A Phase 3 Randomized Controlled Trial to Evaluate Efficacy and Safety of New-Formulation Zenon (Rosuvastatin/Ezetimibe Fixed-Dose Combination) in Primary Hypercholesterolemia Inadequately Controlled by Statins

Abstract

Objective:

In primary hypercholesterolemia many people treated with statins do not reach their plasma LDL-C goals and are at increased risk of cardiovascular disease (CVD). This study aimed to evaluate efficacy and safety of a new fixed-dose combination (FDC) formulation of rosuvastatin/ezetimibe (R/E) in this population.

Methods:

This was a multicenter, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-arm study of FDC R/E in people with primary hypercholesterolemia at very high risk (VHR) or high risk (HR) of CVD, inadequately controlled with 20 mg or 10 mg stable daily dose of rosuvastatin or equipotent dose of another statin. The primary objective was to demonstrate superiority of FDC R/E versus rosuvastatin monotherapy uptitrated to 40 mg (R40) or 20 mg (R20) in reduction of LDL-C after 6 weeks.

Results:

Randomized VHR participants (n = 244) were treated with R40, R40/E10, or R20/E10; randomized HR participants (n = 208) received R10/E10 or R20. In VHR participants, superiority of R40/E10 and R20/E10 versus R40 was demonstrated on LDL-C percent change from baseline to Week 6 with least squares mean differences (LSMD) of −19.66% (95% CI: −29.48% to −9.84%; P < .001) and −12.28% (95% CI: −22.12% to −2.44%; P = .015), respectively. In HR participants, superiority of R10/E10 over R20 was not demonstrated (LSMD −5.20%; 95% CI: −15.18% to 4.78%; P = .306), despite clinically relevant LDL-C reduction with R10/E10. No unexpected safety findings were reported.

Conclusions:

The results from this study suggest that R/E FDCs improve LDL-C reduction and goal achievement in people with primary hypercholesterolemia inadequately controlled with statins and at VHR/HR of CVD.

Keywords

primary hypercholesterolemia cardiovascular disease rosuvastatin ezetimibe fixed-dose combination

Introduction

Cardiovascular diseases (CVD) are the leading cause of death worldwide. In 2019, 32% of all deaths were due to CVD (an estimated 17.9 million people).¹ Dyslipidemia, especially hypercholesterolemia, is a key factor in the development of CVD.² In blood plasma, most of the total cholesterol (TC) is in the form of low-density lipoprotein cholesterol (LDL-C), which is known to be atherogenic³; increased LDL-C and TC are associated with risk of CVD.⁴ Lipid-lowering therapies like statins which reduce endogenous cholesterol synthesis⁵ have been shown to reduce the risk of CVD, yet many patients at risk of coronary heart disease do not achieve recommended LDL-C goals on statin monotherapy, as shown by results from the DYSIS and DA VINCI studies.^6
-8

The European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) dyslipidemia guidelines recommend addition of ezetimibe, a cholesterol absorption inhibitor, to statin therapy for patients with dyslipidemias not adequately controlled with statin monotherapy.⁵ Ezetimibe monotherapy in patients with hypercholesterolemia reduces LDL-C by 15% to 22% and addition of ezetimibe to previous statin therapy reduces LDL-C by a further 21% to 27%.⁵ Moderate-intensity and high-intensity statin monotherapy are expected to reduce LDL-C on average by approximately 30% and 50%, respectively, while combination therapy with highintensity statin plus ezetimibe is expected to reduce LDL-C by approximately 65%.⁵ The EAS Task Force recommends statin-ezetimibe combination therapy be given upfront to patients diagnosed with dyslipidemia at very high risk of CVD to enable them to reach LDL-C goals as early as possible.^9
-11 Statin-ezetimibe combination therapy has been shown to improve LDL-C reduction in diverse patient populations.^12

-16 The IMPROVE-IT study demonstrated that ezetimibe added to simvastatin therapy significantly lowered risk of death from cardiovascular causes and risk of major cardiovascular events compared with simvastatin monotherapy.¹⁶ In the ACTE study, a 6-week, randomized, double-blind clinical trial in adults with hypercholesterolemia, rosuvastatin-ezetimibe treatment resulted in a significantly greater reduction in LDL-C versus doubling the dose of rosuvastatin (15.2% difference, P < .001).¹⁷

Rosuvastatin/ezetimibe (R/E) (Zenon^®, Sanofi, Paris, France) is a fixed-dose combination (FDC), currently indicated as a substitution therapy in patients already treated and adequately controlled with rosuvastatin and ezetimibe. FDCs provide patients with simplified treatment regimens which can improve patient adherence.^18,19 This study aimed to evaluate the efficacy and safety of R/E FDC in people with primary hypercholesterolemia not adequately controlled on rosuvastatin.

Methods

Study Design

This was a Phase 3, multicenter, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-arm study (EudraCT number: 2016-004556-30) of FDC R/E in people with primary hypercholesterolemia at very high risk (VHR; n = 244) or high risk (HR; n = 208) of CVD not adequately controlled with a 20-mg (VHR) or 10-mg (HR) stable daily dose of rosuvastatin or equipotent statin, without any other lipid-modifying therapy (LMT). Patients were screened at 72 centers in Bulgaria, Czech Republic, Italy, Mexico, Poland, Russia, Slovakia, and Ukraine. The study was conducted in accordance with consensus ethics principles derived from international ethics guidelines, including the Declaration of Helsinki, and the ICH guidelines for Good Clinical Practice (GCP), all applicable laws, rules, and regulations. Participants gave signed written informed consent prior to enrolling in the study. The protocol and informed consent were reviewed and approved by local Institutional Review Boards or Ethics Committees. The first participant was enrolled on October 25, 2018, and Study Completion Date was March 4, 2021.

Patients were assigned to the VHR stratum or HR stratum based on the investigators’ assessment. Patients at VHR were defined as those with any of the following: documented clinical CVD; unequivocally documented CVD on imaging including significant plaque on coronary angiography or carotid ultrasound; diabetes mellitus with target organ damage such as proteinuria or with a major risk factor such as smoking, marked hypercholesterolemia, or marked hypertension; severe chronic kidney disease (CKD; glomerular filtration rate [GFR] <30 mL/min/1.73m²); a Systematic Coronary Risk Evaluation (SCORE) value for 10-year risk of first fatal CVD of ≥10% prior to commencing LMT.²⁰

Patients at HR of CVD were defined as those with any of the following: markedly elevated single risk factor, in particular cholesterol >8 mmol/L (310 mg/dL) or blood pressure ≥180/110 mmHg; diabetes mellitus patients other than those at VHR (with the exception of young patients with type 1 diabetes mellitus and patients without major risk factors being at low or moderate CV risk); moderate CKD (GFR ≥30-≤59 mL/min/1.73m²); a SCORE value of ≥5% to <10% for 10-year risk of first fatal CVD.²⁰

FDC R/E was evaluated in 3 doses of rosuvastatin (10 mg, 20 mg, and 40 mg) combined with 10 mg of ezetimibe. The primary objective of the study was to demonstrate the superiority of R40/E10 compared to R40 monotherapy, and superiority of R20/E10 and R10/E10 compared to uptitration to rosuvastatin 40 mg (R40) and R20, respectively, in the reduction of LDL-C after 6 weeks. Secondary objectives were to compare R10/E10 and R20/E10 to run-in treatments rosuvastatin 10 mg (R10) and R20, respectively, in terms of reduction of LDL-C; to evaluate the proportion of participants who attained their LDL-C target; to evaluate the effect of all FDC formulations on other lipid parameters, and to evaluate the safety of all FDC formulations.

The study included a 2-week screening period, a 6-week stabilization run-in period, a 6-week randomized double-blind period, and a 2-week safety follow-up period (Supplementary Figure 1). The screening period with a Screening Visit (V1) was performed between Week −8 and Week −6. The main goal of the stabilization run-in period was to ensure that statin treatment was harmonized and a stable dose of rosuvastatin was administered for 6 weeks prior to randomization in the double-blind treatment period. At the Open-Label Stabilization Visit (V2, Week −6), participants were eligible for enrollment in the stabilization run-in period based on their LDL-C levels measured at the Screening Visit. Rosuvastatin was assigned as an open-label treatment to the eligible participants based on their CVD risk: VHR participants received one R20 tablet daily and HR participants received one R10 tablet daily.

A Qualifying Visit (V3) was performed at Week −1 to obtain the lipid parameters required to assess eligibility for randomization. After the stabilization period, participants not adequately controlled were included in the randomized double-blind treatment period, with a Randomization Visit (V4) and End-of-Treatment (EOT) Visit (V5). Eligibility into this period was based on the LDL-C level measured at the Qualifying Visit (V3). Randomization was performed separately for VHR and HR strata using an interactive response technology to allocate numbered treatment kits and was stratified by country. VHR participants with LDL-C ≥70 to ≤160 mg/dL (1.8-4.1 mmol/L) were randomized 1:1:1 to receive R20/E10, R40/E10, or R40 monotherapy. HR participants with LDL-C ≥100 to ≤190 mg/dL (2.6-4.9 mmol/L), were randomized 1:1 to receive R10/E10 or R20 monotherapy. The EOT Visit (V5, Week 6) was followed by a safety follow-up period and an End-of-Study Visit (V6, Week 8). The visit windows were of ±3 days. The study duration per participant was approximately 16 weeks.

Study Population

Inclusion criteria for entering the study were: VHR patients who had been receiving a stable dose of either R20 or atorvastatin 80 mg for at least 6 weeks prior to the Screening Visit, without any other LMT, and HR participants who had been receiving a stable dose of R10, simvastatin 80 mg or atorvastatin 40 mg for at least 6 weeks prior to the Screening Visit, without any other LMT; age ≥18 years or legal age of majority; diagnosis of primary hypercholesterolemia. The inclusion criterion related to LDL-C thresholds for the run-in period was hypercholesterolemia not adequately controlled based on sample taken at the Screening Visit. Inclusion criteria for the randomized period were hypercholesterolemia not adequately controlled based on sample taken at the Qualifying Visit, despite stabilized dose of rosuvastatin: VHR patients with LDL-C ≥70 to ≤160 mg/dL (1.8-4.1 mmol/L), and HR patients with LDL-C ≥100 to ≤190 mg/dL (2.6-4.9 mmol/L).

The main exclusion criteria were: homozygous familial hypercholesterolemia; unstable angina, myocardial revascularization, coronary artery bypass graft surgery, stroke, or surgical intervention for peripheral vascular disease, within the past 3 months; presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins; history of statin-induced myopathy or rhabdomyolysis; known history of hypersensitivity reaction to statins and/or ezetimibe. A full list of exclusion criteria is included in Supplementary Table 1.

Study Outcomes

The primary efficacy endpoint was the percent change in calculated LDL-C from baseline to Week 6 in the modified intent-to-treat (mITT) population. The comparisons between treatment groups were performed independently in the VHR and HR populations. The secondary efficacy endpoints included: percent change in calculated LDL-C from baseline to Week 6 in participants treated with R20/E10 (VHR) and R10/E10 (HR) versus the run-in rosuvastatin treatments (R20 or R10); achievement of LDL-C goals at Week 6 (<70 mg/dL [1.8 mmol/L] for VHR and <100 mg/dL [2.6 mmol/L] for HR participants); percent change from baseline to Week 6 in TC, high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) plasma levels from baseline to Week 6. Non-HDL-C was calculated post hoc. Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory safety parameters, vital signs, and physical examinations.

After the start of the recruitment period, an exploratory endpoint was added in reference to the attainment of the new LDL-C goals, as recommended by the ESC and the EAS 2019 Guidelines for the Management of Dyslipidemias (i.e., an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <1.4 mmol/L (<55 mg/dL) for VHR patients and an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <1.8 mmol/L (<70 mg/dL) for HR patients).⁵

Statistical Analysis

A total of 71 patients per treatment arm (355 total) were required to achieve a power of 97% to detect a difference for each pairwise comparison using a 2-sample t-test with 2-sided 5% alpha and assuming a common standard deviation (SD) of 20%. Assuming drop-out rates of 40% in the run-in period and 10% in the randomized treatment period, approximately 658 participants were planned to be included in the run-in period, and 395 participants (79 per arm) were planned to be randomized.

The randomized population included any participant who had signed their informed consent and had been allocated to a randomized treatment arm on an intent-to-treat basis. The primary efficacy analysis population was the mITT population defined as all participants in the randomized population with an evaluable primary efficacy endpoint. The primary efficacy endpoint was considered evaluable when both baseline and Week 6 calculated LDL-C values were available. The double-blind safety population was defined as all patients in the randomized population who received any dose of the double-blind investigational medicinal product (IMP), analyzed according to the treatment received. The run-in safety population was defined as all participants who received any dose of the open-label statin IMP, analyzed according to the open-label treatment received.

The VHR and HR strata were analyzed separately for all endpoints. Continuous data were summarized descriptively for each treatment group. Categorical and ordinal data were summarized using the number and percentage of participants in each treatment group. Participants with missing data were not counted in the percentages and not displayed.

Multiplicity Adjustment

VHR and HR were independent strata and conclusions were drawn independently for each stratum; therefore, no adjustment of the overall significance level was needed. To handle multiple primary or secondary endpoints, the overall Type-I error was controlled using a hierarchical inferential approach (Supplementary Figure 2). For the primary endpoint within the VHR stratum, the primary comparison tested first was R40/E10 versus R40. The comparison R20/E10 versus R40 was tested as a second step only if the null hypothesis for the first comparison was rejected. For multiple secondary endpoints, statistical significance of the primary analysis at the 0.05 alpha level was required for a given stratum before drawing inferential conclusions about the first secondary endpoint for that stratum. Inferential conclusions about successive secondary endpoints required statistical significance of the prior one for the corresponding stratum. This fixed hierarchical approach ensured a strong control of the overall Type-I error rate at the P < .05 level.

Analyses of Efficacy Endpoints

Primary efficacy endpoint

Percent change from baseline in calculated LDL-C at Week 6 was analyzed in the mITT population using an analysis of covariance (ANCOVA) model with treatment arm as a fixed effect, and country and baseline LDL-C value as continuous covariates. The primary pairwise comparisons were as follows: VHR stratum: R40/E10 versus R40 and R20/E10 versus R40; HR stratum: R10/E10 versus R20. This model provided adjusted least squares (LS) mean estimates at Week 6 for all treatment arms and the differences of these estimates for each primary pairwise comparison with their corresponding standard errors (SEs) and 95% confidence intervals (CIs).

Secondary efficacy endpoints

Percent changes in calculated LDL-C from baseline to Week 6 in participants treated with R10/E10 and R20/E10 versus the respective rosuvastatin mono component were calculated with 95% CI. Superiority of FDC over rosuvastatin monotherapy was demonstrated if the value 0 was not included in the 95% CI. The proportion of patients achieving LDL-C goal at Week 6 (LDL-C <70 mg/dL for VHR stratum and <100 mg/dL for HR stratum) was compared between treatment arms using a logistic regression adjusted by country and by baseline LDL-C value. This model estimated the odds ratio and 95% CI of FDC versus rosuvastatin monotherapy. Percent changes from baseline to Week 6 in TC, HDL-C, or TG plasma levels were analyzed using ANCOVA, with treatment arm as fixed effect, and country and baseline values as continuous covariates.

Results

Participant Disposition

Overall, 675 VHR and 778 HR participants were screened; of those, 355 (52.6%) VHR participants and 403 (51.8%) HR participants were screen failures, respectively (Supplementary Figure 3, Supplementary Table 2). 244 VHR participants and 208 HR participants were randomized. Seven participants discontinued the treatment period due to AEs: 3 (3.8%) VHR participants in the R40/E10 group, 2 (2.4%) VHR participants in the R20/E10 group, and 2 (1.9%) HR participants in the R20 group. One VHR participant each in the R40/E10 group and R40 group prematurely discontinued treatment due to “other reason” not related to safety.

Baseline Characteristics

Baseline demographic and disease characteristics were generally well balanced between the treatment groups of each stratum (Table 1). In the VHR stratum, median age was 61 years (range 24-84 years) and a higher proportion of participants were male (56.6%). The mean BMI at baseline was 29.1 kg/m² and 80.7% of VHR participants were overweight or obese. In the HR stratum, median age was 58 years (range 18-81 years) and a higher proportion of participants were females (63.0%). In this stratum, 79.3% of participants were overweight or obese (mean BMI 29.1 kg/m²). Duration of hypercholesterolemia in the VHR stratum was 6.3 (SD 5.63) years, while in the HR stratum it was 4.2 (SD 5.20) years. The most common CVD-related health conditions in the VHR stratum were hypertension (81.1% of participants), myocardial infarction (45.1%), diabetes mellitus (39.8%), and heart failure (29.5%). The most common CVD-related health conditions in the HR stratum were hypertension (83.7% of participants), heart failure (25%), and diabetes mellitus (22.6%). Of note, investigators assigned patients with heart failure to either stratum based on the VHR and HR definitions.

Table 1.

1. Baseline Characteristics.

	VHR				HR
	R40/E10 (N = 79)	R20/E10 (N = 82)	R40 (N = 83)	All (N = 244)	R10/E10 (N = 104)	R20 (N = 104)	All (N = 208)
Age (years), mean (SD)	62.9 (8.8)	58.9 (9.8)	60.8 (11.1)	60.8 (10.1)	56.7 (11.1)	57.4 (10.1)	57.1 (10.6)
Sex (male), n (%)	45 (57.0)	51 (62.2)	42 (50.6)	138 (56.6)	35 (33.7)	42 (40.4)	77 (37.0)
Race, n (%)
White	79 (100)	81 (98.8)	83 (100)	243 (99.6)	104 (100)	104 (100)	208 (100)
Not reported	0 (0)	1 (1.2)	0 (0)	1 (0.4)	0 (0)	0 (0)	0 (0)
Weight (kg), mean (SD)	81.9 (17.2)	83.1 (16.4)	79.2 (18.0)	81.4 (17.2)	80.7 (15.2)	82.9 (16.0)	81.8 (15.6)
BMI (kg/m²), mean (SD)	29.4 (4.7)	29.4 (4.2)	28.5 (5.3)	29.1 (4.8)	28.7 (4.9)	29.5 (5.2)	29.1 (5.1)
BMI category, n (%)
<25	13 (16.5)	13 (15.9)	21 (25.3)	47 (19.3)	27 (26.0)	16 (15.4)	43 (20.7)
25-30	33 (41.8)	36 (43.9)	33 (39.8)	102 (41.8)	40 (38.5)	45 (43.3)	85 (40.9)
30-35	24 (30.4)	23 (28.0)	21 (25.3)	68 (27.9)	25 (24.0)	30 (28.8)	55 (26.4)
≥35	9 (11.4)	10 (12.2)	8 (9.6)	27 (11.1)	12 (11.5)	13 (12.5)	25 (12.0)
Hypercholesterolemia duration, years, mean (SD)	6.4 (6.17)	5.6 (4.55)	7.1 (5.99)	6.3 (5.63)	3.8 (4.42)	4.5 (5.87)	4.2 (5.20)
Cardiovascular medical history, n (%)
Hypertension	64 (81.0)	64 (78.0)	70 (84.3)	198 (81.1)	85 (81.7)	89 (85.6)	174 (83.7)
Myocardial infarction	34 (43.0)	40 (48.8)	36 (43.4)	110 (45.1)	0 (0)	0 (0)	0 (0)
Familial history of coronary artery disease	23 (29.1)	14 (17.1)	15 (18.1)	52 (21.3)	8 (7.7)	11 (10.6)	19 (9.1)
Diabetes mellitus	37 (46.8)	33 (40.2)	27 (32.5)	97 (39.8)	23 (22.1)	24 (23.1)	47 (22.6)
Type 2	37 (100)	33 (100)	27 (100)	97 (100)	23 (100)	24 (100)	47 (100)
Heart failure	26 (32.9)	20 (24.4)	26 (31.3)	72 (29.5)	23 (22.1)	29 (27.9)	52 (25.0)
Prior lipid-modifying therapy
Rosuvastatin (10 or 20 mg)	41 (51.9)	46 (56.1)	43 (51.8)	130 (53.3)	71 (68.3)	73 (70.2)	144 (69.2)
Atorvastatin (40 or 80 mg)	38 (48.1)	36 (43.9)	40 (48.2)	114 (46.7)	32 (30.8)	31 (29.8)	63 (30.3)
Simvastatin (80 mg)	0 (0)	0 (0)	0 (0)	0 (0)	1 (1.0)	0 (0)	1 (0.5)
LDL-C, mmol/L, mean (SD)	2.419 (0.618)	2.613 (0.577)	2.447 (0.653)		3.197 (0.786)	3.121 (0.802)

Abbreviations: BMI, body mass index; E10, ezetimibe 10 mg; HR, high risk; LDL-C, low-density lipoprotein cholesterol; R10, rosuvastatin 10 mg; R20, rosuvastatin 20 mg; R40, rosuvastatin 40 mg; SD, standard deviation; VHR, very high risk.

Efficacy Outcomes

LDL-C change from baseline to Week 6

In the VHR stratum, superiority of R40/E10 and R20/E10 over R40 was demonstrated with LS mean differences of LDL-C percent change −19.66% [95% CI: −29.48, −9.84] (P < .001) and −12.28% [−22.12, −2.44] (P = .015), respectively (Figure 1). The mean percent change in LDL-C from baseline to Week 6 was (LS mean [95% CI]) −34.28% [−41.54, −27.02] for the R40/E10 group, −26.90% [−33.99, −19.81] for the R20/E10 group, and −14.62% [−21.78, −7.46] for the R40 group.

Figure 1.

LDL-C change from baseline to Week 6 (mITT population). R40/E10: n = 78; R20/E10: n = 79; R40: n = 78; R10/E10: n = 97; R20: n = 97. Error bars represent standard error. *Statistically significant per fixed hierarchical approach used to ensure strong control of overall type-I error rate at 0.05. E10, ezetimibe 10 mg; HR, high risk; LDL-C, low-density lipoprotein cholesterol; LS, least squares; LSMD, least squares mean difference; R10, rosuvastatin 10 mg; R20, rosuvastatin 20 mg; R40, rosuvastatin 40 mg; SE, standard error; VHR, very high risk.

The superiority of R10/E10 over R20 in the HR stratum was not demonstrated (LS mean [95% CI] difference of LDL-C percent change −5.20% [−15.18, 4.78] (P = .306) (Figure 1). While the mean percent change from baseline to Week 6 in LDL-C was numerically greater in the R10/E10 group (LS mean: −27.02% [−35.19, −18.85]) than that in the R20 group (LS mean: −21.82 [−30.20, −13.44]), the difference was not statistically significant. The hierarchical testing procedure was stopped at this stage in the HR stratum and, therefore, superiority for subsequent secondary endpoints was not evaluated in this stratum.

Percent change in LDL-C levels from baseline to Week 6 in participants randomized to the R10/E10 and R20/E10 groups versus rosuvastatin monotherapy (treatment effect after switching from rosuvastatin monotherapy to FDC R/E)

In the VHR stratum, there was a significant LDL-C reduction from baseline to Week 6 in the R20/E10 group (Figure 2, mean [95% CI]: −29.25% [−36.84, −21.65]; P < .001) representing the treatment effect on LDL-C level for patients switching from R20 (received during the run-in period) to R20/E10 (received during the double-blind period). For HR participants, there was a clinically relevant reduction in LDL-C from baseline to Week 6 in the R10/E10 group (Figure 2; mean: −25.03% [−33.89, −16.17]; nominal P < .001) representing the treatment effect on LDL-C level for patients switching from R10 (received during the run-in period) to R10/E10 (received during the double-blind period).

Figure 2.

LDL-C change from baseline to Week 6 with R20/E10 or R10/E10 versus run-in treatment (R20 or R10; mITT population). R20/E10: n = 79; R10/E10: n = 97. Error bars represent standard error. *Statistically significant per fixed hierarchical approach used to ensure strong control of overall type-I error rate at 0.05. E10, ezetimibe 10 mg; HR, high risk; LDL-C, low-density lipoprotein cholesterol; R10, rosuvastatin 10 mg; R20, rosuvastatin 20 mg.

Proportion of participants achieving LDL-C target at Week 6

The proportion of VHR participants with LDL-C <70 mg/dL at Week 6 was significantly greater (P < .001) in the R40/E10 group (76.9%) than in the R40 group (41.0%). The proportion of VHR participants with LDL-C <70 mg/dL at Week 6 was also significantly greater (P < .001) in the R20/E10 group (59.5%) than in the R40 group (41.0%). Therefore, superiority of R40/E10 and R20/E10 over R40 was demonstrated for this endpoint. The proportion of HR participants with LDL-C <100 mg/dL at Week 6 was greater in the R10/E10 group (66.0%) than in the R20 group (55.7%) (Figure 3A).

Figure 3.

Attainment of LDL-C goals (mITT population). A, Proportion of participants attaining target LDL-C <70 mg/dL at Week 6 in VHR stratum, and LDL-C <100 mg/dL at Week 6 in HR stratum. B, Proportion of participants attaining LDL-C updated <55 mg/dL in VHR stratum and <70 mg/dL in HR stratum (updated EAS/ESC 2019 guidelines; exploratory outcome). *Statistically significant per fixed hierarchical approach used to ensure strong control of overall type-I error rate at 0.05. CI, confidence interval; E10, ezetimibe 10 mg; HR, high risk; LDL-C, low-density lipoprotein cholesterol; n, number of participants; OR, odds ratio; R10, rosuvastatin 10 mg; R20, rosuvastatin 20 mg; R40, rosuvastatin 40 mg; VHR, very high risk.

As per the updated 2019 guidelines,⁵ the new LDL-C targets (defined as <55 mg/dL for VHR patients and <70 mg/dL for HR patients) were assessed in participants at Week 6. The proportion of VHR participants with LDL-C <55 mg/dL at Week 6 was greater in both the R40/E10 group (51.3%) and the R20/E10 group (35.4%) than in the R40 group (24.4%) (Figure 3B). The proportion of HR participants with LDL-C <70 mg/dL at Week 6 was greater in the R10/E10 group (39.2%) than in the R20 group (32.0%).

Change from baseline to Week 6 in TC, HDL-C, TG, and non-HDL-C (mITT population)

TC, HDL-C, and TG were tested simultaneously at the same level, as per the hierarchical testing procedure. In the VHR stratum, the percent change in TC from baseline to Week 6 was numerically greater in the R40/E10 group versus R40 group and numerically greater in the R20/E10 group versus R40 group (Figure 4A). In the HR stratum, percent change in TC was slightly greater in the R10/E10 group versus R20 group. In the VHR stratum, HDL-C was slightly reduced from baseline to Week 6 with R40/E10 (LS mean percent change −2.66%), and R20/E10 (−0.23%), and slightly increased with R40 (+2.27%) (Figure 4B). HDL-C was slightly increased in both HR groups (+1.25% for R10/E10 and +2.10 for R20). In the VHR stratum, there was a numerically greater reduction in TG for R40/E10 versus R40 and for R20/E10 versus R40 (Figure 4C). In the HR stratum, there was a numerically greater reduction in TG with R10/E10 than with R20.

Figure 4.

Change from baseline to Week 6 in (A) TC, (B) HDL-C, (C) TG, and (D) Non-HDL-C (mITT population). R40/E10: n = 78; R20/E10: n = 79; R40: n = 78; R10/E10: n = 97; R20: n = 97. E10, ezetimibe 10 mg; HR, high risk; LDL-C, low-density lipoprotein cholesterol LS, least squares; LSMD, least squares mean difference; R10, rosuvastatin 10 mg; R20, rosuvastatin 20 mg; R40, rosuvastatin 40 mg; SE, standard error; VHR, very high risk.

In the VHR stratum, the percent change in non-HDL-C from baseline to Week 6 was numerically greater in the R40/E10 group versus R40 group and in the R20/E10 group versus R40 group (Figure 4D). In the HR stratum, the percent change in non-HDL-C was slightly greater in the R10/E10 group versus R20 group.

Post hoc analysis: Change in LDL-C levels from baseline to Week 6 excluding outliers

After the database lock, a review of individual data distribution for the LDL-C percent change across all treatment arms revealed 2 outliers (1 participant in the R10/E10 group [LDL-C percent change: +297%] and 1 participant in the R40/E10 group [LDL-C percent change: +223%]). The next highest LDL-C percent change observed in mITT population across all treatment groups was +83.8%. Individual LDL-C percent change from baseline per treatment group in each stratum is presented in Supplementary Figure 4. Although every effort was made to identify the reasons for these outlier values, the results provided no clarity. To assess the potential impact of these values on the primary analysis, a post hoc analysis (a repeat of primary analysis after exclusion of outliers) was conducted.

The superiority of FDC (R40/E10 or R20/E10) over R40 was demonstrated in the VHR stratum with LS mean differences of LDL-C percent change −22.98% [95% CI: −31.45, −14.51] (P < .001) and −12.58% [−21.04, −4.13%] (P = .004), respectively. The mean percent change in LDL-C from baseline to Week 6 was (LS mean [95% CI]): −38.32% [−44.62, −32.02] for the R40/E10 group, −27.92% [−34.02, −21.83] for the R20/E10 group, and −15.34% [−21.50, −9.18] for the R40 group.

The superiority of R10/E10 over R20 was demonstrated in HR participants (LS mean difference of LDL-C percent change −8.84% [−16.61, −1.07]; P = .026). The mean percent change in LDL-C from baseline to Week 6 was (LS mean [95% CI]) −29.84% [−36.19, −23.48] for the R10/E10 group and −21.00% [−27.49, −14.50] for the R20 group. This analysis demonstrated the impact of outlier values on LS means estimates.

Safety Outcomes in the Treatment Period

During the run-in period, almost all participants were treated for more than 5 weeks (mean duration of rosuvastatin exposure was 42.4 days for VHR and 42.7 days for HR participants); mean treatment compliance was 99.8% for VHR and 99.7% for HR participants. During the double-blind period, >96% of the VHR and >99% of the HR participants were treated for more than 5 weeks, with a similar mean duration of rosuvastatin exposure across treatment groups in both strata (VHR: R40/E10: 41.9 days; R20/E10: 42.0 days; and R40: 42.3 days; HR: R10/E10: 42.7 days and R20: 42.3 days). One participant was treated with double-blind IMP without being randomized. Mean treatment compliance during the double-blind period was >98% in all treatment groups. In the VHR stratum, the percentage of participants with study drug compliance ≥80% was 98.7% in the R40/E10 group, and 100% in the R20/E10 and R40 groups. In the HR stratum, study drug compliance ≥80% was 100% in the R10/E10 group and 99.0% in the R20 group. No participant received study medication at a dose greater than the planned dose.

No unexpected safety findings were reported during the study. In the VHR stratum, 1 (1.2%) participant in the R20/E10 group experienced a serious TEAE (chronic pyelonephritis), which was not considered related to study medication (Table 2). Three (3.8%) participants in the R40/E10 group and 2 (2.4%) participants in the R20/E10 group experienced TEAEs leading to treatment discontinuation. In the HR stratum, in the R20 group, 2 (1.9%) participants experienced a serious TEAE and 2 (1.9%) participants experienced a TEAE leading to treatment discontinuation. One TEAE with a fatal outcome (not related to study medication) was reported in the R20 group (pulmonary embolism that occurred following femur fracture). One (1.0%) participant in each HR treatment group experienced an adverse event of special interest (AESI) during the double-blind period (creatine kinase level >3 × upper limit of normal [ULN]). The event in the R10/E10 group was deemed related to study medication and did not resolve until the last available report.

Table 2.

Treatment-Emergent Adverse Events During the Treatment Period (Double-blind Safety Population).

	VHR			HR
n (%)	R40/E10, N = 79	R20/E10, N = 82	R40, N = 83	R10/E10, N = 104	R20, N = 104
Any TEAE	15 (19.0)	15 (18.3)	9 (10.8)	16 (15.4)	21 (20.2)
Any serious TEAE	0 (0)	1 (1.2)	0 (0)	0 (0)	2 (1.9)
Any AESI	2 (2.5)	1 (1.2)	2 (2.4)	1 (1.0)	1 (1.0)
Any TEAE related to double-blind IMP	3 (3.8)	2 (2.4)	3 (3.6)	7 (6.7)	6 (5.8)
Any TEAE leading to death	0 (0)	0 (0)	0 (0)	0 (0)	1 (1.0)
Any TEAE leading to premature double-blind IMP discontinuation	3 (3.8)	2 (2.4)	0 (0)	0 (0)	2 (1.9)

Abbreviations: AESI, adverse event of special interest; E10, ezetimibe 10 mg; HR, high risk; IMP, investigational medicinal product; n, number of participants; R10, rosuvastatin 10 mg; R20, rosuvastatin 20 mg; R40, rosuvastatin 40 mg; TEAE, treatment-emergent adverse event; VHR, very high risk.

In each stratum, the proportion of participants with any TEAE related to double-blind study medication was comparable between the treatment groups. Overall, TEAEs related to double-blind study medication were mainly gastrointestinal, experienced by 1 (1.2%) participant in the R20/E10 group, 2 (2.4%) in the R40 group, and 5 (4.8%) in each the R10/E10 group and the R20 group. The most common gastrointestinal TEAE related to double-blind study medication was dyspepsia occurring in 1 (1.2%) in the R20/E10 group and 4 (3.8%) participants in the R10/E10 group. No clinically meaningful abnormalities in laboratory assessments or vital signs were observed.

Discussion

This study demonstrated the superiority of the FDC in comparison to the maintenance with the same dose of statin, as well as the superiority of the FDC versus doubling the statin dose in the VHR stratum. The superiority of R40/E10 and R20/E10 over R40 in reducing LDL-C was demonstrated in VHR participants, with clinically meaningful decreases in LDL-C after 6 weeks’ treatment. Clinically relevant decreases in LDL-C were observed in HR participants, but superiority of R10/E10 over R20 was not demonstrated.

Several factors could have contributed to the incapacity to demonstrate the superiority of R10/E10 over R20 in the HR stratum. Firstly, the observed LDL-C reduction in the R20 treatment group was higher than expected (21.82%). In the ACTE study, which had a similar design (4 to 5-week stabilization run-in with R10), the LS mean change from baseline to Week 6 with R20 was only −6.3% versus −23.7% for R10/E10.¹⁷ Furthermore, the variability of the LDL-C change was higher than expected (SEs 4.14% and 4.25% observed in each arm correspond to SD ≈40%, compared to 20% used in the sample size calculation). Another contributing factor could be the outlier data from 1 participant in the R10/E10 group with an LDL-C increase of +297%, the reason for which is unknown. There was an unexpected decrease in LDL-C at baseline much below the overall thresholds and in contrast an increase at the end of the double-blind period. The post hoc analysis excluding outlier values demonstrated superiority of R10/E10 over R20 in the HR stratum.

The secondary endpoints showed consistent treatment effect on LDL-C, in terms of reduction in LDL-C after switching from rosuvastatin monotherapy and proportion of participants attaining the recommended LDL-C goal. Relevant decreases were also observed for T and TG plasma levels, although superiority of FDC over rosuvastatin monotherapy could not be demonstrated for TC, HDL-C, or TG following the hierarchical testing procedure. There were no unexpected safety findings and no notable differences across treatment groups in the frequency of TEAEs, including serious TEAE and AESIs.

The proportion of patients with heart failure in the HR stratum (25%) was greater than expected, and similar to that in the VHR stratum (29.3%). However, assignment of patients to the VHR or HR stratum was at the investigator’s discretion based not only on the VHR and HR definitions but also on clinical judgment. For example, a patient without clinical CVD but with heart failure or diabetes could have been allocated to the HR stratum. The proportion of patients with heart failure varies across previous studies. In the ODYSSEY OUTCOMES RCT, 14.9% of participants who had previous acute coronary syndrome had a history of heart failure, and in the SWEDEHEART study only 2.5% of patients with a recent myocardial infarction had heart failure.^21,22 However, in a recent real-world evidence study of acute coronary syndrome, with 97% of participants classified as VHR, the reported rate of heart failure was 35.7%, comparable to the rate observed in the VHR stratum in the present study.²³

The EAS Task Force recommends statin-ezetimibe combination therapy as a first-choice treatment for patients diagnosed with dyslipidemia at very high risk of CVD.^9
-11 The combination of rosuvastatin and ezetimibe in one formulation utilizes the different mechanisms of action of the two products and offers a simplified treatment regimen. Simplifying treatment regimens by reducing the number of pills or the number of administrations contributes to improved treatment adherence.^18,19 As well as being more convenient for patients, FDCs can provide greater drug tolerability, and are also less expensive to manufacture and easier to distribute.²⁴ The current study is focused on LDL-C reduction by a statin-ezetimibe combination therapy. A recent study, the RACING study, with a different primary objective, investigated efficacy of the drug combination toward CV prevention in an atherosclerotic CVD population. Further research will be needed to delineate the full uses and effects of these combination therapies in the treatment landscape.²⁵

Conclusion

The results from this study suggest that the 3 R/E FDC formulations improve LDL-C reduction and enable more people at VHR and HR to achieve LDL-C targets compared with rosuvastatin monotherapy. Improving LDL-C target achievement in VHR and HR people could reduce the global CV disease burden. Overall, the study demonstrated superiority of R40/E10 and R20/E10 over R40 in the VHR stratum and clinically relevant decreases in LDL-C with R10/E10 in the HR stratum after 6 weeks’ treatment, in addition to a favorable safety profile of all FDC formulations.

Supplemental Material

Supplemental Material, sj-docx-1-cpt-10.1177_10742484221138284 - A Phase 3 Randomized Controlled Trial to Evaluate Efficacy and Safety of New-Formulation Zenon (Rosuvastatin/Ezetimibe Fixed-Dose Combination) in Primary Hypercholesterolemia Inadequately Controlled by Statins

Supplemental Material, sj-docx-1-cpt-10.1177_10742484221138284 for A Phase 3 Randomized Controlled Trial to Evaluate Efficacy and Safety of New-Formulation Zenon (Rosuvastatin/Ezetimibe Fixed-Dose Combination) in Primary Hypercholesterolemia Inadequately Controlled by Statins by Alberico L. Catapano, Michal Vrablik, Yuri Karpov, Baptiste Berthou, Megan Loy and Marie Baccara-Dinet in Journal of Cardiovascular Pharmacology and Therapeutics

Footnotes

Authors’ Note

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of our trial participants. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at . EudraCT number: 2016-004556-30.

Acknowledgments

The authors thank the study participants, trial staff, and investigators for their participation. The authors thank Wanda Stipek, PharmD, BCPS, and Erin Reineke, PhD (Sanofi), for coordinating the development and critical review of this manuscript. The authors also thank Genevieve Garon, MBA (Sanofi), for reviewing the manuscript. Medical writing support and editorial assistance was provided by Lois Grant, PhD, and Emiliana Jelezarova, PhD, CMPP™ of Fishawack Communications Ltd, part of Fishawack Health, and was funded by Sanofi.

Author Contributions

Conception and design: ALC, MBD, BB, and MV. Data acquisition: BB. Data analysis/interpretation: all authors. All authors participated in the writing, reviewing and editing of the manuscript, and approved the final version.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AC has received honoraria, lecture fees or research grants from: Akcea, Amgen, Amryt, AstraZeneca, Eli Lilly, Genzyme, Kowa, Mediolanum, Menarini, Merck, Novartis, Pfizer, Recordati, Sanofi, Sigma Tau, Ultragenyx, and Viatris. MV reports fees for clinical trials, consultancy and presentations from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Krka, Mylan, MSD, Novartis, Novo Nordisk, Sanofi, and Zentiva. YK has received honoraria from Amgen, AstraZeneca, Menarini, Merck, MSD, Bayer, Novartis, Novo Nordisk, Krka, and Zentiva as a speaker and from Sanofi for consultancy. ML and MBD are employees of Sanofi. BB is an employee of IT&M Stats, Neuilly-sur-Seine, France, contracted by Sanofi.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by Sanofi.

ORCID iD

Alberico L. Catapano

Supplemental Material

Supplemental material for this article is available online.

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