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Cincinnati, OH, United States

This open-label noncontrolled, phase II multicenter trial was designed to evaluate the safety, tolerability, and efficacy of 200 mg of AFN-1252, a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), given by mouth twice daily in the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to staphylococci. Important aspects of the current study included a comparison of early response efficacy endpoints with end-of-treatment and follow-up endpoints. Many patients in the intent-to-treat population (n=103) had significant comorbidities. The overall early response rate at day 3 was 97.3% (wound, 100%; abscess, 96.6%; cellulitis, 94.4%) in the microbiologically evaluable (ME) population. Within the ME population, 82.9% of patients had a≥20% decrease in the area of erythema, and 77.9% of patients had a≥20% decrease in the area of induration, on day 3. S. aureus was detected in 97.7% of patients (n = 37 patients with methicillin-resistant S. aureus [MRSA], and n=39 with methicillin-sensitive S. aureus [MSSA]). No isolates had increased AFN-1252 MICs posttreatment. Microbiologic eradication rates for S. aureus were 93.2% at short-term follow-up (STFU) and 91.9% at long-term follow-up (LTFU) in the ME population. Eradication rates for MRSA and MSSA were 91.9% and 92.3%, respectively, at STFU and 91.9% and 89.7%, respectively, at LTFU. The most frequently reported drug-related adverse events, which were mostly mild or moderate, were headache (26.2%) and nausea (21.4%). These studies demonstrate that AFN-1252 is generally well tolerated and effective in the treatment of ABSSSI due to S. aureus, including MRSA. (This study has been registered at ClinicalTrials.gov under registration no. NCT01519492.) © 2016, American Society for Microbiology. All Rights Reserved. Source

Riddle M.C.,Oregon Health And Science University | Vlajnic A.,Sanofi S.A. | Zhou R.,Medpace Inc. | Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical City
Diabetes, Obesity and Metabolism | Year: 2013

Aims: To determine whether baseline characteristics, especially haemoglobin A1c (HbA1c), predict the likelihood of reaching HbA1c≤7.0% or the risk of experiencing hypoglycaemia after the addition of insulin glargine to oral therapy in type 2 diabetes. Methods: Pooled patient-level data from 12 prospective, randomized, controlled studies that used insulin glargine in a treat-to-target titration regimen seeking fasting glucose levels ≤5.5mmol/l (100mg/dl) were analysed. Baseline characteristics were evaluated by logistic regression models as predictors of reaching a target HbA1c≤7.0% or experiencing confirmed hypoglycaemia. The effect of prior glycaemic control was further explored by analysis of categorical ranges of baseline HbA1c. Results: Of 2312 participants, 95% completed 24weeks of treatment. Lower HbA1c at baseline was independently associated with reaching HbA1c target [adjusted odds ratio (OR) for 1% difference: 0.538, p<0.0001] and also with likelihood of experiencing confirmed hypoglycaemic events (adjusted OR: 0.835, p<0.0001) at week 24. In an unadjusted analysis by baseline HbA1c range, the strong association between baseline control and attaining target HbA1c was confirmed (75% with baseline HbA1c<8.0%, 60% with baseline HbA1c≥8.0 and <9.0% and 38% with baseline HbA1c≥9.0% attained HbA1c≤7.0%). The incidence of hypoglycaemia confirmed <3.9mmol/l (70mg/dl) was higher in the lower baseline HbA1c ranges but severe hypoglycaemia was infrequent at all baseline HbA1c levels. Conclusions: Systematically titrated insulin glargine, added to oral agents, was effective over a wide range of baseline HbA1c. Lower baseline HbA1c was the best clinical predictor of achieving HbA1c≤7.0% and also associated with higher risk of glucose-confirmed hypoglycaemia. Severe hypoglycaemia was infrequent using this treatment approach. © 2013 Blackwell Publishing Ltd. Source

Pless M.,Medical Oncology | Droege C.,University of Basel | von Moos R.,Medical Oncology | Salzberg M.,Medpace Inc. | Betticher D.,Medical Oncology
Lung Cancer | Year: 2013

Background: Low intensity, intermediate frequency, alternating electric fields (Tumor Treating Fields; TTFields) exhibit anti-mitotic activity in cancer cells. Promising preclinical data have led to a single arm phase I/II trial in NSCLC patients. Methods: Forty-two inoperable stage IIIB (with pleural effusion) and IV NSCLC patients who had had tumor progression received pemetrexed 500mg/m2 iv q3w together with daily TTFields therapy until disease progression. The primary endpoint was time to "in-field" progression. Results: Median age for all patients was 63 years, 76% had stage IV disease, 78% had adenocarcinoma and 17% had performance status of 2. The median time to in-field progression was 28 weeks and the median time to systemic progression was 22 weeks. Six patients (14.6%) had a partial remission (PR) and 20 had stable disease (SD) (48.8%). Median overall survival was 13.8 months and 1 year survival rate was 57%. There were no TTFields-related serious adverse events. Conclusions: The combination of TTFields and pemetrexed as a second line therapy for NSCLC is safe and potentially more effective than pemetrexed alone. TTFields improved disease control within the treatment field and a phase III study is planned to further investigate its role as a novel treatment in NSCLC. © 2013 Elsevier Ireland Ltd. Source

Inzucchi S.E.,Yale University | Umpierrez G.,Emory University | DiGenio A.,Isis Pharmaceuticals | Zhou R.,Medpace Inc. | Kovatchev B.,University of Virginia
Diabetes Research and Clinical Practice | Year: 2015

Aim: Despite links to clinical outcomes in patients with type 2 diabetes mellitus (T2DM), the clinical utility of glycaemic variability (GV) measures is unknown. We evaluated the correlation between baseline GV, and glycated haemoglobin (HbA1c) attainment and hypoglycaemic events during treatment intensification in a large group of patients. Methods: Patient-level data from six 24-week clinical trials of T2DM patients undergoing treatment intensification with basal insulin or comparators (N = 1699) were pooled. Baseline GV measures included standard deviation (SD), mean amplitude of glycaemic excursions (MAGE), mean absolute glucose (MAG), coefficient of variation (CV), high blood glucose index (HBGI), and low blood glucose index (LBGI) were correlated with HbA1c change and hypoglycaemic events. Results: All mean GV measures, excluding CV which worsened, improved significantly from baseline to Week 24, with the largest proportional reduction obtained for HBGI (-65.5%). When assessed as mean individual percentage changes only HBGI improved significantly. Baseline GV correlated positively with Week 24 HbA1c for SD, MAGE, and HBGI. Baseline HBGI and CV correlated negatively and positively, respectively, with Week 24 HbA1c change. Correlations also existed between most baseline GV measures and age, body mass index, Week 24 fasting plasma glucose, Week 24 postprandial plasma glucose, and hypoglycaemic events; statistical significance depended on the specific measure. Conclusions: Pre-treatment GV is associated with glycaemic outcomes in T2DM patients undergoing treatment intensification over 24 weeks. HBGI might be the most robust predictor, warranting validation in dedicated prospective studies or randomized trials to assess the predictive value of measuring GV. © 2015 Elsevier Ireland Ltd. Source

Elis A.,Tel Aviv University | Zhou R.,Medpace Inc. | Stein E.A.,Metabolic and Atherosclerosis Research Center and Cholesterol Treatment Center
Cardiology in the Young | Year: 2014

Background: This study evaluated the effectiveness of long-term intensive lipid-lowering therapy in children and adolescents with familial hypercholesterolaemia. Methods: The charts of 89 children and adolescents with heterozygous familial hypercholesterolaemia among ∼1000 patients treated from 1974 to 2008 were reviewed. Familial hypercholesterolaemia was defined as low-density lipoprotein cholesterol level >90th percentile in individuals with a history of familial hypercholesterolaemia. Results: Of the 89 patients, 51% were male; the mean age at diagnosis was 8 ± 4 years, and the mean follow-up was 13 ± 8 years. Baseline and most recent low-density lipoprotein cholesterol levels (mg/dl) under treatment were 250 ± 50 and 142 ± 49, respectively, reduced 43% from baseline (p < 0.0001). At the most recent visit, 39 patients received statin monotherapy, mainly atorvastatin or rosuvastatin, and 50 (56%) patients received combination therapy, mainly vytorin or rosuvastain/ezetimibe, 15 patients were >30 years of age, and none developed symptomatic cardiovascular disease or needed revascularisation. Conclusions: Long-term statin-based therapy can reduce low-density lipoprotein cholesterol levels in most children and adolescents with heterozygous familial hypercholesterolaemia and decrease cardiovascular risk significantly. © Cambridge University Press 2013. Source

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