Median Percent Change Research Articles

Evaluation of the Effectiveness of Making Weight Watchers Available to Tennessee Medicaid (TennCare) Recipients

In 2006, Tennessee Medicaid (TennCare) offered its recipients access to Weight Watchers for a nominal fee. The aim of this study was to determine the weight change among adult participants. This is a retrospective analysis of weight change among overweight and obese TennCare recipients who participated in the program. Weight change was calculated as the median difference from the first date of participation to the last. Weight change was also calculated as median percentage change from initial weight and categorized as weight loss or gain of 0 to 5, ≥5 to 10, and ≥10 %. During the study period, 1,605 individuals started the program and 1192 had at least one follow-up weight measurement and thus met the inclusion criteria for the study. Women (n = 1149) had a BMI of 39.6 kg/m(2) and men (n = 43) had a BMI of 43.0 kg/m(2). The median weight loss for all participants was 1.9 kg, or 1.8 % of initial weight. Twenty percent of participants lost 5 % or more of their initial body weight while participating in the program. Over 13 % of participants only attended two meetings; on average, these participants lost 0.5 % of initial weight. Over 23 % of participants attended 13 or more meetings, and they lost an average of 6.4 % of initial weight. Twenty percent of TennCare recipients who joined Weight Watchers lost a clinically significant amount of weight. Participants who attended more meetings lost more weight. Reimbursement for Weight Watchers has been maintained by all of the Medicaid managed care organizations in Tennessee. Partnerships that allow low-income populations to access weight loss programs may provide a valuable weight management tool.

Over 100 cases of zero-ischemia robotic/laparoscopic partial nephrectomy: Is global renal ischemia necessary?

e15060 Background: We report peri-operative and short-term outcomes of a novel technique of zero-ischemia robotic and laparoscopic partial nephrectomy (PN) for renal masses. Methods: From March 2010 to July 2011, 100 zero-ischemia robotic (n=40) and laparoscopic (n=60) PN were performed at our institution. The technique consists of performing micro-dissection of tertiary or higher-order renal arterial branches to super-selectively devascularize the tumor and surrounding parenchyma. Blood flow continues uninterrupted to the remainder of the kidney. As such, PN is performed without hilar cross-clamping. The procedure was offered to all-comers regardless of the tumor complexity or renovascular anatomy. Results: Median patient age was 59 years, tumor size was 3cm (0.9-13.6), baseline serum creatinine (SCr) was 1 mg/dl (0.5-2.6), and estimated glomerular filtration rate (eGFR) was 73 ml/min per 1.73m2 (24-149). 9 patients had a solitary kidney and 8 patients had multiple ipsilateral tumors. Overall, 70% of tumors were complex: central (43%), completely intra-renal (23%), cT1b >4cm (21%), and hilar (19%). Median (range) RENAL, PADUA and C-Index scores were 8 (4-11), 9 (6-13), 2.2 (0.5 c 13.2), respectively. Warm ischemia time was zero, median operative time was 275 min (126-534), estimated blood loss was 200cc, percent of kidney excised was 20 (5-70) and hospital stay was 4 days (2-20). There were 13 complications in 12 patients, with major complications, Clavien grade ≥3, in 4 patients. Histology confirmed malignancy in 80% of tumors. All surgical margins were negative for cancer. There were no significant difference for median percent change in SCr, 0 mg/dl (-31 to 215), and eGFR, -1 (-74 to 53), at discharge. In 65 patients with more than 2 months (median 219 days) follow up data available, median percent change in SCr and eGFR were 18 (-31 to 154), p<.001 and -18 (-66 t0 53), p<.001, respectively. 1 patient developed pulmonary metastases at 1 year follow up. Conclusions: Zero-ischemia robotic/laparoscopic PN without hilar clamping is feasible and safe. It could be performed even in the setting of complex tumors and various vascular anatomy scenarios. Eliminating global renal ischemia now appears achievable.

Vitamin D3 Alters the Crystallization and Volume Expansion of Cholesterol∗

median percent change in non-HDL-C was 235.2% in the pitavastatin 4 mg group and 224.3% in the pravastatin 40 mg group; the treatment difference (211.0%) was statistically significant (P , .0001). There were no clinically important differences in the safety profiles between treatment groups (Table 2). Conclusions: Pitavastatin 4 mg provided significantly greater LDL-C reduction compared with pravastatin 40 mg after 12 weeks of therapy in adults with primary hyperlipidemia or mixed dyslipidemia.

Efficacy of Adjunctive Perampanel in Phase III Clinical Trials: Subanalysis of Change in Seizure Frequency and Responder Rates by Concomitant Antiepileptic Drug Use (S56.006)

Objective: Assess effect of concomitant antiepileptic drugs (AEDs) on seizure frequency and responder rate in a pooled analysis of perampanel phase III studies. Background In phase III trials, adjunctive perampanel was efficacious in reducing uncontrolled partial-onset seizures (4-12 mg/day). Design/Methods: Following Baseline, patients (≥12 years, receiving 1-3 AEDs) were randomized to once-daily double-blind treatment with placebo or perampanel 2, 4, 8, or 12 mg. Efficacy endpoints were analyzed with respect to concomitant use of the most frequently taken AEDs (in any combination) to test if addition of these AEDs with other mechanisms of action affected the efficacy of perampanel. Endpoints analyzed were: percent change in seizure frequency/28 days (Double-blind Phase vs Baseline) and 50% responder rate (Maintenance vs Baseline). Results: Across the phase III studies, 1478 patients were randomized and treated (placebo, n=441; perampanel 2 mg, n=180; 4 mg, n=172; 8 mg, n=431; 12 mg, n=254), and were taking an average of 2.2 concomitant AEDs. The most common AEDs (≥45 patients/treatment group), used in combinations of 1-3 concomitant AEDs, were: carbamazepine (n=491), valproate (n=478), lamotrigine (n=457), and levetiracetam (n=435). Median differences (Hodges-Lehmann) in median percent change in seizure frequency/28 days in patients receiving concomitant AED combinations including carbamazepine, valproate, lamotrigine, or levetiracetam compared with placebo ranged from: 7.7% to -7.8% with perampanel 2 mg; -3.0% to -12.7% with 4 mg; -8.9% to -20.8% with 8 mg; and -12.4% to -16.7% with 12 mg. Responder rate ranges for these patients were: 13.6-23.1% with placebo; 13.8-21.4% with perampanel 2 mg; 19.6-34.7% with 4 mg; 29.7-38.3% with 8 mg; and 30.6-43.0% with 12 mg. Conclusions: Perampanel (4-12 mg/day) decreased seizure frequency and increased responder rates in patients concomitantly taking at least one of the four most common AEDs. The presence of another AED mechanism did not appear to reduce the efficacy of perampanel. Supported by: Eisai Inc. Disclosure: Dr. French has nothing to disclose. Dr. Ben-Menachem has received personal compensation for activities with Eisai Inc, UCB Pharma, Cyberonics, Inc., GlaxoSmithKline, Inc. and Lundbeck Research USA as an advisory board participant and/or speaker. Dr. Ben-Menachem has received personal compensation in an editorial capacity for Acta Neurologica Scandinovica. Dr. Ben-Menachem has received research support from Eisai Inc, UCB Pharma and Bial. Dr. Brodie has received personal compensation for activities with Pfizer Inc, UCB Pharma, Eisai Inc., GlaxoSmithKline, Inc., Sanofi-Aventis Pharmaceuticals, Inc., and Lundbeck Research USA, Inc. Dr. Brodie has received research support from Eisai Inc. Dr. Squillacote has received personal compensation for activities with Eisai as an employee. Dr. Yang has received personal compensation for activities with Eisai, Inc. as an employee. Dr. Kumar has received personal compensation for activities with Eisai Inc. as an employee. Dr. Laurenza has received personal compensation for activities with Eisai as an employee.

Perampanel, a Selective, Non-Competitive AMPA Receptor Antagonist as Adjunctive Therapy in Patients with Refractory Partial-Onset Seizures: A Dose Response Analysis from Phase III Studies (P06.117)

Objective: Examine perampanel dose-response by pooled analysis of randomized, double-blind phase III studies (304/305/306) and open-label extension (OLE) study (307). Background Pharmacokinetic/pharmacodynamic analyses show a linear perampanel exposure-response relationship, without change in slope across doses tested (2-12 mg/day). However, randomized dose efficacy analyses did not consistently demonstrate improvement with 12 mg/day versus 8 mg. Dose-response analyses utilizing actual-dose data were performed to better understand these differences. Design/Methods: Analyses used integrated actual-dose data from the double-blind studies and OLE blinded Conversion Period (data cut-off 01/12/10). Seizure frequency data were analyzed from patients randomized to and completing at 8 mg during the double-blind studies, and whose last dose was 12 mg during the Conversion Period. Additionally, pooled analysis of patients completing studies 304 and 305 (trials including 12 mg doses) was performed. All analyses excluded Central/South American patients due to a significant treatment-by-region interaction. Results: Of 372 patients randomized to 8 mg (double-blind), 273 completed at this dose; 267/273 entered the OLE; 209/267 (78.3%) had dose increases from 8 mg (double-blind) to 12 mg (Conversion Period) by data cut-off. Median percent change in seizure frequency/28 days improved from -32.4% to -43.3%; 50% responder rate increased from 37.8% to 43.5%. Patients completing the double-blind studies and the Conversion Period on 12 mg experienced similar benefits (change in seizure frequency -39.5% to -42.1%; responder rate 41.8% to 42.9%). In a 304/305 combined completers analysis (actual dose: placebo n=182; 8 mg n=158; 12 mg n=114), 12 mg improved seizure-free rates versus 8 mg (4.4% versus 2.5%). Secondarily generalized seizures also improved with 12 mg versus 8 mg (change in seizure frequency -54.0% versus -46.0%). Conclusions: In actual-dose analyses, perampanel 12 mg/day demonstrated slightly improved efficacy over 8 mg/day. Inter-related factors intrinsic to standard epilepsy study designs may not reflect the effect of the target randomized doses. Supported by: Eisai, Inc. Disclosure: Dr. Kramer has received personal compensation for activities with Eisai Inc. as an employee. Dr. Kramer has received research support from Eisai Inc. Dr. Perucca has received personal compensation for activities with UCB Pharmaceuticals as a speaker.Dr. Perucca has received personal compensation in an editorial capacity for Epilepsia. Dr. Ben-Menachem has received personal compensation for activities with Eisai Inc, UCB Pharma, Cyberonics, Inc., GlaxoSmithKline, Inc. and Lundbeck Research USA as an advisory board participant and/or speaker. Dr. Ben-Menachem has received personal compensation in an editorial capacity for Acta Neurologica Scandinovica. Dr. Ben-Menachem has received research support from Eisai Inc, UCB Pharma and Bial. Dr. Kwan has received personal compensation for activities with Pfizer Inc and UCB Pharma for serving on an advisory board for Pfizer and for speaking activities for UCB Pharma and Sanofi-Aventis Pharmaceuticals, Inc. as a consultant, speaker and participant on an advisory board. Dr. Kwan has received personal compensation in an editorial capacity for Epilepsy & Behavior, Epilepsy Research, Epileptic Disorders, CNS Special Issue editor, and Advanced Drug Delivery Review. Dr. Kwan has received research support from UCB Pharma, Pfizer Inc, and Eisai Inc. Dr. Shih has nothing to disclose. Dr. Squillacote has received personal compensation for activities with Eisai as an employee. Dr. Yang has received personal compensation for activities with Eisai, Inc. as an employee. Dr. Zhu has received personal compensation for activities with Eisai Inc., as an employee. Dr. Laurenza has received personal compensation for activities with Eisai as an employee.

Effect of BG-12 on Brain Atrophy and Lesions Volume: MRI Results from the DEFINE Study during First and Second Year of Treatment (IN3-2.002)

Objective: To report results of BG-12 on tertiary magnetic resonance imaging (MRI)-related outcomes from the Phase 3 DEFINE study. Background BG-12 is an experimental oral treatment for relapsing-remitting multiple sclerosis (RRMS) that may have anti-inflammatory and neuroprotective effects via the Nrf2 pathway. DEFINE, a randomized, double-blind, placebo-controlled study evaluating BG-12 over 2 years in RRMS patients, showed significant reductions in clinical relapses, accumulation of disability progression, and number of lesions on brain MRI images. Design/Methods: Patients aged 18-55 years with RRMS (McDonald criteria) and EDSS score of 0.0-5.0 were enrolled. Patients were randomized 1:1:1 to placebo or BG-12 240 mg twice (BID) or three times daily (TID). A subset of patients from 76 sites had MRI scans at baseline, 24 weeks, 1 year, and 2 years. Tertiary endpoints included brain atrophy from 6 months to 2 years measured using the SIENA method and the volume of T2, gadolinium-enhancing (Gd+), and T1 hypointense lesions at 1 and 2 years. Results: The MRI intent-to-treat cohort comprised 540 patients. The median percent whole brain volume change from 6 months to 2 years was -0.660% in placebo compared with -0.460% and -0.550% in the BG-12 BID and TID groups, respectively, representing reductions of 30% (P=0.0214) and 17% (P=0.2478) versus placebo. Over 2 years, the median percent change of T2 hyperintense lesion volume from baseline was 20.1% with placebo versus -6.2% (P Conclusions: Results of the MRI analysis of the DEFINE study demonstrate reduced brain atrophy and lesion volume compared with placebo and supports BG-129s potential as an effective oral treatment for RRMS patients. Supported by: Biogen Idec Inc. Disclosure: Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received research support from Biogen Idec. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

Randomized phase III study 306

To evaluate the efficacy and safety of perampanel 2, 4, and 8 mg/day added to 1-3 concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. During this double-blind, placebo-controlled trial, patients with persisting seizures on 1-3 AEDs were randomized to perampanel 2, 4, and 8 mg/day or placebo following a 6-week baseline phase. Perampanel was titrated weekly by 2 mg/day and maintained at the dose achieved for 13 weeks. Primary endpoints were median percent change in seizure frequency and 50% responder rate. Analysis of covariance was performed on all treated patients with any seizure data (recorded in daily diaries) in the double-blind phase. A total of 706 patients were randomized and received trial medication; 623 completed the trial. Median percent change in seizure frequency-the primary efficacy endpoint-was -10.7%, -13.6%, -23.3%, and -30.8% for placebo, perampanel 2, 4, and 8 mg/day, respectively. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0026) and 8 mg/day (p < 0.0001). The corresponding 50% responder rates were 17.9%, 20.6%, 28.5%, and 34.9%. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0132) and 8 mg/day (p = 0.0003). An apparent dose response was suggested for dizziness, which was the most frequent treatment-emergent adverse event. This trial demonstrated that adjunctive perampanel effectively reduced seizure frequency and possessed a favorable tolerability profile in patients ≥12 years with partial-onset seizures (with or without secondary generalization), with a minimum effective dose of 4 mg/day. This study provides Class I evidence that 4 and 8 mg/day doses of adjunctive perampanel are effective and tolerated in reducing partial-onset seizures.

1846 OVER 100 CASES OF ZERO-ISCHEMIA ROBOTIC/LAPAROSCOPIC PARTIAL NEPHRECTOMY: IS GLOBAL RENAL ISCHEMIA NECESSARY?

You have accessJournal of UrologyKidney Cancer: Localized V1 Apr 20121846 OVER 100 CASES OF ZERO-ISCHEMIA ROBOTIC/LAPAROSCOPIC PARTIAL NEPHRECTOMY: IS GLOBAL RENAL ISCHEMIA NECESSARY? Andre Luis de Castro Abreu, Dennis Lee, Andre K. Berger, Alvin Goh, Mukul Patil, Casey Ng, Osamu Ukimura, Monish Aron, Mihir Desai, and Inderbir Gill Andre Luis de Castro AbreuAndre Luis de Castro Abreu Los Angeles, CA More articles by this author , Dennis LeeDennis Lee Los Angeles, CA More articles by this author , Andre K. BergerAndre K. Berger Los Angeles, CA More articles by this author , Alvin GohAlvin Goh Los Angeles, CA More articles by this author , Mukul PatilMukul Patil Los Angeles, CA More articles by this author , Casey NgCasey Ng Los Angeles, CA More articles by this author , Osamu UkimuraOsamu Ukimura Los Angeles, CA More articles by this author , Monish AronMonish Aron Los Angeles, CA More articles by this author , Mihir DesaiMihir Desai Los Angeles, CA More articles by this author , and Inderbir GillInderbir Gill Los Angeles, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1956AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The aim is to report peri-operative and short-term outcomes of a novel technique of zero-ischemia robotic and laparoscopic partial nephrectomy (PN). METHODS From March/10 to July/11, 100 zero-ischemia robotic (n=40)/laparoscopic (n=60) PN were performed at our institution. The technique consists of performing micro-dissection of tertiary or higher-order renal arterial branches to super-selectively devascularize the tumor. Blood flow continues uninterrupted to the remainder of the kidney. As such, PN is performed without hilar cross-clamping. The procedure was offered to all comers regardless the tumor complexity or renovascular anatomy. RESULTS Median patient age was 59 years, tumor size was 3cm (0.9-13.6), baseline serum creatinine (SCr) was 1 mg/dl (0.5-2.6), and estimated glomerular filtration rate (eGFR) was 73 ml/min per 1.73m2 (24-149). 21% of patients had imperative indication for PN, 10 had past history of PN, 5 had bilateral masses, 9 had solitary kidney and 8 patients had multiple ipsilateral tumors. Overall, 70% of tumors were complex: central (43%), completely intra-renal (23%), cT1b >4cm (21%), and hilar (19%). Median (range) RENAL, PADUA and C-Index scores were 8 (4-11), 9 (6-13), 2.2 (0.5 – 13.2), respectively. In 1 patient, zero-ischemia LPN was converted to clamped LPN. There were no conversions to radical nephrectomy or open surgery. Warm ischemia time was zero, median operative time was 275 min (126-534), estimated blood loss was 200cc, percent of kidney excised was 20 (5-70) and hospital stay was 4 days (2-20). There were 13 complications in 12 patients, with major complications, Clavien grade ≥3, in 4 patients. None patient died. Histology confirmed malignancy in 80% of tumors. All surgical margins were negative for cancer. There were no significant difference for median percent change in SCr, 0 mg/dl (-31 to 215), and eGFR, -1 (-74 to 53), at discharge. In 65 patients with more than 2 months (median 219 days) follow up data available, median percent change in SCr and eGFR were 18 (-31 to 154), p<.001 and -18 (-66 t0 53), p<.001, respectively. In those patients, there was no significant percent change in eGRF (-3.2; p=0.98), comparing the actual eGRF with the predict eGFR (Predict eGFR = pre-eGFR x total kidney remaining). 1 patient developed pulmonary metastases at 1 year follow up. CONCLUSIONS Zero-ischemia robotic/laparoscopic PN without hilar clamping is feasible and safe. It could be performed even in the setting of complex tumors and various vascular anatomy scenarios. Eliminating global renal ischemia now appears achievable. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e746 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andre Luis de Castro Abreu Los Angeles, CA More articles by this author Dennis Lee Los Angeles, CA More articles by this author Andre K. Berger Los Angeles, CA More articles by this author Alvin Goh Los Angeles, CA More articles by this author Mukul Patil Los Angeles, CA More articles by this author Casey Ng Los Angeles, CA More articles by this author Osamu Ukimura Los Angeles, CA More articles by this author Monish Aron Los Angeles, CA More articles by this author Mihir Desai Los Angeles, CA More articles by this author Inderbir Gill Los Angeles, CA More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

One-Year Efficacy and Safety of Rosuvastatin + Fenofibric Acid Combination Therapy in Patients with Mixed Dyslipidemia

Statins are the standard-of-care therapy for reducing low-density lipoprotein cholesterol (LDL-C) levels; however, combination with other lipid-modifying agents may be necessary to normalize lipid profiles in patients with mixed dyslipidemia who, in addition to high LDL-C, also have high triglycerides (TG) and low levels of high-density lipoprotein cholesterol (HDL-C). This study aimed to evaluate the 1-year efficacy and safety of rosuvastatin in combination with fenofibric acid in a subgroup of patients treated for 12 weeks with rosuvastatin 10 mg + fenofibric acid 135 mg and subsequently treated for up to 52 weeks with rosuvastatin 20 mg + fenofibric acid 135 mg. The efficacy and safety of combination therapy with rosuvastatin + fenofibric acid were demonstrated in a 12-week controlled study (NCT00300482) of patients with mixed dyslipidemia who were randomized to rosuvastatin 10, 20, or 40 mg, fenofibric acid 135 mg, or rosuvastatin 10 or 20 mg + fenofibric acid 135 mg. All patients who completed the controlled study were eligible to enroll in a subsequent 52-week open-label extension study (NCT00300430) and received rosuvastatin 20 mg + fenofibric acid 135 mg. The present post hoc analysis evaluated patients who were treated with rosuvastatin 10 mg + fenofibric acid 135 mg in the controlled study and received rosuvastatin 20 mg + fenofibric acid 135 mg in the open-label extension study. The study was carried out at investigative sites in the US (including Puerto Rico) and Canada. Patients included in the study were men and women ≥18 years of age with mixed dyslipidemia, defined as TG ≥150 mg/dL, LDL-C ≥130 mg/dL, and HDL-C <40/50 mg/dL for men/women (at screening in the controlled trial). Efficacy variables included mean percentage changes in LDL-C, HDL-C, non-HDL-C, and apolipoprotein B (ApoB), and median percentage changes in TG and high-sensitivity C-reactive protein (hsCRP) from baseline (i.e. start of the open-label extension after 12 weeks of treatment with rosuvastatin 10 mg + fenofibric acid 135 mg) to incremental time points up to 52 weeks in the extension study, and the proportion of patients achieving individual and combined goals for LDL-C and non-HDL-C. Adverse events (AEs) and clinical laboratory values were also assessed. Of the 261 patients initially randomized to rosuvastatin 10 mg + fenofibric acid 135 mg, 220 completed the controlled study and 187 continued treatment with rosuvastatin 20 mg + fenofibric acid 135 mg in the extension study. Increasing the rosuvastatin dose from 10 mg to 20 mg in combination with fenofibric acid 135 mg for up to 52 weeks resulted in significant (p ≤ 0.005 for all comparisons) mean percentage changes from baseline in LDL-C (-9.5%), non-HDL-C (-6.0%), ApoB (-8.5%), and HDL-C (3.6%), while median TG levels remained largely unchanged (0.8%, p = 0.055) at the week 52 visit. Greater percentages of patients achieved their risk-stratified lipid goals at week 52 compared with baseline for LDL-C (89% vs 84%), non-HDL-C (50% vs 25%), and both LDL-C and non-HDL-C (50% vs 19%). Combination therapy was generally well tolerated. The incidence of muscle-, hepatic-, and renal-related AEs and laboratory values were within the expected range. This study demonstrates that 1-year therapy with rosuvastatin + fenofibric acid is well tolerated and that increasing the rosuvastatin dose from 10 mg to 20 mg in the combination results in additional beneficial effects on key lipid parameters in patients with mixed dyslipidemia. Clinicaltrials.gov identifiers NCT00300482 and NCT00300430.

Radiographic Response of Brain Metastasis after Linear Accelerator Radiosurgery

Background: Radiographic response of brain metastasis to stereotactic radiosurgery (SRS) over time has not been well characterized. Being able to predict SRS-induced changes in tumor size over time may allow improved counseling of patients and potentially earlier recognition of poor response to SRS. Objective: To quantify the rate of change in size of metastatic brain tumors after treatment with a linear accelerator (LINAC) SRS. Methods: We performed a retrospective analysis of patients with single metastatic brain tumors treated with LINAC SRS at the University of Florida between 1992 and 2009 who had at least one MRI after treatment. A total of 218 patients with 406 follow-up MRI scans were included in the study. Tumor area was calculated by measuring the largest tumor area on axial imaging and using the equation for area of an ellipse. Primary outcome was percent change in tumor size. The contribution of several factors including gender, primary tumor histology, synchronous or asynchronous presentation, prior treatment, primary tumor control, and SRS dose were examined using multivariate analysis. Results: Mean patient age was 58.3 years (range 4–86), and 48.6% of patients were female. Sixty-three percent of patients had primary tumor control and 70.6% had asynchronous presentation of their brain metastases. SRS peripheral dose range was 1,000–2,250 cGy with a median of 1,750 cGy. The mean percent size change was –22.6% with a mean rate of change of –7.0% per month. The median percent change was –49.7% with a median rate of change of –8.8% per month. The median follow-up was 4.8 months (range 0.3–52.5). Female gender and melanoma histology were found to be significant predictors of an increase in tumor size. Lack of previous surgical resection was a significant predictor of a decrease in tumor size after SRS. Other factors tested with multivariate analysis, including age, synchronicity of presentation, dose, dose volume, Karnofsky performance score, and primary tumor control, were not significant in predicting tumor size change after SRS. Conclusion: In this study, brain metastases decreased in size by a median of 50% for a median follow-up of 4.8 months after SRS. The overall rate of decrease was 9% per month after treatment with SRS. Melanoma histology was a predictor of poor tumor control.

Niacin extended-release/simvastatin combination therapy produces larger favorable changes in high-density lipoprotein particles than atorvastatin monotherapy

BackgroundThe purpose of this research was to compare the effects of niacin extended-release in combination with simvastatin (NER/S) versus atorvastatin monotherapy on high-density lipoprotein (HDL) particle number and size in patients with hyperlipidemia or dyslipidemia from the SUPREME study.MethodsThis was a post hoc analysis of patients (n = 137) who completed the SUPREME study and who had lipid particle number and size measurements at both baseline and at week 12 by nuclear magnetic resonance spectroscopy. Following ≥4 weeks without lipid-modifying therapy (washout period), the patients received NER/S 1000/40 mg/day for 4 weeks followed by NER/S 2000/40 mg/day for 8 weeks, or atorvastatin 40 mg/day for 12 weeks. Median percent changes in HDL particle number and size from baseline to week 12 were compared between the NER/S and atorvastatin treatment groups using the Wilcoxon rank-sum test. Distribution of HDL particle subclasses at week 12 was compared between the treatment groups using the Cochran–Mantel–Haenszel test.ResultsTreatment with NER/S resulted in a significantly greater percent reduction in small HDL particle number at week 12 compared with atorvastatin monotherapy (−1.8% versus 4.2%, P = 0.014), and a numerically greater percent increase in large HDL particle number (102.4% versus 39.2%, P = 0.078) compared with atorvastatin monotherapy. A significantly greater percent increase in HDL particle size from baseline at week 12 was observed with NER/S compared with atorvastatin (6.0% versus 1.3%, P < 0.001). NER/S treatment also resulted in a significant shift in HDL particle size from small and medium at baseline to large at week 12 (P < 0.0001).ConclusionTreatment with NER/S resulted in larger favorable changes in number and size of HDL particle subclasses compared with atorvastatin monotherapy, including a numerically greater increase in number of large HDL particles, and a significantly greater decrease in number of small HDL particles compared with atorvastatin monotherapy. In addition, NER/S treatment resulted in a significant change in HDL particle size distribution from small and medium to large.

Tolerability, pharmacokinetics and pharmacodynamics of CMAB007, a humanized anti-immunoglobulin E monoclonal antibody, in healthy Chinese subjects

The goal of the studies presented here was to determine the tolerability, pharmacokinetic and pharmacodynamic profiles of CMAB007, a biosimilar of omalizumab (Xolair; a humanized anti-immunoglobulin E monoclonal antibody), in healthy, male Chinese subjects. Thirty-six healthy Chinese men participated in two open-label, dose-escalation studies: 27 in a single-dose study (150, 300 or 600 mg) and 9 in a multiple-dose study (150 or 300 mg every 4 weeks for 20 weeks). The safety profiles of both studies were generally unremarkable. No drug-related adverse event was observed. CMAB007 exhibited a linear PK profile over the dose range of 150–600 mg. In the single-dose study, maximum concentration (Cmax) was reached within 6–8 d, and Cmax and area under concentration-time curve (AUC) increased linearly with the dose. In the multiple-dose study, steady-state appeared to have been achieved after the third dose. Css-max and AUCτ also showed dose-linearity. A dose-dependent suppression of free IgE was observed during treatment, as a median percentage change from baseline, 91.9–98.8%, in the three single-dose groups. No anti-CMAB007 antibodies were detected after dosing in any subject. Subcutaneous administration of CMAB007 was well-tolerated and seemed to be effective in reducing free IgE in healthy Chinese volunteers, which provides important information for further clinical studies.

Sixteen-Year Longitudinal Changes in Serum Prostate-Specific Antigen Levels: The Olmsted County Study

Objective To determine the distribution of longitudinal changes in serum prostate-specific antigen (PSA) levels from a population-based sample of men. Patients and Methods In this prospective cohort study, a random sample of Olmsted County, Minnesota, men aged 40 to 79 years in 1990 were followed up biennially from January 1, 1990, through August 29, 2007. Serum PSA levels were determined at each examination, and men were censored for follow-up with a diagnosis of prostate cancer or treatment for benign prostatic hyperplasia. The empirical distributions of annual percent change and annual absolute change in serum PSA level were calculated and tabulated, including the median and 75th and 95th percentiles. Results For men with PSA measurements 2 years apart, the median annual percent change in serum PSA level was 4.83% and the 95th percentile was about 49.76%. The variability in estimated annual change decreased with increasing time between assessments, with a 95th percentile of 21.82% after 8 or more years between assessments. Although the median absolute change per year increased with increasing age, the median percent change per year was fairly consistent across age groups. Conclusion These data demonstrate that, with shorter intervals between assessments, greater variability should be expected. These distributions should prove helpful to patients and clinicians in interpreting changes in serum PSA levels observed in typical clinical practices.

Abstract PR-6: Pharmacodynamic analysis of ENCORE 301, a placebo-controlled, randomized phase 2 study of exemestane with and without entinostat in postmenopausal ER+ breast cancer patients demonstrates an association of lysine hyperacetylation with clinical outcome.

Abstract Despite promising preclinical data and extensive clinical testing, histone deacetylase inhibitors (HDACi) as a class have not demonstrated significant activity in solid tumors as single agents or in combination. Even where HDACi have proven to be effective e.g. T-cell lymphomas, there is still an inability to identify those patients most likely to benefit due to a lack of association between outcome and acetylation. We report that pharmacodynamic (PD) analysis of patient samples from ENCORE-301, a recently completed randomized phase 2 placebo controlled study of exemestane with and without the HDACi entinostat in post-menopausal breast cancer patients (n=130), demonstrates an association of HDACi-induced lysine hyperacetylation with improved clinical outcome. Protein lysine acetylation was measured in circulating B cells (B), T cells (T) and monocytes (M) by multi-parameter flow cytometry from samples taken at pre-treatment, D1, D8, and D15 of cycle 1 from patients treated with exemestane plus entinostat (EE) or exemestane plus placebo (EP). Percent change was calculated and related to progression free survival (PFS) outcome data. Hyperacetylation independent of treatment arm is defined as a percent change increase above the calculated median percent change for each cell type. Pre- and post treatment samples were obtained in a subset of 49 patients (EE = 27; EP = 22). Review of baseline characteristics in this subset indicates that they appear to be consistent with the entire study population. Hyperacetylation across all cell types in EE vs EP was associated with prolonged median PFS (B: 8.54 months vs 1.92 HR=0.24 (95% CI 0.081, 0.690); T: 6.57 vs 1.77 HR=0.24 (95% CI 0.087, 0.640); M: 6.21 vs 1.87 HR=0.50 (95% CI 0.211, 1.203). Preliminary trends in overall survival also favor the EE hyperacetylation group. Samples taken for plasma concentration measurements of entinostat indicate that entinostat levels at the D8 and D15 timepoints used for the PD analysis were generally at or below the assay detection limits (&amp;lt; 0.5 ng/ml) preventing a correlation to be made between acetylation increase and entinostat concentration. Characterization of adverse events with 10% or greater difference between treatments in the ENCORE-301 safety population (n = 129) in the 49 patient biomarker patient subset indicates that thrombocytopenia incidence may be associated with hyperacetylation in the EE group while incidence of other AEs including fatigue do not appear to be associated with hyperacetylation. These data provide for the first time a clear association of HDACi induced protein lysine hyperacetylation and clinical outcome. Several factors may contribute to the success in demonstrating this association including the randomized, controlled study design, positive outcome of ENCORE-301 and a sensitive pharmacodynamic assay that allows for measurement of global protein lysine acetylation changes. Combined with the overall positive results of ENCORE-301 (median PFS EE vs EP 4.28 vs 2.27 months HR 0.73 (95% CI 0.49, 1.09); and OS with median follow up of 18 months EE vs EP 26.9 vs 20.3 months HR 0.56 (95% CI 0.31, 1.02)), these data provide evidence of a potential breakthrough in the expansion of epigenetic therapy to solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr PR-6.

Effect of initial combination therapy with sitagliptin and metformin on β‐cell function in patients with type 2 diabetes

To examine the effect of sitagliptin and metformin, alone and in combination, on modelled parameters of β-cell function in patients with type 2 diabetes. The data used in the present analyses are from a 104-week study, which included a 24-week, placebo- and active controlled phase followed by a 30-week, active controlled, continuation phase and an additional 50-week, active controlled extension phase. Patients were randomised to one of six blinded treatments: sitagliptin 50 mg + metformin 1000 mg b.i.d., sitagliptin 50 mg + metformin 500 mg b.i.d., metformin 1000 mg b.i.d., metformin 500 mg b.i.d., sitagliptin 100 mg q.d. or placebo. Patients on placebo were switched in a blinded manner to metformin 1000 mg b.i.d. at week 24. Subsets of patients volunteered to undergo frequently sampled meal tolerance tests at baseline and at weeks 24, 54 and 104. β-cell responsivity was assessed with the C-peptide minimal model. The static component (Φ(s)) estimates the rate of insulin secretion related to above-basal glucose concentration. The dynamic component (Φ(d)) is related to the rate of change in glucose. The total index (Φ(total)) represents the overall response to a glycaemic stimulus and is calculated as a function of Φ(s) and Φ(d). Insulin sensitivity was estimated with the Matsuda index (ISI). The disposition index, which assesses insulin secretion relative to the prevailing insulin sensitivity, was calculated based on the Φ(total) and ISI. At week 24, substantial reductions in postmeal glucose were observed with all active treatment groups relative to the placebo group. Φ(s), Φ(total) and the disposition index were significantly improved from baseline at week 24 with all active treatments relative to placebo. Generally larger effects were observed with the initial combination of sitagliptin and metformin relative to the monotherapy groups. When expressed as median percent change from baseline, Φ(s) increased from baseline by 137 and 177% in the low- and high-dose combination groups and by 85, 54, 73 and -9% in the high-dose metformin, low-dose metformin, sitagliptin monotherapy and placebo groups, respectively. At weeks 54 and 104, the combination treatment groups continued to demonstrate greater improvements in β-cell function relative to their respective monotherapy groups. After 24 weeks of therapy, relative to placebo, initial treatment with sitagliptin or metformin monotherapy improved β-cell function; moreover, initial combination therapy demonstrated larger improvements than the individual monotherapies. Improvements in β-cell function were found with treatments for up to 2 years.

Emergency Department Adherence to American Heart Association Guidelines for Blood Pressure Management in Acute Ischemic Stroke

Severely elevated blood pressure (BP) and aggressive BP reduction are both associated with poor outcome in acute ischemic stroke (AIS). In nontissue-type plasminogen activator patients, the American Heart Association recommends antihypertensive therapy only if BP is ≥ 220/120 mm Hg with a goal of 15% to 25% reduction in the first 24 hours. We hypothesized that patients with AIS often receive antihypertensives in the emergency department below the recommended threshold and that BP reduction is often >20%. In 2005, AIS cases were ascertained at all 16 hospitals in Greater Cincinnati. BP was recorded at emergency department presentation and before and after antihypertensive treatment. Hypertension was defined as BP ≥ 220/120 mm Hg. Chi-square and Mann-Whitney U tests were used for comparisons. A total of 1739 patients with AIS met inclusion criteria. Median age was 72 years with 43% male and 25% black. Of 218 treated with antihypertensives, 65 (30.0%) met treatment criteria immediately before treatment. Treated patients were younger (66 versus 73 years, P<0.001) with greater stroke severity than untreated patients (National Institutes of Health Stroke Scale score 4 versus 3, P=0.028). Median change in systolic BP was -25 mm Hg (range, -96 to 25 mm Hg). Median percentage change in systolic BP was -12.3% (range, -49.2% to 16.1%). Systolic BP decreased > 20% in 52 treated patients (23.7%). Only one third of patients with AIS treated with antihypertensives met American Heart Association-recommended treatment criteria, and the rate of change of BP was frequently greater than recommended. Further studies are warranted to determine the impact of practice patterns on AIS outcomes.

First trimester serum markers stability during sample transportation from the obstetrical site to the screening laboratory

Objective: To investigate the effect of temperature on first trimester free β-hCG and PAPP-A in serum during transportation. Methods: Maternal blood was collected from 30 East Asian women attending for Down syndrome screening at the primary obstetrical site. The extracted serum was split into two equal aliquots, placed in identical thermally insulated pouches with a temperature data logger and shipped to the screening laboratory. An 800 g frozen ice pack was placed in one of the pouches. Free β-hCG and PAPP-A levels were determined in the ‘Cooled’ and ‘Uncooled’ serum samples using a DELFIA® Xpress analyzer. The proportion of ‘Uncooled’ samples not within 5% of the ‘Cooled’ sample marker level was assessed. Results: The median age of subjects was 36 years, half were nulliparous and all were non-smokers. The assay stability ranged from 2.38% to 4.41%. The median total transport time from the obstetrical site to the laboratory was 17.37 h. Median recorded temperatures within the ‘Cooled’ pouch were significantly lower throughout the transportation of the samples (p < 0.0001). The median percentage change of free β-hCG and PAPP-A concentrations in ‘Uncooled’ samples relative to ‘Cooled’ samples were 2.72% (range 0.27–7.64%) and 1.10% (range 0.03%–4.29%), respectively. Free β-hCG concentrations differed by greater than 5% in eleven (37%) subjects. Conclusions: Insulated packaging, cooling media and temperature monitoring devices may be needed as additional measures to determine, minimize and exclude effects of ambient temperature on serum marker levels especially when travelling times are long or ambient temperatures are high.

An open-label, add-on study of pregabalin in patients with partial seizures: A multicenter trial in Greece

Introduction Pregabalin efficacy and safety as an adjunctive treatment for partial seizures was evaluated using an open-label, flexible-dose. Study design In 98 adults with refractory partial epilepsy taking 1–3 anti-epileptic drugs with ≥2 seizures during an 8-week baseline period. Methods Pregabalin was increased to ≤600 mg/day during a 9-week dose optimization period with dosage maintained for 12 additional weeks. Primary endpoint was the percentage change in partial seizure frequency between the 8-week baseline and 12-week observation period. Results Pregabalin treatment was associated with a significant reduction in partial seizure frequency: median percent change in partial seizure frequency from baseline to 12 weeks was −33% and −22% in patients with a baseline seizure frequency of ≤3 and >3 per 28 days, respectively. The 50% and 75% responder rates were 41.94% (95% CI: 31.91–51.96) and 30.11% (95% CI: 20.78–39.43), respectively. Nineteen percent of subjects were seizure-free throughout the last 12 weeks. Pregabalin administration resulted in a significant reduction in anxiety (mean reduction in Hospital Anxiety and Depression Scale scores of 1.68 units, 95% CI: −2.60 to −0.76). Most patients were much improved or very much improved on Patient Global Impression of Change (53.8%) and Clinical Global Impression of Change (53.8%). The most frequently self-reported adverse events (AEs) were mild or moderate somnolence (20.4%) and dizziness (5.1%) with a low AE discontinuation rate (5.1%). Conclusions The efficacy and side-effect profile of pregabalin were similar to previous pregabalin double-blind, controlled studies. Additionally, pregabalin, as an add-on treatment for partial epilepsy, exhibits significant anti-anxiety properties.

An In Vitro Investigation of the Coagulation Effects of Exogenous Oxytocin Using Thromboelastography in Healthy Parturients

We investigated the coagulation effects in vitro of exogenous oxytocin in whole blood of healthy term parturients. Thromboelastography (TEG®) was performed on kaolin-activated citrated blood samples from 25 healthy, term, nonlaboring parturients. We compared the in vitro effects on the maternal thromboelastographic profile of 3 different exogenous oxytocin concentrations (22.5, 30.1, and 32.9 μU/mL) and a control (0 μU/mL). These exogenous oxytocin concentrations were chosen to approximate maternal plasma oxytocin concentrations during elective cesarean delivery, vaginal delivery, and nonelective cesarean delivery, respectively. Increasing the oxytocin concentration was significantly associated with hypercoagulable effects as observed with TEG® (decreasing reaction time, clot formation time, and Tmax; increasing α angle and maximum rate of thrombus generation). Compared with control samples, the median percentage change (interquartile range) in TEG® values for samples with the highest exogenous oxytocin concentration (32.9 μU/mL) was largest for reaction time: -40.3% (-45.8%, -22.2%); and Tmax: -39.2% (-42.9%, -28.5%). The results of this in vitro investigation suggest that exogenous oxytocin is associated with modest hypercoagulable effects in the maternal blood of healthy term parturients.

Long-Term Effects of Fenofibric Acid + Statin Combination Therapy in Patients with High Triglycerides and Low HDL-C †

Synopsis: Three 12-week controlled studies demonstrated the efficacy and safety of combination therapy with fenofibric acid (FA) + statins in patients with mixed dyslipidemia defined as high triglycerides (TG $150 mg/dL), low highdensity lipoprotein cholesterol (HDL-C; men/women ,40/ ,50 mg/dL), and elevated low-density lipoprotein cholesterol (LDL-C; $130 mg/dL). A subsequent 52-week, openlabel extension study evaluated the long-term safety and efficacy of FA 135 mg + moderate-dose statin (MDS; rosuvastatin 20 mg, simvastatin 40 mg, or atorvastatin 40 mg). Purpose: To evaluate the long-term efficacy of combination therapy with FA + MDS in patients initially treated for 12 weeks with statin monotherapy. Methods: This prespecified analysis included the subset of patients who completed 12 weeks of treatment with statin monotherapy (rosuvastatin 10, 20, or 40 mg; simvastatin 20, 40, or 80 mg; or atorvastatin 20, 40, or 80 mg) in 1 of 3 controlled studies and subsequently received $1 dose of FA + MDS in the open-label extension study. Baseline was defined as the last value prior to the first dose of FA + MDS in the extension study. Mean or median percent changes from baseline in efficacy parameters were determined. Results: The mean age of patients in this analysis (n 5 893) was 55 years; 49% were women, 94% were white, and 21% had type 2 diabetes. At baseline of the extension study (after 12 weeks of statin monotherapy), mean HDL-C, TG, and LDL-C were 41.2 mg/dL, 199.2 mg/dL, and 94.4 mg/dL, respectively. Switching to combination therapy with FA + MDS for 52 weeks resulted in a mean percent increase in HDL-C (14.1%) and a mean percent decrease in TG (–25.4%; Figure). Non-HDL-C, apolipoprotein B (ApoB), VLDL-C, high-sensitivity C-reactive protein, and total-C were also improved after 52 weeks of combination therapy. Although modest mean percent increases in LDL-Cwere observed in the first 12 weeks of combination therapy, the increases gradually became smaller over time. After 52 weeks of therapy, mean LDL-C was 91.9 mg/dL, remaining at less than recommended levels for high-risk patients. Combination therapy was generallywell tolerated and no case of rhabdomyolysiswas reported. Conclusions: In patients with high TG and low HDL-C initially treated with statin monotherapy, long-term treatment with FA + MDS resulted in incremental and sustained.