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.

Efficacy and Safety of Single-Pill Combination of Rosuvastatin and Ezetimibe in Chinese Patients with Primary Hypercholesterolemia Inadequately Controlled by Statin Treatment (ROZEL): A Randomized, Double-Blind, Double Dummy, Active-Controlled Phase 3 Clinical Trial

“…Similar results were also reported in previous studies [29,31]. In a similar global trial, the decrease in TC was greater in the R/E group than in the rosuvastatin group in veryhigh-risk participants, while the difference in the changes in TG were not statistically significant [31]. In I-ROSETTE, compared with R, SPC R/E led to higher decreases in TC, but a numeric decrease in TG and an increase in HDL-C were not statistically significant [28].…”

“…The mechanism of action on TG decrease with ezetimibe is probably based on promoting the expression of PPARγ protein (a lipid storage promoting protein) and downregulating the expression of PPARα and β proteins (lipid mobilization promoting proteins), thereby promoting TG storage [ 36 ]. Similar results were also reported in previous studies [ 29 , 31 ]. In a similar global trial, the decrease in TC was greater in the R/E group than in the rosuvastatin group in very-high-risk participants, while the difference in the changes in TG were not statistically significant [ 31 ].…”

“…The achievement of the LDL-C target at week 8 was similar between the SPC R10/E10 (66.0%) and R20 (55.7%) groups at week 6 in the global trial [ 31 ]; the present study reported a significantly higher proportion of participants achieving the LDL-C target in the SPC R10/E10 group (54.1%) than in the R10 group (29.2%), similar to the R20 group in the global trial (55.7%) [ 31 ], and demonstrated in the I-ROSETTE trial (100% with R/E and 83.3% with rosuvastatin) [ 28 ]. Similar results were observed in the EXPLORER trial (R40/E10 94.0% vs. R40 79.1%) [ 33 ], MRS-ROSE trial (R/E 94.1% vs. rosuvastatin 86.3%) [ 34 ], Yang et al trial [ 35 ] (R/E 87–95% vs. ezetimibe 64–87%), and Lee et al trial [ 29 ] (R2.5/E10 100% vs. R2.5 47.6% and R5 65.2%).…”

“…Furthermore, in patients with primary hypercholesterolemia inadequately controlled by statin, a better reduction in LDL-C level was achieved with R/E compared with R10 (− 27.7% vs. − 16.9%) in the IN-CROSS trial [ 30 ]. In the global RCT study of SPC R/E, SPC R40/E10 and SPC R20/E10 significantly reduced LDL-C than R40 in patients with hypercholesterolemia inadequately controlled by statin who were at very high risk of CVD [ 31 ]. Similarly, in the present trial, the percent changes in LDL-C of the SPC R10/E10 were significantly greater than in the R10 groups, with a difference of − 13.85%, showing a consistent efficacy with previous trials.…”

“…Nevertheless, comparison with western trials must be performed cautiously since non-Asian patients can tolerate higher doses of statins than Asians [ 18 , 19 ]. From these findings [ 28 , 29 , 31 , 32 ], the SPC formulation of SPC R10/E10 could effectively lower LDL-C levels and might contribute to lightening the burden of cardiovascular events.…”