Effectiveness of Treatment of Hypercholesterolemia With Rosuvastatin and Ezetimibe (ROSEZE)

The Impact of the Time of Drug Administration on the Effectiveness of Combined Treatment of Hypercholesterolemia With ROSuvastatin and EZEtimibe (ROSEZE) - A Single-center, Crossover, Open-label Study

The aim of the study is to demonstrate, whether the time of day of administration of the study drug (containing rosuvastatin and ezetimibe) has an impact on the effectiveness of lipid-lowering therapy.

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Drug: Rosuvastatin and Ezetimibe morning or evening administration

Detailed Description

The current guidelines recommend statins as drugs of first choice in the treatment of hypercholesterolemia. If the target LDL cholesterol is not achieved, combination of a statin with a cholesterol absorption inhibitor -ezetimibe may be considered.

According to meta-analyzes of studies assessing statins, each 1.0 mmol / L (~ 40 mg / dL) reduction in LDL-C corresponds to a 10% reduction in all-cause mortality and a 20% reduction in the number of deaths from coronary artery disease. Each 1 mmol / L (40 mg / dL) reduction in LDL-C also translates into a 23% and 17% reduction of the risk of major coronary events and stroke, respectively. Similar results concerning the efficacy and safety of lipid-lowering therapy using statins were obtained in meta-analyzes of studies on primary prevention. Statins are a heterogenous group of drugs with respect to their LDL-C reduction power. So far, the most potent statin is rosuvastatin. Despite intensive statin therapy provided, a large group of patients still does not reach therapeutic goals. Statin dose titration seems to be less effective compared with the combined therapy with statin and ezetimibe. The combination of statin with ezetimibe reduces the LDL-C by additional 15-20%.

Tablets comprising both of these drugs (statin and ezetimibe) simplify the drug administration and increase the probability of drug compliance. This may increase the probability for achieving therapeutic goals in hypercholesterolemia treatment.

Taking into account the metabolism of cholesterol and possible drug-drug interactions it is recommended to administer simvastatin in the evening. Rosuvastatin may be administer at any time of the day.

The study is designed as an open-label, single-center, cross-over study evaluating the effectiveness of combined therapy with rosuvastatin and ezetimibe for hypercholesterolemia depending on timing of the day of administration of the study treatment. After enrollment the participants will be allocated into two arms, each receiving rosuvastatin and ezetimibe. The study drug (rosuvastatin with ezetimibe) will be given: 1) in the morning (8:00) for 6 weeks and then in the evening for the next 6 weeks; 2) in the evening (20:00) for the first 6 weeks and then in the morning for the following 6 weeks. The change in total cholesterol and LDL-cholesterol at 6 and 12 weeks of the tested therapy will be measured as the primary outcome of the study. Moreover, other parameters including: HDL-cholesterol, triglycerides, apolipoprotein B (ApoB), ApoAI, nonHDL-cholesterol, sd-LDL-cholesterol, lipoprotein (a), glucose, HBA1c, high sensitivity C reactive protein (hsCRP), ALT, aspartate aminotransferase (AST), creatine kinase (CK ) will be assessed as secondary outcomes.

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 4

Contacts and Locations

Study Locations

• Poland
  • Kujawsko-Pomorskie
    • Bydgoszcz, Kujawsko-Pomorskie, Poland, 85-094
      • Cardiology Department, Dr. A. Jurasz University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Hypercholesterolemia
2. Ineffectiveness of statin monotherapy in the treatment of hypercholesterolemia after at least 6 weeks

Exclusion Criteria:

1. Active liver disease
2. Unexplained persistent increase in serum transaminase levels, including more than 3 times the upper limit of normal activity of one of them
3. Severe renal impairment (creatinine clearance <30 ml / min)
4. Myopathy
5. Concomitant treatment with cyclosporine, gemfibrozil
6. Pregnancy
7. Lactation
8. Women of childbearing age not using effective methods of contraception
9. Symptoms of muscle damage after using statins or fibrates in the past.
10. The activity of creatine kinase> 5 times the upper limit of normal

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm I: R+E morning->evening; Rosuvastatin and Ezetimibe morning or evening administration: Rosuvastatin (R) plus Ezetimibe (E) administration in the morning (8:00) for 6 weeks. After 6 weeks - intervention - change of the timing of study drug administration to the evening hours (20:00).	Drug: Rosuvastatin and Ezetimibe morning or evening administration; Timing of the drug administration: morning -> evening evening -> morning; Other Names: Rosuvastatin, Ezetimibe
Active Comparator: ARM II: R+E evening->morning; Rosuvastatin and Ezetimibe evening or morning administration: Rosuvastatin (R) plus Ezetimibe (E) administration in the evening (20:00) for 6 weeks. After 6 weeks - intervention - change of the timing of study drug administration to the morning hours (8:00).	Drug: Rosuvastatin and Ezetimibe morning or evening administration; Timing of the drug administration: morning -> evening evening -> morning; Other Names: Rosuvastatin, Ezetimibe

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in total cholesterol and LDL-Cholesterol	Change in total cholesterol and LDL-Cholesterol at 6 and 12 weeks of study drug treatment (combination of ezetimibe and rosuvastatin), depending on the time of day of study drug administration	6 and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HDL-Cholesterol	Change in HDL-Cholesterol at 6 and 12 weeks of study drug treatment (combination of ezetimibe and rosuvastatin), depending on the time of day of study drug administration	6 and 12 weeks
Change in triglycerides	Change in triglycerides at 6 and 12 weeks of study drug treatment (combination of ezetimibe and rosuvastatin), depending on the time of day of study drug administration	6 and 12 weeks
Change in apolipoproteins ApoB, APO AI	Change in apolipoproteins ApoB, APO AI at 6 and 12 weeks of study drug treatment (combination of ezetimibe and rosuvastatin), depending on the time of day of study drug administration	6 and 12 weeks
Change in non - HDL-Cholesterol	Change in non - HDL-Cholesterol at 6 and 12 weeks of study drug treatment (combination of ezetimibe and rosuvastatin), depending on the time of day of study drug administration	6 and 12 weeks
Change in sd-LDL-Cholesterol	Change in sd-LDL-Cholesterol at 6 and 12 weeks of study drug treatment (combination of ezetimibe and rosuvastatin), depending on the time of day of study drug administration	6 and 12 weeks
Change in lipoprotein (a)	Change in lipoprotein (a) at 6 and 12 weeks of study drug treatment (combination of ezetimibe and rosuvastatin), depending on the time of day of study drug administration	6 and 12 weeks
Assessment of change of glucose concentration	Assessment of glucose at baseline and at 6 and 12 weeks of treatment with study drug	Baseline, 6 and 12 weeks
Assessment of HbA1c	Assessment of HbA1c at baseline and at 6 and 12 weeks of treatment with study drug	Baseline, 6 and 12 weeks
Assessment of hsCRP	Assessment hsCRP at baseline and at 6 and 12 weeks of treatment with study drug	Baseline, 6 and 12 weeks
Assessment of ALT	Assessment ALT at baseline and at 6 and 12 weeks of treatment with study drug	Baseline, 6 and 12 weeks
Assessment of AST	Assessment AST at baseline and at 6 and 12 weeks of treatment with study drug	Baseline, 6 and 12 weeks
Assessment of CK	Assessment CK at baseline and at 6 and 12 weeks of treatment with study drug	Baseline, 6 and 12 weeks
Assessment of plasma fluorescence using stationary and time-resolved spectrofluorimetry	Assessment of plasma fluorescence using stationary and time-resolved spectrofluorimetry at baseline, at 6 and 12 weeks of treatment with study drug	Baseline, 6 and 12 weeks

Collaborators and Investigators

• Sponsor: Collegium Medicum w Bydgoszczy
• Investigators: Principal Investigator: Jacek Kubica, MD, PhD, Collegium Medicum w Bydgoszczy

Publications and helpful links

General Publications

• Obonska K, Kasprzak M, Sikora J, Obonska E, Racki K, Gozdzikiewicz N, Krintus M, Kubica J. 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. Trials. 2017 Jul 11;18(1):316. doi: 10.1186/s13063-017-2047-8.

Helpful Links

• Study results

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): January 1, 2019
• Study Completion (Actual): May 1, 2020

Study Registration Dates

• First Submitted: March 28, 2016
• First Submitted That Met QC Criteria: May 12, 2016
• First Posted (Estimate): May 13, 2016

Study Record Updates

• Last Update Posted (Actual): February 2, 2021
• Last Update Submitted That Met QC Criteria: January 29, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Cholesterol; Coronary artery disease; Hypercholesterolemia; Secondary prevention; Compliance; Statin; Rosuvastatin; Ezetimibe; Cholesterol absorption inhibitor
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rosuvastatin Calcium; Ezetimibe
• Other Study ID Numbers: AMI9

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No