The impact of the time of drug administration on the effectiveness of combined treatment of hypercholesterolemia with Rosuvastatin and Ezetimibe (RosEze): study protocol for a randomized controlled trial

Abstract

BackgroundHypercholesterolemia is one of the main risk factors for cardiovascular disease. The first line treatment for hypercholesterolemia is statin therapy. When the expected low-density lipoprotein cholesterol (LDL-C) concentration is not achieved, the pharmacotherapy may be extended by combining the statin with the cholesterol absorption inhibitor ezetimibe.Methods/designThe study is designed as a randomized, open-label, single-center, crossover study evaluating the effectiveness of combined therapy with rosuvastatin and ezetimibe for hypercholesterolemia. The study is planned to include 200 patients with hypercholesterolemia ineffectively treated with statins for at least 6 weeks. After enrollment participants are randomized into one of two arms receiving rosuvastatin and ezetimibe. In the first arm the study drug is administered in the morning (8:00 am) for 6 weeks and then in the evening for the next 6 weeks; in the second arm the study drug is administered at first in the evening (8:00 pm) for the first 6 weeks and then in the morning for the following 6 weeks. In order to minimize non-adherence to the treatment, all patients will receive the study drug free of charge. The primary outcome of the study is change in LDL-C at 6 and 12 weeks of the treatment, depending on the time of day of study drug administration. The secondary endpoints include change in total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoproteins ApoB and Apo AI, non-HDL cholesterol, small, dense (sd)-LDL cholesterol, lipoprotein(a), glucose, glycated hemoglobin, high-sensitivity C-reactive protein, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, and creatine kinase at 6 and 12 weeks of the study drug treatment, as well as assessment of plasma fluorescence using stationary and time-resolved fluorescence spectroscopy at baseline and at 6 and 12 weeks of the therapy.DiscussionThe RosEze trial is expected to demonstrate whether there is a significant difference in the effectiveness of the lipid-lowering therapy in reducing the concentration of cholesterol when the medications are taken in the morning compared with the evening time of day.Trial registrationClinicalTrials.gov, NCT02772640. Registered on 28 March 2016.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-2047-8) contains supplementary material, which is available to authorized users.

Statin Dosing Instructions, Medication Adherence, and Low-Density Lipoprotein Cholesterol: a Cohort Study of Incident Statin Users

“…20 The optimal timing of statin administration is currently being evaluated in a randomized clinical trial (RCT). 21 The investigators of this study seek to examine the efficacy of morning vs. evening rosuvastatin-ezetimibe administration on LDL-c lowering for up to 12 weeks. 21 While a RCT is the gold standard for clinical efficacy, this study may have limited generalizability to clinical practice for addressing the question of optimal statin dosing instructions.…”

“…21 The investigators of this study seek to examine the efficacy of morning vs. evening rosuvastatin-ezetimibe administration on LDL-c lowering for up to 12 weeks. 21 While a RCT is the gold standard for clinical efficacy, this study may have limited generalizability to clinical practice for addressing the question of optimal statin dosing instructions. For example, the study drug is provided free of charge and rosuvastatinezitimibe, only one of several statin products, is not the most commonly prescribed.…”

Low dose of ROSuvastatin in combination with EZEtimibe effectively and permanently reduce low density lipoprotein cholesterol concentration independently of timing of administration (ROSEZE): A randomized, crossover study — preliminary results

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“…A detailed description of blood collection and laboratory measurements has been previously published [10]. Routine laboratory measurements were performed in fresh serum (…”

Pragmatic Analysis of Dyslipidemia Involvement in Coronary Artery Disease: A Narrative Review

“…In a long-term follow-up study on 200 hypercholesterolemic patients, less than a quarter of the patients with autosomal recessive hypercholesterolemia reached LDL-C levels <100 mg/dL under high dose statin treatment and ezetimibe and even in combination with lipoprotein apheresis in a long-term follow-up study [ 89 ]. The RosEze trial is underway and studies whether the administration of rosuvastatin and ezetimibe in the morning or evening is more effective in lowering cholesterol levels in 200 hypercholesterolemic patients [ 90 ].…”