A Phase III, Multicenter, Randomized, Double-blind, Active Comparator Clinical Trial to Compare the Efficacy and Safety of Combination Therapy with Ezetimibe and Rosuvastatin Versus Rosuvastatin Monotherapy in Patients with Hypercholesterolemia: I-ROSETTE (Ildong Rosuvastatin &Ezetimibe for Hypercholesterolemia) Randomized Controlled Trial

Soon Jun Hong, Han Saem Jeong, Jeong Cheon Ahn, Dong-Hun Cha, Kyung Heon Won, Weon Kim, Sang Kyoon Cho, Seok-Yeon Kim, Byung-Su Yoo, Ki Chul Sung, Seung-Woon Rha, Joon-Han Shin, Kyoo Rok Han, Wook Sung Chung, Min Su Hyon, Han Cheol Lee, Jang-Ho Bae, Moo-Yong Rhee, Jun Kwan, Dong Woon Jeon, Ki Dong Yoo, Hyo-Soo Kim

OBJECTIVE

Combination therapy with ezetimibe and statins is recommended in cases of statin intolerance or insufficiency. The objective of this study was to compare the efficacy and safety of combination therapy with ezetimibe and rosuvastatin versus those of rosuvastatin monotherapy in patients with hypercholesterolemia.

Endpoints

The primary endpoint was to evaluate the efficacy of combination therapy with ezetimibe and rosuvastatin versus rosuvastatin monotherapy by comparing the mean percent change from baseline in LDL-C level after 8 weeks of treatment.

The secondary endpoints were the mean percent change from baseline in the following: (1) total cholesterol (TC), TG, HDLC, non–HDL-C, apolipoprotein (Apo)B, and ApoA1; (2) high-sensitivity C-reactive protein (hs-CRP); and (3) LDL-C/HDL-C, TC/HDL-C, non–HDL-C/HDL-C, and Apo B/Apo A1 after 4 and 8 weeks of treatment.

Methods

I-ROSETTE was an 8-week, double-blind, multicenter, Phase III randomized controlled trial conducted at 20 hospitals in the Republic of Korea. Patients were Korean men and women aged between 19 and 79 years with hypercholesterolemia requiring medical treatment according to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines were eligible for participation in the study.

Patients were randomly assigned to receive ezetimibe 10mg/rosuvastatin 20mg, ezetimibe 10mg/rosuvastatin 10mg, ezetimibe 10mg/rosuvastatin 5mg, rosuvastatin 20mg, rosuvastatin10mg, or rosuvastatin 5mg in a 1:1:1:1:1:1 ratio.

Results

A total of 396 patients were randomly assigned to receive ezetimibe 10mg/rosuvastatin 20mg (n = 67), ezetimibe 10mg/rosuvastatin 10 mg (n = 67), ezetimibe 10mg/rosuvastatin 5mg (n = 65), rosuvastatin20mg (n = 65), rosuvastatin 10 mg (n = 66), or rosuvastatin 5mg (n = 66).

After 8 weeks of double-blind treatment, the percent changes in adjusted mean LDL-C levels at week 8 compared with baseline values were -57.0% (2.1%) and -44.4% (2.1%) in the total ezetimibe/rosuvastatin and total rosuvastatin groups, respectively (P < 0.001). The LDL-C-lowering efficacy of each of the ezetimibe/rosuvastatin combinations was superior to that of each of the respective doses of rosuvastatin. The number of patients who achieved target LDL-C levels at week 8 was significantly greater in the ezetimibe/rosuvastatin group (180 [92.3%] of 195 patients) than in the rosuvastatin monotherapy group (155 [79.9%] of 194 patients) (P < 0.001).

The percent changes in TC, TG, non–HDL-C, and Apo B were also greater in the total ezetimibe/ rosuvastatin group than in the total rosuvastatin alone group. The changes in HDL-C and Apo A1 levels were not significantly different between the combination and monotherapy groups. The changes after 4 and 8 weeks in hs-CRP were similar between the combination and monotherapy groups.

Conclusion

Fixed-dose combinations of ezetimibe/rosuvastatin significantly improved lipid profiles in patients with hypercholesterolemia compared with rosuvastatin monotherapy. All groups treated with rosuvastatin and ezetimibe reported a decrease in mean LDL-C level >50%. The safety and tolerability of ezetimibe/rosuvastatin therapy were comparable with those of rosuvastatin monotherapy.

    Hong, S.J., Jeong, H.S., Ahn, J.C., Cha, D.H., Won, K.H., Kim, W., Cho, S.K., Kim, S.Y., Yoo, B.S., Sung, K.C. and Rha, S.W., 2018. A phase III, multicenter, randomized, double-blind, active comparator clinical trial to compare the efficacy and safety of combination therapy with ezetimibe and rosuvastatin versus rosuvastatin monotherapy in patients with hypercholesterolemia: I-ROSETTE (Ildong Rosuvastatin & Ezetimibe for Hypercholesterolemia) Randomized Controlled Trial. Clinical therapeutics, 40(2), pp.226-241.

MAT-AE-2100384 /V1/JUN2021