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Bays H.E.,Louisville Metabolic and Atherosclerosis Research Center | Ballantyne C.M.,Baylor College of Medicine | Isaacsohn J.L.,Medpace Inc. | Braeckman R.A.,Amarin | Soni P.N.,Amarin
American Journal of Cardiology | Year: 2011

AMR101 is an omega-3 fatty acid agent containing ≥96% eicosapentaenoic acid ethyl ester and no docosahexaenoic acid. Previous smaller studies suggested that highly purified eicosapentaenoic acid lowered triglyceride (TG) levels without increasing low-density lipoprotein (LDL) cholesterol levels. TG-lowering therapies such as fibrates, and fish oils containing both eicosapentaenoic acid and docosahexaenoic acid, can substantially increase LDL cholesterol levels when administered to patients with very high TG levels (≥500 mg/dl). The present double-blind study randomized 229 diet-stable patients with fasting TG (≥500 mg/dl and (≥2,000 mg/dl (with or without background statin therapy) to AMR101 4 g/day, AMR101 2 g/day, or placebo. The primary end point was the placebo-corrected median percentage of change in TG from baseline to week 12. The baseline TG level was 680, 657, and 703 mg/dl for AMR101 4 g/day, AMR101 2 g/day, and placebo. AMR101 4 g/day reduced the placebo-corrected TG levels by 33.1% (n = 76, p <0.0001) and AMR101 2 g/day by 19.7% (n = 73, p = 0.0051). For a baseline TG level >750 mg/dl, AMR101 4 g/day reduced the placebo-corrected TG levels by 45.4% (n = 28, p = 0.0001) and AMR101 2 g/day by 32.9% (n = 28, p = 0.0016). AMR101 did not significantly increase the placebo-corrected median LDL cholesterol levels at 4 g/day (-2.3%) or 2 g/day (+5.2%; both p = NS). AMR101 significantly reduced nonhigh-density lipoprotein cholesterol, apolipoprotein B, lipoprotein-associated phospholipase A 2, very low-density lipoprotein cholesterol, and total cholesterol. AMR101 was generally well tolerated, with a safety profile similar to that of the placebo. In conclusion, the present randomized, double-blind trial of patients with very high TG levels demonstrated that AMR101 significantly reduced the TG levels and improved other lipid parameters without significantly increasing the LDL cholesterol levels. © 2011 Elsevier Inc. All rights reserved.

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 under registration no. NCT01519492.) © 2016, American Society for Microbiology. All Rights Reserved.

Maki K.C.,Biofortis Clinical Research | Orloff D.G.,Medpace Inc | Nicholls S.J.,South Australian Health and Medical Research Institute | Dunbar R.L.,University of Pennsylvania | And 5 more authors.
Clinical Therapeutics | Year: 2013

Background: A novel omega-3 formulation in free fatty acid form (OM3-FFA) has as much as 4-fold greater bioavailability than ethyl ester forms and reduces triglyceride (TG) levels in patients with severe hypertriglyceridemia. Objective: This study was designed to evaluate the efficacy of adding OM3-FFA (2 or 4 g/d) to statin therapy for lowering non-HDL-C and TG levels in subjects with persistent hypertriglyceridemia and at high risk for cardiovascular disease. Methods: In this double-blind, parallel-group study, 647 diet-stable patients with fasting TG levels ≥200 mg/dL and <500 mg/dL (treated with a maximally tolerated dose of statin or statin with ezetimibe) and at high risk for cardiovascular disease were randomized to 6 weeks of treatment with capsules of control (olive oil [OO]) 4 g/d, OM3-FFA 2 g/d (plus 2 g/d OO), or OM3-FFA 4 g/d. Assessments included fasting serum levels of lipids and apolipoproteins (apo); plasma concentrations of eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and arachidonic acid; and laboratory safety values and adverse events. Results: In the 627 subjects in the intention to treat sample, non-HDL-C levels were reduced with OM3-FFA 2 g/d and OM3-FFA 4 g/d (-3.9% and -6.9%, respectively) compared with OO (-0.9%) (both, P < 0.05), as were TG levels (-14.6% and -20.6%, respectively, vs -5.9%; both, P < 0.001). LDL-C levels increased with OM3-FFA 2 g/d (4.6%) compared with OO (1.1%) (P = 0.025) but not with OM3-FFA 4 g/d (1.3%). Total cholesterol and VLDL-C concentrations were reduced compared with OO with both OM3-FFA dosages, and the total cholesterol/HDL-C ratio and apo AI and apo B levels were significantly lowered with OM3-FFA 4 g/d only (all at least P < 0.05). Percent changes from baseline in HDL-C did not differ between OO and either OM3-FFA group. Plasma concentrations of docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid were significantly increased and arachidonic acid was significantly reduced in both OM3-FFA treatment groups compared with the OO responses (all, P < 0.001). Withdrawals related to treatment-emergent adverse events ranged from 0.9% with OO to 3.2% with OM3-FFA 4 g/d. Conclusions: OM3-FFA was well tolerated and lowered non-HDL-C and TG levels at both 2- and 4-g/d dosages in patients with persistent hypertriglyceridemia taking a statin, with the 4-g/d dosage providing incremental improvements compared with 2 g/d. © 2013 Elsevier HS Journals, Inc.

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.

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.

Pless M.,Medical Oncology | Droege C.,University of Basel | von Moos R.,Medical Oncology | Salzberg M.,Medpace Inc. | Betticher D.,Cantonal Hospital Fribourg
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.

Karl D.,Endocrine Clinic | Zhou R.,Medpace Inc. | Vlajnic A.,Sanofi S.A. | Riddle M.,Oregon Health And Science University
Diabetic Medicine | Year: 2012

Aims To evaluate whether fasting plasma glucose values measured early during insulin therapy can identify patients with Type2 diabetes who may not achieve adequate glycaemic control after 6months and will require additional treatment. Methods Patient-level data from seven prospective, randomized, controlled studies using treat-to-target methods were pooled to evaluate the efficacy of insulin glargine. Fasting plasma glucose was measured at baseline, week6 or 8 (6/8) and week12. HbA1c was measured at week24 to assess glycaemic control. Results One thousand and thirty-six patients (56% male, 81% white) were included in the analysis (mean age 56.3years; duration of diabetes 8.4years). Baseline mean fasting plasma glucose was 11.2mmol/l and mean HbA1c was 73mmol/mol (8.8%). After 24weeks of treatment, mean HbA1c decreased to 53mmol/mol (7.0%); 56% of patients reached a target HbA1c≤53mmol/mol (7.0%). Significant correlations with week24 HbA1c were obtained for fasting plasma glucose measured at week6/8 and week12 (r=0.32; P<0.0001 for both). Patients with fasting plasma glucose >10mmol/l at week6/8 or week12 were significantly less likely to achieve the HbA1c target at the end of treatment than patients with fasting plasma glucose <8.9mmol/l (P<0.0001 for both). If fasting plasma glucose was >10mmol/l at week 6/8 or week12, patients had only a 27% chance of reaching the HbA1c goal. Conclusions Fasting plasma glucose remaining >10mmol/l after 6-12weeks of glargine therapy indicates that reaching target HbA1c≤53mmol/mol (7.0%) is unlikely and calls for individualized attention to consider further therapeutic options. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Medpace Inc. | Date: 2016-12-07

a web-based mobile application allowing enrolled clinical-trial participants and patients to enter data securely into an on-line clinical database that allows researchers and investigators access to the data.

Medpace Inc. | Date: 2016-12-08

a web-based mobile application allowing enrolled clinical-trial participants and patients to enter data securely into an on-line clinical database that allows researchers and investigators access to the data.

PubMed | Medpace Inc., University of South Florida, Wuhan University of Technology and Huazhong University of Science and Technology
Type: | Journal: Statistical methods in medical research | Year: 2017

In medical studies, heterogeneous- and skewed-longitudinal data with mis-measured covariates are often observed together with a clinically important binary outcome. A finite mixture of joint models is currently used to fit heterogeneous-longitudinal data and binary outcome, in which these two parts are connected by the individual latent class membership. The skew distributions, such as skew-normal and skew-t, have shown beneficial in dealing with asymmetric data in various applications in literature. However, there has been relatively few studies concerning joint modeling of heterogeneous- and skewed-longitudinal data and a binary outcome. In this article, we propose a joint model in which a flexible finite mixture of nonlinear mixed-effects models with skew distributions is connected with binary logistic model by a latent class membership indicator. Simulation studies are conducted to assess the performance of the proposed models and method, and a real example from an AIDS clinical trial study illustrates the methodology by modeling the viral dynamics to compare potential models with different distribution specifications; the analysis results are reported.

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