with those with no recurrence. On 1-year mortality, recurrent syncope was associated with a 3.2-fold increase in risk and on 30-day mortality associated with a threefold increase. The increased mortality risk was consistent over age groups 15 to 39, 40 to 59, and 60 to 89 years, and a similar pattern of increase in both long-term and short-term risk of cardiovascular death was evident. In conclusion, recurrent syncope is independently associated with all-cause and cardiovascular mortality across all age groups exhibiting a high prognostic influence. Increased awareness on high short- and long-term risk of adverse events in subjects with recurrent syncope is warranted for future risk stratification.

Safety, Pharmacokinetics and Pharmacodynamics of Gs-9620, An Oral Toll-Like Receptor 7 Agonist

GS-9620 is a novel oral agonist of Toll-like receptor 7 (TLR7) in development for the treatment of chronic viral hepatitis. TLR7 is a highly conserved innate immune receptor expressed primarily on plasmacytoid dendritic cells and B lymphocytes. The aim of this double-blind, placebo-controlled, single ascending-dose study was to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of GS-9620 in healthy volunteers. In total, 75 healthy volunteers (8 subjects in each of the 10 cohorts; 5 subjects participated in two cohorts) were randomized (6:2) to receive a single dose of GS-9620 (0.3, 1, 2, 4, 6, 8 or 12 mg) or placebo. GS-9620 was well-absorbed and well-tolerated in oral doses up to 12 mg. Minimal treatment-related adverse events were seen at doses up to 8 mg. Serum interferon (IFN)-α was only detected in subjects who received 8 or 12 mg doses, and the adverse event profile at 8 and 12 mg doses was generally consistent with that associated with IFN-α exposure (flu-like symptoms), consistent with the mechanism of TLR7 agonism. All adverse events resolved within 72 h. Induction of chemokines/cytokines and IFN-stimulated genes were seen at GS-9620 doses ≥ 2 mg, well below doses that induced serum IFN-α or led to clinical adverse events. GS-9620 demonstrates safety and pharmacodynamic activity at doses up to 12 mg. Pharmacodynamic activity is seen before adverse events, suggesting the potential for induction of an antiviral response without systemic adverse events in subjects with chronic viral hepatitis.