The cholesteryl ester transfer protein (CETP) inhibitor evacetrapib has been previously shown to increase high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels, as monotherapy or in combination with statins. In this study, 165 Japanese patients with elevated LDL-C or low HDL-C levels were randomly assigned to receive placebo, evacetrapib monotherapy 30 mg, 100 mg, or 500 mg, atorvastatin 10 mg, or evacetrapib 100 mg in combination with atorvastatin 10 mg. After 12 weeks, evacetrapib monotherapy increased HDL-C levels by 74%, 115%, and 136% and decreased LDL-C levels by 15%, 23%, and 22% and CETP activity by 50%, 83%, and 95% (for the 30-mg, 100-mg, and 500-mg dose groups, respectively) versus placebo. In combination with atorvastatin 10 mg, evacetrapib 100 mg increased HDL-C levels by 103% and decreased LDL-C levels by 15% and CETP activity by 68% versus atorvastatin alone. After a 4- to 6-week washout, HDL-C, LDL-C, and CETP mass and activity returned to baseline levels in the evacetrapib-treated groups, and most patients had evacetrapib concentrations below the quantitation limit. Evacetrapib monotherapy or in combination with atorvastatin was not likely to be associated with any significant change in blood pressure and did not have any adverse effects on mineralocorticoid or glucocorticoid measures. Notably, plasma evacetrapib concentrations were mostly undetectable, and all pharmacodynamic biomarkers (HDL-C and LDL-C levels and CETP mass and activity) returned to baseline after a 4- to 6-week washout. In conclusion, evacetrapib as monotherapy or in combination with atorvastatin effectively decreased CETP activity and LDL-C levels and increased HDL-C levels after 12 weeks in Japanese patients with dyslipidemia.
Although pharmacologic inhibition of cholesteryl ester transfer protein (CETP) leads to substantial increase in high-density lipoprotein cholesterol (HDL-C) and significant decrease in low-density lipoprotein cholesterol (LDL-C) levels, torcetrapib resulted in an increased risk of cardiovascular (CV) morbidity and mortality, and dalcetrapib was not different from placebo in reducing CV events. Treatment with torcetrapib, but not with other CETP inhibitors, was also associated with significant increase in blood pressure (BP) and plasma sodium, bicarbonate, and aldosterone levels and decrease in potassium levels. Moreover, recent data show that persistent effects on lipids and residual plasma levels of anacetrapib were observed 12 weeks after cessation of treatment with anacetrapib in the Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib (DEFINE) trial, and similar findings were also reported during a Japanese phase 2b study (8-week treatment with anacetrapib followed by an 8-week off-drug reversal period). Evacetrapib has been shown to inhibit CETP activity both in human plasma and in a human CETP transgenic mouse model, without increases in aldosterone or BP. In a phase 1 study conducted in healthy Japanese subjects, evacetrapib was well tolerated when administered for 14 days over the dose range of 30 to 600 mg and significantly increased HDL-C and decreased LDL-C levels. In a 12-week phase 2 study conducted in the United States and Europe, evacetrapib raised HDL-C levels up to 129% and lowered LDL-C up to 36% in nearly 400 patients with dyslipidemia and was also well tolerated without showing any adverse effect on either BP or mineralocorticoid levels. The present study evaluated efficacy, safety, tolerability, and pharmacokinetic profile of evacetrapib monotherapy at doses up to 500 mg and evacetrapib 100 mg in combination with 10 mg of atorvastatin in Japanese patients with dyslipidemia.
Methods
This study was a multicenter, randomized, double-blind, parallel group, placebo- and active-controlled, phase 2, dose-response study ( ClinicalTrials.gov identifier is NCT01375075 ). The institutional review boards of all participating centers approved the protocol, and all patients provided written informed consent. This 12-week study included placebo, evacetrapib monotherapy (30 mg, 100 mg, or 500 mg), atorvastatin 10 mg monotherapy, or evacetrapib 100 mg in combination with atorvastatin 10 mg, administered orally once daily.
The study included 4 consecutive phases: screening, diet lead-in/washout, treatment, and follow-up. After screening, eligible patients were instructed to discontinue lipid-related medications and begin a diet therapy in accordance with the Japan Atherosclerosis Society guidelines for diagnosis and prevention of atherosclerotic CV disease. The diet lead-in/washout phase was either 2 weeks (for patients not taking any lipid-modifying medication) or 4 weeks (for those undergoing washout of statins, ezetimibe, bile acid sequestrants, ethyl icosapentate, or over-the-counter medications or health foods used to treat lipids).
Patients who remained eligible after following the diet lead-in/washout phase were equally randomized into 1 of the 6 treatment groups: placebo, evacetrapib monotherapy (30 mg, 100 mg, or 500 mg), atorvastatin 10 mg monotherapy, or evacetrapib 100 mg in combination with atorvastatin 10 mg. Randomization was performed by an interactive voice response system and was stratified by baseline levels of serum triglycerides (<150 or ≥150 mg/dl) and HDL-C (<45 or ≥45 mg/dl for men; <50 or ≥50 mg/dl for women). A follow-up visit was conducted 4 weeks (+2-week allowance) after cessation of the study drug.
Men and women aged ≥20 years were included in this study. Eligible patients were required to meet either low HDL-C or high LDL-C lipid criteria. Patients meeting the low HDL-C criteria had an HDL-C level of <45 mg/dl for men or <50 mg/dl for women, plus LDL-C <190 mg/dl (and 0 to 1 risk factors), <160 mg/dl (and 2 risk factors), or <130 mg/dl (and ≥3 risk factors). Patients meeting the high LDL-C criteria had an LDL-C level of >100 mg/dl but <190 mg/dl (and 0 to 1 risk factors), <160 mg/dl (and 2 risk factors), or <130 mg/dl (and ≥3 risk factors). Risk factors were defined as age (men ≥45 years, women ≥55 years), hypertension, diabetes (including impaired glucose tolerance), smoking, family history of coronary artery disease (assessed by the clinical investigator), and low HDL-C (<40 mg/dl). All patients were required to have a fasting triglyceride level of <400 mg/dl.
Patients were excluded if they had any clinical manifestations of coronary heart disease (stable or unstable angina pectoris, acute coronary syndrome, or myocardial infarction) or a coronary revascularization procedure including stent placement, symptomatic carotid artery disease, or symptomatic peripheral arterial disease. Patients were also excluded if they had a systolic blood pressure (SBP) of >140 mm Hg or diastolic blood pressure (DBP) >90 mm Hg, had symptoms consistent with moderate or severe heart failure, or had an electrocardiographic abnormality consistent with QTc prolongation, wide QRS complexes, atrial fibrillation, congenital long QT syndrome, or history of ventricular tachycardia. Other exclusion criteria were recent history of a rash, chronic skin disorder (psoriasis, eczema, or urticaria), or history of any drug-related rash; patients expected to start, or were unwilling to undergo adequate washout of, lipid-modifying therapies (as described previously); and patients taking probucol, fibrate, or nicotinic agents within 8 weeks before screening.
Patients were examined during scheduled visits at weeks 2, 4, 8, and 12 (during the treatment phase), and at the follow-up visit, and were required to fast for at least 8 hours before sample collections. Serum lipid parameters (including total cholesterol, LDL-C, HDL-C, and triglyceride levels) were measured at all visits, and CETP activity and mass were measured at weeks 4, 8, and 12 and at the follow-up visit. Plasma evacetrapib concentrations were also measured before and after dose at weeks 2, 4, 8, and 12 and at the follow-up visit.
Screening laboratory tests were performed locally; all other laboratory tests were performed at a central laboratory (Covance Central Laboratory Services, Indianapolis, Indiana). Plasma concentrations of evacetrapib were measured at Bioanalytical Systems, Inc. (West Lafayette, Indiana) and were assayed using a validated liquid chromatography-tandem mass spectrometry method. 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.
Safety was evaluated by means of adverse event assessment, clinical laboratory tests, vital signs (BP and pulse in sitting position), electrocardiograms, and rash assessment. Rash evaluation included history and examination, rash photography, laboratory assessments, and rash punch biopsy for nonlocalized, clinically significant rashes. Skin biopsies were read by a central dermatopathologist. Rash cases were adjudicated by a central dermatologist blinded to study treatment.
Assuming SDs of 30% and 25% for percent changes in HDL-C and LDL-C, respectively, Pearson correlation coefficient of 0.4 between changes, and a 15% dropout rate of enrolled patients, a sample size of 25 patients randomized to each treatment group (22 completers per treatment group) was calculated to provide 83% power to simultaneously detect a 40% increase from baseline in HDL-C and a 20% decrease from baseline in LDL-C in patients treated with evacetrapib compared with placebo (2-sided t test, significance level 0.1).
The intent-to-treat (ITT) population was defined as randomized patients who received at least 1 dose of study treatment. The modified ITT population consisted of ITT patients who had at least 1 baseline measurement and 1 postbaseline HDL-C measurement. Efficacy analyses were conducted for the active treatment phase on the modified ITT population. Safety analyses were conducted on the ITT population.
The primary efficacy analysis of the primary variables was restricted maximum likelihood–based mixed-effects model for repeated measures with baseline measurement as covariate; treatment, visit (weeks 2, 4, 8, or 12), and treatment-by-visit interaction as fixed effects; and patient as a random effect. Least squares (LS) means, LS mean differences, 90% confidence intervals, and p values were reported by treatment and by visit.
CETP activity and percent change from baseline, as well as CETP mass and change from baseline, were analyzed using a similar mixed-effects model for repeated measures with treatment, visit (weeks 4, 8, or 12), and treatment-by-visit interaction as fixed effects; baseline measurement as a covariate; and patient as a random effect with LS means, LS mean differences, 90% confidence intervals, and p values being reported by treatment and by visit. A mixed-effects model for repeated measures with baseline measurement, treatment, visit, and treatment by visit as independent variables was used to analyze vital signs and laboratory parameters (i.e., mineralocorticoid and electrolytes).
No formal adjustment for multiplicity was made for all planned efficacy and safety analyses. Unless otherwise specified, data were analyzed with a 2-sided significance level of 0.1. Statistical analyses were carried out using SAS (SAS Institute, Cary, North Carolina).
Results
From June 2011 to November 2011, a total of 225 patients were screened at 15 sites in Japan. A total of 165 patients were randomized and a total of 156 patients completed the study by March 2012. The disposition of these patients is shown in Figure 1 . Baseline characteristics of the patients were similar among the different treatment groups studied and are listed in Table 1 . The mean age of patients was 49 years, and 67% of the patients were male. The baseline lipid profile was characterized by mean LDL-C, HDL-C, and triglycerides of 141 mg/dl, 51 mg/dl, and 143 mg/dl, respectively. Sixty-seven of 165 patients (41%) met the low HDL-C criteria (<45 mg/dl for men or <50 mg/dl for women).
| Variable | Placebo (n = 28) | EVA 30 mg (n = 27) | EVA 100 mg (n = 28) | EVA 500 mg (n = 27) | ATO 10 mg (n = 27) | ATO 10 mg plus EVA 100 mg (n = 28) |
|---|---|---|---|---|---|---|
| Age (years), mean ± SD | 50 ± 9.6 | 49 ± 11 | 48 ± 12 | 49 ± 8.1 | 49 ± 8.8 | 50 ± 10 |
| Female | 10 (36%) | 8 (30%) | 10 (36%) | 9 (33%) | 8 (30%) | 10 (36%) |
| Height (cm), mean ± SD | 166 ± 8.6 | 165 ± 9.5 | 165 ± 10 | 167 ± 9.3 | 167 ± 6.8 | 165 ± 8.3 |
| Weight (kg), mean ± SD | 69 ± 14 | 69 ± 14 | 66 ± 12 | 69 ± 16 | 67 ± 13 | 70 ± 18 |
| Body mass index (kg/m 2 ), mean ± SD | 25 ± 3.7 | 25 ± 3.4 | 24 ± 3.2 | 24 ± 4.1 | 24 ± 3.3 | 26 ± 5.5 |
| LDL-C (mg/dL), mean ± SD | 140 ± 27 | 144 ± 24 | 144 ± 23 | 143 ± 30 | 134 ± 32 | 140 ± 20 |
| HDL-C (mg/dL), mean ± SD | 51 ± 14 | 50 ± 13 | 52 ± 16 | 49 ± 11 | 49 ± 14 | 52 ± 14 |
| Triglycerides (mg/dL), median (range) | 119 (47, 303) | 142 (50, 380) | 124 (52, 355) | 134 (55, 379) | 147 (49, 322) | 118 (50, 296) |
Evacetrapib treatment for 12 weeks in Japanese patients with hypercholesterolemia or low HDL-C resulted in statistically significant dose-related increases in HDL-C and decreases in LDL-C. Percent changes in HDL-C, LDL-C, and triglycerides are summarized in Table 2 . The relative changes in HDL-C between evacetrapib monotherapy and placebo were 74%, 115%, and 136% for the 30-mg, 100-mg, and 500-mg treatment groups, respectively. The relative changes in LDL-C between monotherapy and placebo were −15%, −23%, and −22% for the 30-mg, 100-mg, and 500-mg dose groups, respectively. When evacetrapib 100 mg was administered in combination with atorvastatin 10 mg, the magnitude of change in HDL-C (+103%) and LDL-C (−15%) levels relative to atorvastatin alone was similar to that of evacetrapib 100 mg as monotherapy.
| Measures | Placebo (n = 28) | EVA 30 mg (n = 27) | EVA 100 mg (n = 27) | EVA 500 mg (n = 27) | ATO 10 mg (n = 27) | ATO 10 mg plus EVA 100 mg (n = 28) |
|---|---|---|---|---|---|---|
| LDL-C (mg/dL) | ||||||
| Baseline | 140 ± 27 | 144 ± 24 | 145 ± 22 | 143 ± 30 | 134 ± 32 | 140 ± 20 |
| Week 12 | 141 ± 30 | 122 ± 28 | 111 ± 24 | 108 ± 36 | 84 ± 28 | 61 ± 17 |
| Percentage change | 1.2 ± 3.4 | −14 ± 3.5 | −22 ± 3.4 | −21 ± 3.6 | −38 ± 3.4 | −52 ± 3.5 |
| Relative change | −15 (−24, 7.4) ∗ | −23 (−31, 15) ∗∗ | −22 (−30, −14) ∗∗ | −15 (−23, −6.6) ∗∗∗ | ||
| HDL-C (mg/dL) | ||||||
| Baseline | 51 ± 14 | 50 ± 13 | 53 ± 16 | 49 ± 11 | 49 ± 14 | 52 ± 14 |
| Week 12 | 54 ± 16 | 91 ± 27 | 111 ± 30 | 125 ± 34 | 57 ± 14 | 109 ± 30 |
| Percentage change | 8.0 ± 8.8 | 82 ± 8.9 | 123 ± 8.9 | 144 ± 9.2 | 17 ± 8.9 | 121 ± 8.9 |
| Relative change | 74 (53, 95) ∗∗ | 115 (95, 136) ∗∗ | 136 (115, 157) ∗∗ | 103 (82, 124) ∗∗ | ||
| Triglycerides (mg/dL) | ||||||
| Baseline | 119 (47, 303) | 142 (50, 380) | 124 (52, 355) | 134 (55, 379) | 147 (49, 322) | 118 (50, 296) |
| Week 12 | 115 (54, 324) | 123 (59, 392) | 100 (58, 390) | 115 (46, 797) | 88 (50, 231) | 95 (38, 199) |
| Percentage change | 5.1 ± 9.7 | 3.7 ± 9.9 | 12 ± 9.7 | 12 ± 10 | −25 ± 9.7 | −21 ± 10 |
| Relative change | −1.3 (−24, 22) | 6.8 (−16, 30) | 7.0 (−16, 30) | 3.5 (−20, 27) | ||
No statistically significant difference was observed in percent change in fasting triglycerides with evacetrapib monotherapy compared with placebo or with evacetrapib in combination with atorvastatin compared with atorvastatin alone.
Percent changes in CETP activity and CETP mass are summarized in Table 3 . The relative changes in corrected CETP activity between evacetrapib monotherapy and placebo were −50%, −83%, and −95% for the 30-mg, 100-mg, and 500-mg dose groups, respectively. When evacetrapib 100 mg was administered in combination with atorvastatin 10 mg, the decrease in CETP activity relative to atorvastatin alone was −68%. The mean baseline CETP mass was from 2.2 to 2.4 μg/ml for all groups. At 12 weeks, CETP mass decreased (9% on average) in the atorvastatin 10-mg group, whereas it significantly increased in a dose-dependent manner (between 82% and 139% on average) on evacetrapib monotherapy. CETP mass also significantly increased (88% on average) when evacetrapib 100 mg was administered in combination with atorvastatin 10 mg.
| Measures | Placebo (n = 28) | EVA 30 mg (n = 27) | EVA 100 mg (n = 27) | EVA 500 mg (n = 27) | ATO 10 mg (n = 27) | ATO 10 mg plus EVA 100 mg (n = 28) |
|---|---|---|---|---|---|---|
| CETP activity (pmol/mL/min) | ||||||
| Baseline | 22 ± 4.6 | 21 ± 4.3 | 23 ± 4.8 | 23 ± 6.4 | 23 ± 6.2 | 23 ± 6.9 |
| Week 12 | 24 ± 6.1 | 12 ± 4.1 | 5.7 ± 3.3 | 3.1 ± 3.2 | 21 ± 6.7 | 5.7 ± 4.7 |
| Percentage change | 9.2 ± 3.5 | −41 ± 3.6 | −74 ± 3.6 | −85 ± 3.7 | −5.7 ± 3.5 | −73 ± 3.7 |
| Relative change | −50 (−59, −42) ∗ | −83 (−91, −75) ∗ | −95 (−103, −86) ∗ | −68 (−76, −59) ∗ | ||
| CETP mass (μg/mL) | ||||||
| Baseline | 2.3 ± 0.5 | 2.2 ± 0.5 | 2.3 ± 0.4 | 2.3 ± 0.5 | 2.2 ± 0.4 | 2.4 ± 0.5 |
| Week 12 | 2.4 ± 0.5 | 4.2 ± 1.1 | 5.3 ± 1.7 | 5.7 ± 1.7 | 2.0 ± 0.4 | 4.6 ± 1.5 |
| Percentage change | 5.8 ± 11 | 87 ± 31 | 127 ± 55 | 152 ± 71 | −8.6 ± 12 | 93 ± 41 |
| Relative change | 1.8 (1.3, 2.3) ∗ | 2.8 (2.3, 3.3) ∗ | 3.2 (2.7, 3.7) ∗ | 2.1 (1.7, 2.6) ∗ | ||
At the follow-up visit, HDL-C and LDL-C levels ( Figure 2 ) as well as CETP activity and mass ( Figure 3 ) returned to baseline in all evacetrapib monotherapy and evacetrapib-plus-atorvastatin groups. Most of the patients (87%) across all dose groups had evacetrapib concentrations that were below the quantitation limit of the assay (<1.00 ng/ml) at the follow-up visit, while the remaining patients had a concentration near the quantitation limit (from 1.0 to 3.5 ng/ml; 12 of them in the 500-mg and 1 in the 100-mg group; Figure 4 ).
Adverse event rates and important laboratory and BP measurements are summarized in Table 4 . Overall, 65 patients (39%) experienced at least 1 treatment-emergent adverse event (TEAE), but there was no statistically significant difference in the incidence of these TEAEs across the treatment groups. Sixteen patients (9.7%) experienced at least 1 TEAE considered possibly related to study drug, and 5 patients (3.0%) discontinued from the study because of an adverse event. Frequently observed TEAEs were nasopharyngitis (n = 22, 13%), hepatic function abnormality (n = 5, 3.0%), back pain (n = 4, 2.4%), gastroenteritis (n = 3, 1.8%), and headache (n = 3, 1.8%), but there was no statistically significant difference in the incidence of these TEAEs across the treatment groups. During the course of the study, 2 patients experienced treatment-emergent serious adverse events (SAEs). In 1 patient in the evacetrapib 500-mg treatment group, the treatment-emergent SAEs (toxic skin eruption and pyrexia) were judged to be related to the study drug. However, this patient had undergone a tooth extraction and had been treated with several medications, including a cephalosporin, before developing the symptoms. This patient was discontinued from the study as a result of the event. The other patient (in the placebo treatment group) experienced multiple unrelated SAEs caused by a car accident, including sternal fracture, traumatic lung injury, and lumbar vertebral fracture.
| Variable | Placebo (n = 28) | EVA 30 mg (n = 27) | EVA 100 mg (n = 28) | EVA 500 mg (n = 27) | ATO 10 mg (n = 27) | ATO 10 mg plus EVA 100 mg (n = 28) |
|---|---|---|---|---|---|---|
| TEAEs | 9 (32%) | 12 (44%) | 12 (43%) | 11 (41%) | 10 (37%) | 11 (39%) |
| Study drug-related TEAEs | 1 (3.6%) | 4 (15%) | 2 (7.1%) | 3 (11%) | 3 (11%) | 3 (11%) |
| Adverse events leading to discontinuation | 1 (3.6%) | 0 | 0 | 3 (11%) | 0 | 1 (3.6%) |
| Serious adverse events | 1 (3.6%) | 0 | 0 | 1 (3.6%) | 0 | 0 |
| ALT > 3x ULN | 0 | 0 | 0 | 1 (3.7%) | 1 (3.7%) | 1 (3.6%) |
| AST > 3x ULN | 0 | 0 | 0 | 0 | 1 (3.7%) | 1 (3.6%) |
| Creatine kinase >5x ULN | 1 (3.6%) | 1 (3.7%) | 1 (3.6%) | 0 | 1 (3.7%) | 0 |
| Elevation in SBP ≥15 mm Hg | 4 (14%) | 6 (22%) | 5 (18%) | 7 (26%) | 6 (22%) | 5 (18%) |
| Elevation in DBP ≥10 mm Hg | 10 (36%) | 13 (48%) | 7 (25%) | 12 (44%) | 7 (26%) | 9 (32%) |
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