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

• ClinicalTrials.gov Identifier: NCT02772640
• Recruitment Status: Unknown
• First Posted: May 13, 2016
• Last Update Posted: May 25, 2016
• Sponsor: Collegium Medicum w Bydgoszczy
• Information provided by (Responsible Party): Jacek Kubica, Collegium Medicum w Bydgoszczy

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hypercholesterolemia	Drug: Rosuvastatin and Ezetimibe morning or evening administration	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: March 2016
• Estimated Primary Completion Date: December 2016
• Estimated Study Completion Date: December 2016

Arms and Interventions

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 Name: 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 Name: Rosuvastatin, Ezetimibe

Outcome Measures

Primary Outcome Measures :

1. Change in total cholesterol and LDL-Cholesterol [ Time Frame: 6 and 12 weeks ]
   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

Secondary Outcome Measures :

1. Change in HDL-Cholesterol [ Time Frame: 6 and 12 weeks ]
   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
2. Change in triglycerides [ Time Frame: 6 and 12 weeks ]
   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
3. Change in apolipoproteins ApoB, APO AI [ Time Frame: 6 and 12 weeks ]
   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
4. Change in non - HDL-Cholesterol [ Time Frame: 6 and 12 weeks ]
   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
5. Change in sd-LDL-Cholesterol [ Time Frame: 6 and 12 weeks ]
   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. Change in lipoprotein (a) [ Time Frame: 6 and 12 weeks ]
   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
7. Assessment of change of glucose concentration [ Time Frame: Baseline, 6 and 12 weeks ]
   Assessment of glucose at baseline and at 6 and 12 weeks of treatment with study drug
8. Assessment of HbA1c [ Time Frame: Baseline, 6 and 12 weeks ]
   Assessment of HbA1c at baseline and at 6 and 12 weeks of treatment with study drug
9. Assessment of hsCRP [ Time Frame: Baseline, 6 and 12 weeks ]
   Assessment hsCRP at baseline and at 6 and 12 weeks of treatment with study drug
10. Assessment of ALT [ Time Frame: Baseline, 6 and 12 weeks ]
    Assessment ALT at baseline and at 6 and 12 weeks of treatment with study drug
11. Assessment of AST [ Time Frame: Baseline, 6 and 12 weeks ]
    Assessment AST at baseline and at 6 and 12 weeks of treatment with study drug
12. Assessment of CK [ Time Frame: Baseline, 6 and 12 weeks ]
    Assessment CK at baseline and at 6 and 12 weeks of treatment with study drug
13. Assessment of plasma fluorescence using stationary and time-resolved spectrofluorimetry [ Time Frame: Baseline, 6 and 12 weeks ]
    Assessment of plasma fluorescence using stationary and time-resolved spectrofluorimetry at baseline, at 6 and 12 weeks of treatment with study drug

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Karolina Obońska, MD, PhD; +48525854023; kalaobonska@op.pl

Locations

Poland

Cardiology Department, Dr. A. Jurasz University Hospital; Recruiting

Bydgoszcz, Kujawsko-Pomorskie, Poland, 85-094

Contact: Karolina Obońska, MD, PhD +48 52 5854023 kalaobonska@op.pl

Sponsors and Collaborators

Collegium Medicum w Bydgoszczy

Investigators

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Obońska K, Kasprzak M, Sikora J, Obońska E, Racki K, Goździkiewicz 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.

• Responsible Party: Jacek Kubica, Professor Jacek Kubica MD, PhD., Collegium Medicum w Bydgoszczy
• ClinicalTrials.gov Identifier: NCT02772640
• Other Study ID Numbers: AMI9
• First Posted: May 13, 2016
• Last Update Posted: May 25, 2016
• Last Verified: May 2016

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Jacek Kubica, Collegium Medicum w Bydgoszczy:

Hypercholesterolemia; Rosuvastatin; Statin; Ezetimibe; Compliance; Cholesterol; Secondary prevention; Coronary artery disease; Cholesterol absorption inhibitor

Additional relevant MeSH terms:

Hypercholesterolemia; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Rosuvastatin Calcium; Ezetimibe; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors