Context Interest remains high in cholesteryl ester transfer protein (CETP) inhibitors as cardioprotective agents. Few studies have documented the efficacy and safety of CETP inhibitors in combination with commonly used statins.
Objective To examine the biochemical effects, safety, and tolerability of evacetrapib, as monotherapy and in combination with statins, in patients with dyslipidemia.
Design, Setting, and Participants Randomized controlled trial conducted among 398 patients with elevated low-density lipoprotein cholesterol (LDL-C) or low high-density lipoprotein cholesterol (HDL-C) levels from April 2010 to January 2011 at community and academic centers in the United States and Europe.
Interventions Following dietary lead-in, patients were randomly assigned to receive placebo (n = 38); evacetrapib monotherapy, 30 mg/d (n = 40), 100 mg/d (n = 39), or 500 mg/d (n = 42); or statin therapy (n = 239) (simvastatin, 40 mg/d; atorvastatin, 20 mg/d; or rosuvastatin, 10 mg/d) with or without evacetrapib, 100 mg/d, for 12 weeks.
Main Outcome Measures The co–primary end points were percentage changes from baseline in HDL-C and LDL-C after 12 weeks of treatment.
Results The mean baseline HDL-C level was 55.1 (SD, 15.3) mg/dL and the mean baseline LDL-C level was 144.3 (SD, 26.6) mg/dL. As monotherapy, evacetrapib produced dose-dependent increases in HDL-C of 30.0 to 66.0 mg/dL (53.6% to 128.8%) compared with a decrease with placebo of −0.7 mg/dL (−3.0%; P < .001 for all compared with placebo) and decreases in LDL-C of −20.5 to −51.4 mg/dL (−13.6% to −35.9%) compared with an increase with placebo of 7.2 mg/dL (3.9%; P < .001 for all compared with placebo). In combination with statin therapy, evacetrapib, 100 mg/d, produced increases in HDL-C of 42.1 to 50.5 mg/dL (78.5% to 88.5%; P < .001 for all compared with statin monotherapy) and decreases in LDL-C of −67.1 to −75.8 mg/dL (−11.2% to −13.9%; P < .001 for all compared with statin monotherapy). Compared with evacetrapib monotherapy, the combination of statins and evacetrapib resulted in greater reductions in LDL-C (P <.001) but no greater increase in HDL-C (P =.39). Although the study was underpowered, no adverse effects were observed.
Conclusions Compared with placebo or statin monotherapy, evacetrapib as monotherapy or in combination with statins increased HDL-C levels and decreased LDL-C levels. The effects on cardiovascular outcomes require further investigation.
Trial Registration clinicaltrials.gov Identifier: NCT01105975
The development of statins for reducing low-density lipoprotein cholesterol (LDL-C) has revolutionized cardiovascular disease prevention.1-6 Nonetheless, cardiovascular disease remains the number one cause of death.7 Accordingly, considerable efforts have focused on development of novel therapeutic agents designed to address residual cardiovascular risk. Because individuals from the general population with elevations of high-density lipoprotein cholesterol (HDL-C) have a reduced incidence of coronary heart disease,8 it has been assumed that finding an appropriate therapy to increase HDL-C levels would yield substantial clinical benefit.
However, development of drugs that increase HDL-C levels has been challenging and fraught with failures, including the premature termination of a large outcomes trial studying the effects of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib.9 Despite failure of the first drug in the class, considerable interest remains in CETP inhibition as a therapeutic strategy, by virtue of the ability of these agents to substantially increase HDL-C levels and, in some cases, reduce LDL-C levels.10 The observation that CETP inhibition has a favorable effect on atherosclerotic lesion formation in animal species that express CETP11 provides hope for potential benefit for humans.
While several CETP inhibitors are currently undergoing clinical evaluation, their effects in combination with the most commonly used statins have not been fully characterized. Evacetrapib is a novel, potent CETP inhibitor that has shown no demonstrable effects on blood pressure or adrenal synthesis of aldosterone or cortisol in preclinical studies.12 The current study evaluated the biochemical efficacy, safety, and tolerability of evacetrapib as monotherapy and in combination with statin agents commonly used in clinical practice.
The study was a multicenter, randomized, double-blind, parallel, placebo-controlled clinical trial. The trial was designed by the Cleveland Clinic Coordinating Center for Clinical Research in collaboration with the sponsor. The institutional review boards of all participating centers approved the protocol and all patients provided written informed consent. Patients were at least 18 years old and were eligible on the basis of meeting low HDL-C or high LDL-C criteria, in the presence of triglyceride levels less than 400 mg/dL, after the dietary lead-in period. (To convert HDL-C and LDL-C to millimoles per liter, multiply by 0.0259. To convert triglycerides to millimoles per liter, multiply by 0.0113.)
Patients meeting the low HDL-C criteria had an HDL-C level of less than 45 mg/dL for men or 50 mg/dL for women, with an LDL-C level that currently met the National Cholesterol Education Program (NCEP) Adult Treatment Panel III goal. Patients meeting the high LDL-C criteria had an LDL-C level between 100 and 190 mg/dL in the presence of 0 or 1 risk factors; between 100 and 160 mg/dL with at least 2 risk factors and a 10-year coronary risk of less than 10%; or between 100 and 130 mg/dL with at least 2 risk factors and a 10-year risk of 10% to 20%, in the presence of any level of HDL-C.
Patients were excluded if they had any clinical manifestation of atherosclerotic disease, hypertension (systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg), documented hyperaldosteronism, uncontrolled diabetes (hemoglobin A1c ≥8%), or significant liver, kidney, cardiac, or neuromuscular disease.
All patients entered a 2- to 8-week dietary lead-in period to evaluate the effect of the NCEP Therapeutic Lifestyle Changes diet and permit washout of any lipid-modifying therapies. The study evaluated the effects of 12 weeks of treatment with evacetrapib as monotherapy and in combination with statins. For the monotherapy evaluation, patients were randomly assigned to receive either placebo or evacetrapib at a dosage of 30 mg/d, 100 mg/d, or 500 mg/d. Monotherapy dosages were selected based on modeling of the results from phase 1 studies, in combination with literature data from other CETP inhibitors in development. For the combination treatment groups, patients were randomly assigned to receive either placebo or evacetrapib, 100 mg/d, in combination with the 3 most commonly prescribed statins, at typical dosages prescribed in clinical practice (simvastatin, 40 mg/d; atorvastatin, 20 mg/d; or rosuvastatin, 10 mg/d). Assignment to statin groups was performed during randomization to 1 of the 10 treatment groups. Randomization was performed by an interactive voice response system and was stratified according to geographic region and baseline levels of HDL-C and triglycerides.
Clinic Visits and Laboratory Tests
Patients were examined during scheduled visits at weeks 2, 4, 8, and 12 during the treatment phase and a follow-up visit 4 to 6 weeks after cessation of the study drug. Lipoprotein levels and safety laboratory measurements were obtained at all visits. Blood pressure was measured at each visit by 3 replicate measurements using a standard automated blood pressure device. A central laboratory (Covance) performed all biochemical determinations. Standard lipid profiles (LDL-C, HDL-C, and triglycerides) were determined by enzymatic assay. High-sensitivity C-reactive protein (CRP) was determined by immunonephelometry. Measurement of CETP mass in serum samples was performed by enzyme-linked immunosorbent assay. Serum CETP activity was measured by fluorometric assay and expressed after correction for the maximum inhibitable CETP activity with evacetrapib. All reported cardiovascular events and rashes were evaluated and adjudicated by a blinded clinical end-point committee.
A sample size of 35 patients per group was calculated to provide 87% power to simultaneously detect a 40% (SD, 30%) increase in HDL-C and 10% (SD, 15%) decrease in LDL-C compared with a statin alone for each of the combined therapy groups (.10 type I error rate for a 2-sided test). These changes reflect an increase in HDL-C greater than observed with niacin therapy13 and an incremental reduction in LDL-C of at least 10% in addition to statin therapy, both thought to be of potential clinical benefit. Demographic and baseline information are summarized using frequencies for categorical variables and means with standard deviations or medians with interquartile ranges for continuous variables.
The efficacy analyses were performed in the modified intention-to-treat population, consisting of those with a baseline and at least 1 postbaseline efficacy measurement. For the monotherapy evaluation of evacetrapib, comparisons were made between each individual dosage and placebo. The statin combination evaluation reflects comparisons of each individual statin with that statin in combination with evacetrapib, 100 mg/d. In addition, evacetrapib, 100 mg/d, monotherapy was compared with evacetrapib, 100 mg/d, in combination with any statin.
A mixed model for repeated measurements was used to evaluate the percentage change from baseline in primary and secondary laboratory measurements. The model included terms for baseline measurement, treatment group, visit, and treatment × visit interaction. Least-squares means with 90% confidence intervals are reported. The safety analyses were conducted to evaluate change from baseline in the safety profile in the intention-to-treat population using the same modeling strategy. Safety data are reported as least-squares means with 90% confidence intervals or as frequencies. All analyses were conducted using SAS, version 9.2 (SAS Institute Inc) and were performed by academic statisticians (M.S., B.H.).
Between April 15, 2010, and January 14, 2011, 1154 patients were screened in the study at 70 sites. A total of 398 patients proceeded to the randomization phase of the study. The dispositions of these patients are shown in Figure 1. Baseline characteristics of the patients are shown in Table 1, Table 2, and eTable 1). Characteristics were similar for all treatment groups and are presented as summary data. The mean age was 58.3 years and approximately 56% of patients were women. Baseline lipid profiles were as follows: for LDL-C, mean, 144.3 (SD, 26.6) mg/dL; for HDL-C, mean, 55.1 (SD, 15.3) mg/dL; and for triglycerides, median, 121.3 (interquartile range, 88.6-176.3) mg/dL.
Percentage changes in lipoprotein and apolipoprotein measurements and C-reactive protein are summarized in Table 3, Table 4, eTable 2, and eTable 3. Evacetrapib monotherapy produced dose-dependent increases in HDL-C ranging from 30.0 to 66.0 mg/dL (53.6% to 128.8%; P < .001 compared with placebo) and decreases in LDL-C of −20.5 to −51.4 mg/dL (−13.6% to −35.9%; P < .001 compared with placebo). A significant 26.7-mg/dL (10.8%) reduction in triglyceride levels also was observed with the 500-mg/d dosage (P = .006 compared with placebo). These effects resulted in dose-dependent reductions in non–HDL-C by −23.2 to −45.8 mg/dL (−12.9% to −26.4%; P < .001 compared with placebo) and apolipoprotein B by −13.8 to −29.7 mg/dL (−12.4% to −26.6%; P < .001 compared with placebo).
When administered in combination with statin therapy, evacetrapib, 100 mg/d, increased HDL-C levels by 42.1 to 50.5 mg/dL (78.5% to 88.5%; P < .001 compared with statin alone) and resulted in greater reductions in LDL-C (P < .001) and non–HDL-C (P < .05 for atorvastatin and rosuvastatin) compared with effects observed with statin monotherapy. Compared with evacetrapib monotherapy, the combination of a statin and evacetrapib resulted in greater reductions in LDL-C by 71.0 vs 34.2 mg/dL (48.6% vs 23.7%; P < .001) but no greater increase in HDL-C by 45.9 vs 48.4 mg/dL (86.8% vs 91.3%; P = .39), consistent with known lipid effects of statins. Increases in HDL-C and decreases in atherogenic lipid levels with evacetrapib administration occurred rapidly, with most of these effects observed at 2 weeks.
Increases in HDL-C with evacetrapib produced dose-dependent increases in apolipoprotein A-I ranging from 35.7 to 72.6 mg/dL (22.7% to 49.6%; P < .001 compared with placebo), in apolipoprotein A-II by 4.8 to 7.4 mg/dL (12.7% to 19.7%; P < .001 compared with placebo), and in apolipoprotein E by 5.7 to 9.2 mg/dL (15.8% to 83.7%; P < .001 for the 2 highest dosages compared with placebo). A dose-dependent decrease in CETP activity ranging from −11.5 to −20.8 pmol/mL per minute (−49.5% to −89.1%; P < .001 compared with placebo) and an increase in CETP mass ranging from 1.5 to 3.2 μg (63.9% to 136.7%; P < .001 compared with placebo) were observed with evacetrapib monotherapy. C-reactive protein levels remained unchanged during 12 weeks of administration of evacetrapib, either as monotherapy or in combination with statins.
Within prespecified subgroups, there were significant interactions for evacetrapib monotherapy and placebo, with greater percentage increases in HDL-C (eFigure 1) among patients who were younger (P = .002), had lower baseline HDL-C (P < .001), and had higher baseline triglycerides (P = .005). Similarly, significant interactions were observed with greater percentage decreases in LDL-C among patients who were younger (P = .03) and had lower baseline LDL-C levels (P = .03).
Adverse event rates and laboratory safety measurements are summarized in Table 5, and achieved blood pressure levels are shown in eFigure 2. Administration of evacetrapib as monotherapy was not associated with an increase in blood pressure compared with placebo. A greater increase in diastolic blood pressure was observed when evacetrapib, 100 mg/d, was administered in combination with simvastatin, 40 mg/d, compared with simvastatin monotherapy (P = .02). No other differences were observed in diastolic or systolic blood pressure changes when evacetrapib was administered in combination with statin therapy. No differences were observed between patients treated with or without evacetrapib with regard to the rate of systolic blood pressure elevations in excess of 15 mm Hg. No significant changes in aldosterone, cortisol, or electrolytes were observed with administration of evacetrapib.
There was no difference between evacetrapib and control groups in either the monotherapy or statin combination studies with regard to the rate of treatment-related adverse events and discontinuation rates. Two significant rashes were observed during the course of the study. One participant treated with simvastatin monotherapy developed angioedema, which resolved with steroids and study drug discontinuation. A second participant treated with evacetrapib, 100 mg/d, in combination with rosuvastatin developed a morbilliform reaction 40 days after cessation of study drug that resolved with conservative measures. Evacetrapib administered as monotherapy or in combination with statin therapy was not associated with significant laboratory abnormalities related to liver, kidney, or muscle toxicity. No adjudicated cardiovascular events were observed during the study.
Current guidelines for lipid-modulating therapy in both primary and secondary prevention populations emphasize reduction in apolipoprotein B–containing atherogenic lipoproteins.14,15 Although this approach has yielded major clinical benefits, residual risk remains substantial16 and has eluded effective treatment for decades. Essentially, no new classes of antiatherosclerotic therapies with clinically proven benefits have emerged since the introduction of statins in 1987. Considerable current interest has focused on drugs that increase HDL-C levels, although these efforts have not yet yielded drugs with benefits on clinical outcomes. Drugs that inhibit CETP produce the largest increases in HDL-C levels and represent a potentially important strategy for addressing residual risk in statin-treated patients.
In the current study, we characterized the lipid efficacy, safety, and tolerability of a novel CETP inhibitor, evacetrapib, in patients with either hypercholesterolemia or low HDL-C levels. The study demonstrated that CETP inhibition with evacetrapib produced marked alterations in important lipoproteins, including large increases in HDL-C levels and decreases in LDL-C levels. The magnitude of these changes was substantial, demonstrating increases in HDL-C levels exceeding 125% and decreases in LDL-C levels exceeding 35% for the highest tested dosage. These HDL-C changes were significantly greater among patients with lower levels of HDL-C or higher triglyceride levels at baseline. Although evacetrapib was well tolerated, the study was underpowered to rule out uncommon adverse effects.
Because of the robust clinical benefits of statins, any new lipid-modulating agent will likely be administered on a background of statin therapy. Accordingly, we tested evacetrapib both as monotherapy and in combination with the most commonly used dosages of the most frequently prescribed statins. In combination with a broad range of statins, evacetrapib produced a similar degree of HDL-C increase compared with evacetrapib monotherapy, reaching 94% for the 100-mg/d dosage. Similarly, while the incremental decreases in LDL-C were predictably smaller in combination with statins than observed with monotherapy, these changes still represented potentially useful effects, resulting in 11% to 14% additional LDL-C lowering. These preliminary findings suggest that evacetrapib could be administered with statins and may yield potentially clinically important incremental effects on lipoproteins. The finding of less LDL-C lowering with evacetrapib monotherapy in patients with higher baseline LDL-C levels needs further investigation.
The initial enthusiasm for CETP inhibitors waned following reports that torcetrapib did not slow disease progression17-19 and increased mortality.9 Some observers postulated that these adverse findings reflected a potential detrimental effect of CETP inhibition on HDL functionality.20 However, subsequent investigations determined that torcetrapib had off-target effects that likely contributed to the observed adverse effect on cardiovascular outcomes.21 Accordingly, there is renewed interest in the pursuit of other CETP inhibitors that lack such off-target effects but retain the favorable lipid effects. Subsequent development of all novel CETP inhibitors has required comprehensive characterization of safety and tolerability. Equipoise for the study of evacetrapib in dyslipidemic patients was provided by the lack of apparent off-target adverse effects in phase 1 studies and the potential of this agent to provide clinically important effects on lipoproteins.
In the current 12-week study, administration of evacetrapib was well tolerated, with a low rate of treatment-related adverse events or discontinuation of therapy. No increase in blood pressure was observed in evacetrapib-treated patients, and no effects on mineralocorticoid and glucocorticoid activity were observed. These data suggest that evacetrapib favorably affects lipoproteins without apparent major toxic effects. Because a few rashes occurred during early-phase studies, we also carefully collected information on skin changes during the current study. No evidence emerged suggesting serious drug eruptions with evacetrapib. However, a full safety assessment of evacetrapib will require exposure of a much larger number of patients.
In addition to standard lipid measurements, we performed a comprehensive analysis of the effects of evacetrapib on the major apolipoproteins carried on HDL particles. Both apolipoproteins A-I and A-II increased substantially with administration of evacetrapib, a finding that likely reflects a predominant increase in concentrations of larger HDL particles as a result of accumulation of cholesteryl ester. A marked increase in circulating apolipoprotein E levels was also observed, which may be relevant because previous reports with torcetrapib demonstrated that apolipoprotein E enrichment of HDL particles was associated with an increase in cholesterol efflux capacity.22
Free cholesterol efflux to HDL particles and subsequent transfer to other lipid particles have been demonstrated to involve highly complex pathways (Figure 2).23 The effects of evacetrapib on HDL subclasses and composition continue to be elucidated, and the impact of this agent on lipid transport would require additional investigations. Although CETP inhibitors have been developed primarily to increase HDL-C levels, more potent members of this class also lower LDL-C.24 The current study demonstrates that evacetrapib has favorable effects on LDL-C and apolipoprotein B in both monotherapy- and statin-treated patients. Although these effects may ultimately translate into cardiovascular benefits, the role of CETP inhibition as a therapeutic strategy to reduce cardiovascular events remains to be established.
Epidemiological studies of the relationship between CETP and cardiovascular risk have shown variable results, with some10 but not all25,26 investigators reporting an association between low CETP activity and protection against cardiovascular disease. Studies in animal models generally show that reduced CETP activity is atheroprotective,11,27,28 but not all animals have lipid metabolic pathways comparable with that of humans. The inability of torcetrapib to slow disease progression in humans raised concerns about HDL functionality. However, there is currently no evidence that CETP inhibitors impair the ability of HDL to promote efflux of cholesterol. Post hoc analysis of torcetrapib trials showed that patients with the largest increases in HDL-C exhibited regression of coronary atherosclerosis29 and fewer cardiovascular events.30
However, a number of other issues remain unresolved. The current study included numerous parallel treatment groups with multiple unadjusted statistical comparisons. While the analysis prespecified a type I error rate of .10 for efficacy measures, additional testing with an error rate of .05 did not alter the findings (eTable 3). Predictably, CETP mass increased, although it is unknown if this has any effect beyond lipid transfer. The optimal degree of CETP inhibition has not been elucidated. Recent speculation suggests that dalcetrapib, a less potent CETP inhibitor, may selectively modulate CETP pathways in a manner that preserves levels of lipid-deplete pre-β HDL.31 However, the cardiovascular effects of this finding remain uncertain. No studies have yet demonstrated that any CETP inhibitor reduces disease progression or promotes plaque regression.
Two additional CETP inhibitors are currently undergoing clinical evaluation. The lipid changes observed with evacetrapib appeared to be more similar to those of anacetrapib, producing substantial elevation of HDL-C and lowering of LDL-C. Evacetrapib, like both anacetrapib and dalcetrapib, appeared to be well tolerated with no discernible adverse effects on blood pressure and mineralocorticoid levels. Ultimately, the benefits of each of these novel CETP inhibitors must be determined through prospective, randomized, clinical outcome trials. The results of the current study provide the foundation for a large phase 3 clinical trial designed to assess the efficacy and safety of evacetrapib.
Corresponding Author: Stephen J. Nicholls, MBBS, PhD, Department of Cardiovascular Medicine, Mail Code JJ-65, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (nichols1@ccf.org).
Author Contributions: Drs Nicholls and Nissen and the Cleveland Clinic Coordinating Center for Clinical Research had full and independent access to all of the data in the study, and Dr Nicholls takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Nicholls, Krueger, Wang, McErlean, Nissen.
Acquisition of data: Wang, McErlean.
Analysis and interpretation of data: Nicholls, Brewer, Kastelein, Krueger, Wang, Shao, Hu, McErlean, Nissen.
Drafting of the manuscript: Nicholls, Wang, Nissen.
Critical revision of the manuscript for important intellectual content: Nicholls, Brewer, Kastelein, Krueger, Wang, Shao, Hu, McErlean, Nissen.
Statistical analysis: Shao, Hu.
Obtained funding: Nicholls, Nissen.
Administrative, technical, or material support: McErlean.
Study supervision: Krueger.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Nicholls reports receiving research support from AstraZeneca, Novartis, Eli Lilly, Anthera, LipoScience, Roche, and Resverlogix and receiving honoraria or serving as a consultant for AstraZeneca, Roche, Esperion, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo-Nordisk, sanofi-aventis, Atheronova, Anthera, CSL Behring, and Boehringer Ingelheim. Dr Brewer reports serving on advisory boards and receiving consulting fees and honoraria from Merck, Pfizer, Abbott, Roche, Eli Lilly, and sanofi-aventis. Dr Kastelein reports serving as a consultant for Eli Lilly, Merck, Roche, Boehringer Ingelheim, Cerenis, Novartis, Genzyme, and Isis. Drs Krueger and Wang are employees of Eli Lilly. Dr Nissen reports receiving research support from AstraZeneca, Eli Lilly, Pfizer, Takeda, Sankyo, and sanofi-aventis. He has consulted for a number of pharmaceutical companies without financial compensation. All honoraria, consulting fees, or any other payments from any for-profit entity are paid directly to charity so that neither income nor any tax deduction is received. No other disclosures were reported.
Funding/Support: The study was funded by Eli Lilly.
Role of the Sponsor: Eli Lilly participated actively in designing the study, developing the protocol, and provided logistical support during the trial. Monitoring of the study was performed by a contract research organization, Quintiles, under contract with the sponsor. The sponsor maintained the trial database. Statistical analysis was performed by statisticians employed by Eli Lilly, although the analyses reported in the article represent those performed by the academic statisticians (Mr Shao and Dr Hu). After completion of the trial, as specified in the study contract, a complete copy of the database was transferred to the Cleveland Clinic Coordinating Center for Clinical Research, where analyses were verified by the independent statisticians, Mr Shao and Dr Hu. The manuscript was prepared by Dr Nicholls and modified after consultation with the coauthors. The sponsor was permitted to review the manuscript and suggest changes, but the final decision on content was exclusively retained by the academic authors.
Independent Statistical Analysis: For the purpose of the academic interpretation of the study, Mr Shao and Dr Hu performed all primary statistical analyses. All results presented in the article were performed by Dr Hu. Mr Shao is an employee of the Cleveland Clinic Coordinating Center for Clinical Research. Dr Hu is a faculty member within the Department of Quantitative Health Sciences at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.
Study Investigators:Data and Safety Monitoring Board: James H. Stein, MD, University of Wisconsin, Madison (chair); George L. Bakris, MD, University of Chicago, Chicago, Illinois; Philip Barter, MD, director, the Heart Research Institute, Sydney, Australia; Pooja Khera, MD, Cleveland Clinic, Cleveland, Ohio; Carl Pepine, MD, University of Florida, Gainesville; Walter Offen, PhD, senior research fellow, Eli Lilly, Indianapolis, Indiana (nonvoting). Participating Investigators for Lilly EIAF: Denmark: CCBR A/S, Vejle (Peter Alexandersen, MD), CCBR A/S, Ballerup (Pernille Lundqvist, MD). Germany: ClinPharm International, Goerlitz, SN (Hartwin Berge, DrMed), Synexus ClinPharm, Leipzig, SN (Elizaveta Degtyareva, MS), Synexus ClinPharm, Berlin, BE (Janna Stoessel, MD), Synexus ClinPharm, Bochum, NW (Andrea Rinke, DrMed), Synexus ClinPharm, Dresden, SN (Hans-Detlev Stahl, DrMed). Netherlands: Andromed, Rotterdam (J. J. C. Jonker, MD), Andromed, Eindhoven (Lindy Diepenmaat, MD), Andromed, Breda (V. Köse, MD), Andromed, Leiden, Leiderdorp (I. Agous, MD), Andromed, Zoetermeer (Miente Everts, MD), Andromed, Oost, Velp (J. Hoogendijk, MD), Andromed, Groningen (Willem Van Kempen, MD), Academisch Medisch Centrum, Amsterdam (Mieke Trip, MD), PreCare Trial and Recruitment, Geleen (V. E. K. M. Van de Walle, MD). Poland: Synexus SCM, Wroclaw (Katarzyna Szymkowiak, MD), Centrum Leczenia Chorob, Warszawa (Magda Dabrowska, MD). United Kingdom: Synexus, Chorley (Ravi Pawa, MD), Synexus, Manchester (Irina Pavel-Knox, MD), Merseyside Clinical Research Centre, Liverpool (Essam Abdulhakim, FRCS, MS, MBChB), Synexus Midland Clinical Research Centre, Birmingham (Rex Sarmiento, MD), Synexus Scotland Clinical Research Centre, Glasgow (Rahul Ellahbadi, MD), Synexus, Reading (Hilary Shaw, MD), Synexus Wales Clinical Research Centre, Cardiff (Hawys Thomas, MD). United States: Jeffrey A. Lindebaum, DO, PC, Yardley, Pennsylvania (Patrick Adler, DO), Great Lakes Medical Research, Westfield, New York (Donald Brautigam, MD), Holston Medical Group, Bristol, Tennessee (Andrew Brockmyre, MD), Hillcrest Clinical Research, Simpsonville, South Carolina (Robert Broker, MD), New West Physicians Clinical Research, Golden, Colorado (Kenneth Cohen, MD), Anderson and Collins Clinical Research, Edison, New Jersey (Harry Collins, MD), Dairyland Medical Center, Red Lion, Pennsylvania (Drake DeHart, DO), Scripps Clinical Research, San Diego, California (Margaret Drehobl, MD), PMG Research of Hickory, Hickory, North Carolina (John Earl, MD), Endwell Family Physicians, Endwell, New York (Victor Elinoff, MD), Radiant Research, Greer, South Carolina (William Ellison, MD), the Research Group of Lexington, Lexington, Kentucky (Neil Farris, MD), Village Research, Houston, Texas (Harold Fields, MD), Mississippi Medical Research, Picayune, Mississippi (Ahmad Haidar, MD), PMG Research of Wilmington, Wilmington, North Carolina (Charles Herring, MD), Alan Hoffman, MD, Houston, Texas, Wichita Clinic, Wichita, Kansas (Kevin Hoppock, MD), Health Trends Research, Baltimore, Maryland (Boris Kerzner, MD), Jacksonville Center for Clinical Research, Jacksonville, Florida (Michael Koren, MD), Progressive Clinical Research, Vista, California (Jon LeLevier, MD), Encompass Clinical Research, Spring Valley, California (Robert Lipetz, DO), Pulmonary Associates of Brandon, Brandon, Florida (Daniel Lorch Jr, MD), PMG Research of Salisbury, Salisbury, North Carolina (Robert McNeill, MD), PMG Research of Charleston, Mt Pleasant, South Carolina (Richard Mills, MD), Family Practice, Stoneboro, Pennsylvania (Joseph Morelli, MD), American Health Network of Indiana, Indianapolis (Thomas Moretto, MD), Holston Medical Group, Kingsport, Tennessee (David Morin, MD), PharmQuest, Greensboro, North Carolina (Alexander Murray, MD), Dean Clinic Oregon, Oregon, Wisconsin (Zorba Paster, MD), Northeast Iowa Medical Education Foundation, Waterloo, Iowa (James Poock, MD), PMG Research of Bristol, Bristol, Tennessee (Stephanie Powell, MD), PMG Research of Charlotte, Charlotte, North Carolina (George Raad, MD), Radiant Research, Dallas, Texas (Michele Reynolds, MD), PMG Research of Raleigh, Raleigh, North Carolina (John Rubino, MD), Medical Associates of Northwest Arkansas, Fayetteville, Arkansas (James Salmon, MD), NorthWest Family and Spinal Clinic, Tacoma, Washington (Kenneth Scherbarth, DO), St Johns Center for Clinical Research, Ponte Vedra, Florida (Erich Schramm, MD), PMG Research of Wilmington, Wilmington, North Carolina (Jonathan Staub, MD), Genesis Research International, Longwood, Florida (Raul Tamayo, MD), PMG Research of Cary, Cary, North Carolina (Martin Van Cleeff, MD), Maine Research Associates, Auburn (Robert Weiss, MD), PMG Research of Winston-Salem, Winston-Salem, North Carolina (Jonathan Wilson, MD), Founders Research Corporation, Philadelphia, Pennsylvania (Gary Yeoman, DO).
Online-Only Material: The Author Video Interview is available here.
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