Provident Perspective Volume 3, Issue 3

Provident News

New Staff Members

The last half of the year has been once again busy for Provident. We are pleased to welcome the following staff:

• Yolanda Cartwright, PhD, RD. Medical Writer/Clinical Research Scientist
• Wenqing Fan, MS. Biostatistician
• Morgan Fleck, MS, RD, CD. Dietitian
• Laurie Justice, MT (ASCP). Clinical Research Coordinator
• Brianna Miller, Research Assistant
• Anne Niess, Research Assistant
• Arianne Orcutt, Statistical Analyst
• Jaci Robinson, Scheduler
• Mitch Silverman, Clinical Data Analyst
• Frances Stefanovich, Lab Technician

Announcements

• Earlier this year Tia M. Rains, PhD was promoted to Director of Medical Writing. Congratulations Tia!
• Dr. Maki recently passed the National Lipid Association examination to become a Clinical Lipid Specialist.
• Provident Clinical Research & Consulting, Inc. is very pleased to announce the opening of its Data Management and Biostatistics Department in the Glen Ellyn, IL office.
• The book Therapeutic Lipidology edited by Drs. Michael Davidson, Peter Toth and Kevin Maki, will start shipping on December 17, 2007.
• The manuscript for Practical Lipid Management: Concepts and Controversies by Drs. Peter Toth and Kevin Maki will be turned in to the publisher (Wiley Medical) by the end of the year and the text should be available in mid-2008.

Recent and Upcoming Publications and Presentations

Abstracts/Presentations

Maki KC, Carson ML, Miller MP, Turowski M, Jones F, Wilder DM, Rains TM, Reeves MS. Effects of high-viscosity hydroxypropylmethylcellulose and methylcellulose on postprandial glucose and insulin responses in overweight and obese men and women. Obesity. 2007;15. Abstract 304-P.

Davidson M, Maki KC, Doyle RT, Shalwitz R, Bays HE, Stein E. Correlates of the apolipoprotein C-lll response to the addition of prescription Omega-3 in adults with hypertriglyceridemia despite stable stain therapy. Circulation. 2007;116(suppl):S192.

Davidson, MH, Maki KC, Zavoral JH, Yu S, Price GD. Lapaquistat acetate, a novel squalene synthase inhibitor, co-administered with atorvastatin reduces plasma lipids and c-reactive protein levels in subjects with primary hypercholesterolemia. Circulation. 2007;116(suppl):S193.

Maki KC, Rains TM. Designing a Clinical Trial. Proceedings of the IFT Annual Meeting and Food Expo, 2007, Abstract 210-03.

Publications

Izumi R, Hurt J, Maki KC, Bell M, Zavras AI, McCamish M. Clinical predictors of glycosylated hemoglobin response to thiazolidinedione therapy. Diabetes Technol Ther. 2007;9:553-562.

Maki KC, Carson ML, Miller MP, Turowski M, Bell M, Wilder D, Rains TM, Reeves MS. High-viscosity hydroxypropylmethylcellulose lowers postprandial insulin levels. J Nutr. 2008;(in press).

Davidson MH, Stein EA, Bays H, Maki KC, Doyle R, Shalwitz RA, Ballantyne CM, Ginsberg HN. The lipid and lipoprotein effects of adding prescription Omega-3 fatty acids to a statin in hypertriglyceridemic subjects – The COMBOS Trial. Clin Therapeutics. 2007;29:1354-1367.

In the Literature

Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study (The COMBOS Trial). Davidson MH, Stein EA, Bays HE, Maki KC, Doyle RT, Shalwitz RA, Ballantyne CM, Ginsberg HN; COMBination of prescription Omega-3 with Simvastatin (COMBOS) Investigators.

Background: The use of a statin is suggested as a first line therapy for lowering non-high-density lipoprotein cholesterol (HDL-C) in patients with hypertriglyceridemia (serum triglyceride [TG] level 200-499 mg/dL). However, statin monotherapy alone may not be sufficient to reduce non-HDL-C to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) target levels in many patients. Coadministration of omega-3 fatty acids within statins has been shown to be more effective than use of statins alone in improving lipid profiles in patients with hypertryglyceridemia. This study was conducted to assess the efficacy and safety of a highly concentrated form of prescription fatty acids (P-OM3) (OMACOR®, Reliant Pharmaceuticals, Inc., Liberty Corner, NJ), administered in combination with simvastatin (Zocor®, Merck & Co., Inc., West Point, PA) for lowering nonHDL-C in subjects with persistent hypertriglyceridemia despite statin therapy.

Methods: This was a multi-center, randomized, double-blind, placebo-controlled trial conducted at 41 clinical sites. Male and female subjects, aged 18 to 79 years, were eligible for enrollment if they were receiving a statin for control of low-density lipoprotein cholesterol (LDL-C) at a dose that had been stable for at least 8 weeks prior to screening; had an average fasting TG level between 200 and 500 mg/dL; and had an average LDL-C concentration below or within 10% of their NCEP ATP III target goal. After an initial screening visit, eligible subjects participated in an 8-week lead-in phase of the study in which they received single-blind treatment with simvastatin 40 mg oncedaily (QD) (all other lipid-altering drugs and supplements were to be discontinued) and dietary counseling regarding the NCEP therapeutic changes diet. After the leadin phase, subjects with ≥ 80% compliance with simvastatin therapy and who were otherwise eligible were randomly assigned to the 8-week double-blind treatment phase of the study in which they continued to receive simvastatin 40 mg with either P-OM3 4 g or placebo.

Results Efficacy: and safety analyses were conducted with data from 254 subjects, 122 in the POM3 group and 132 in the placebo group, who returned for at least 1 postrandomization evaluation. At the end of the 8-week treatment period, the reduction in non-HDL-C levels was significantly greater (P < 0.0001) in the POM3 group compared with the placebo group (-9.0% vs. 2.2%, respectively). Statistically significant differences were observed between the POM3 and placebo treatment groups with regard to changes in levels of TG (29.5% vs. 6.3%; P < 0.0001); VLDL-C (-27.5% vs. -7.2%; P < 0.0001); total-C (-4.8% vs. 1.7%; P = 0.001); apolipoprotein B (-4.2% vs. -1.9%; P = 0.023); the total:HDL-C ratio (-9.6% vs. 0.7%; P < 0.0001) and HDL-C (3.4% vs. -1.2%; P < 0.0001). The median percent change from baseline in LDL-C was 0.7% in the P-OM3 group -2.8% in the placebo group (P = 0.052).

Conclusion: The administration of P-OM3 with simvastatin resulted in statistically significant improvements in nonHDL-C, TG, VLDL-C, HDL-C, total-C, the total:HDL-C ratio, and apolipoprotein B compared with administration of simvastatin with placebo, and was well tolerated in subjects with persistent hypertriglyceridemia.

Dr. Maki’s Commentary: Considerable controversy exists regarding the best approach to the management of patients with hypertriglyceridemia who fail to achieve treatment targets with statin monotherapy. In addition to intensification of lifestyle modification (weight loss, physical activity, plant sterols/stanols and viscous fiber), the clinician may choose to add a second lipid-altering agent. Options include adding a cholesterol absorption inhibitor to target a further reduction in LDL-C, or using a drug to target VLDL-C and TG reduction such as a fibrate, niacin or P-OM3. COMBOS was the first large-scale trial to assess the efficacy of adding P-OM3 to statin therapy in subjects with persistent hypertriglyceridemia, despite statin therapy. The results showed that P-OM3 was well tolerated and produced incremental changes in the lipid profile that were favorable and very similar to those produced by adding fenofibrate to simvastatin, as demonstrated in the SAFARI Trial (Grundy et al. Am J Cardiol 2005;95:462-468). These findings suggest that P-OM3 is a useful adjunct in such patients. Several large outcomes trials are underway to assess the influence of P-OM3 on morbidity and mortality.

About Provident

Provident has a team of research professionals with extensive experience in the design and conduct of clinical trials to evaluate pharmaceuticals, medical and functional foods, dietary supplements and medical devices.

For more information, visit our web site: http://www.providentcrc.com.

Or, contact us directly:

Tia Rains: trains@providentcrc.com, Director of Medical Writing / Principal Scientist