Clinical trial NCT02772640: Effectiveness of Treatment of Hypercholesterolemia With Rosuvastatin and Ezetimibe
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypercholesterolemia
Keywords: Hypercholesterolemia
Rosuvastatin
Statin
Ezetimibe
Compliance
Cholesterol
Secondary prevention
Coronary artery disease
Cholesterol absorption inhibitor
Lead sponsor: Collegium Medicum w Bydgoszczy
Sponsor class: OTHER
First posted: 2016-05-13
Enrollment: 83
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Change in total cholesterol and LDL-Cholesterol
timeFrame: 6 and 12 weeks
Secondary outcomes:
measure: Change in HDL-Cholesterol
timeFrame: 6 and 12 weeks
measure: Change in triglycerides
timeFrame: 6 and 12 weeks
measure: Change in apolipoproteins ApoB, APO AI
timeFrame: 6 and 12 weeks
measure: Change in non - HDL-Cholesterol
timeFrame: 6 and 12 weeks
measure: Change in sd-LDL-Cholesterol
timeFrame: 6 and 12 weeks
measure: Change in lipoprotein (a)
timeFrame: 6 and 12 weeks
measure: Assessment of change of glucose concentration
timeFrame: Baseline, 6 and 12 weeks
measure: Assessment of HbA1c
timeFrame: Baseline, 6 and 12 weeks
measure: Assessment of hsCRP
timeFrame: Baseline, 6 and 12 weeks
measure: Assessment of ALT
timeFrame: Baseline, 6 and 12 weeks
measure: Assessment of AST
timeFrame: Baseline, 6 and 12 weeks
measure: Assessment of CK
timeFrame: Baseline, 6 and 12 weeks
measure: Assessment of plasma fluorescence using stationary and time-resolved spectrofluorimetry
timeFrame: Baseline, 6 and 12 weeks
Other outcomes:
Locations:
city: Bydgoszcz
country: Poland
facility: Cardiology Department, Dr. A. Jurasz University Hospital
state: Kujawsko-Pomorskie
Study officials:
affiliation: Collegium Medicum w Bydgoszczy
name: Jacek Kubica, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.