Clinical efficacy of cerivastatin: phase IIa dose-ranging and dose-scheduling studies

Abstract

Phase IIa clinical studies with cerivastatin--including 2 pilot US and European dose-ranging studies, and 1 US dose-scheduling study--were conducted to establish a dosage regimen and effective therapeutic doses of cerivastatin in the treatment of hypercholesterolemia. Both dose-ranging studies included a 10-week dietary run-in, to which placebo was added in the last 6 weeks, before patients (n = 385) were randomized to 1 of 6 4-week treatment groups: cerivastatin (0.025, 0.05, 0.1, and 0.2 mg/day), 40 mg/day lovastatin (US), 20 mg/day simvastatin (Europe), or placebo. The dose-scheduling study also included a 10-week dietary run-in and 6-week single-blind placebo run-in phase, before patients (n = 319) were randomized to 4 weeks of treatment with either 0.1 mg cerivastatin twice daily, 0.2 mg cerivastatin with the evening meal, 0.2 mg cerivastatin at bedtime, or placebo in a 2:2:2:1 ratio. The 4-week dose-ranging studies showed that all 4 doses of cerivastatin produced significantly greater reductions in low-density lipoprotein (LDL) cholesterol than placebo. Cerivastatin 0.2 mg decreased LDL cholesterol by 30.5%. Cerivastatin also significantly decreased total cholesterol, triglycerides, and apolipoprotein B, and significantly increased high-density lipoprotein (HDL) cholesterol. Similar reductions in LDL cholesterol and total cholesterol occurred with 0.2 mg/day cerivastatin in the dose-scheduling study, although the reductions were significantly greater when cerivastatin was administered once daily with either the evening meal or at bedtime compared with 2 divided doses. LDL cholesterol reductions were similar when cerivastatin was taken with the evening meal and at bedtime. Cerivastatin was well tolerated, with the incidence of adverse events comparable to that of placebo treatment. No clinically significant increases in either hepatic isoenzymes or creatine phosphokinase were observed after treatment with cerivastatin.