Rosuzet-IVUS: Usual Dose Rosuvastatin Plus Ezetimibe Versus High-dose Rosuvastatin on Coronary Atherosclerotic Plaque

Sponsor

Samsung Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT03169985

Collaborator

Hanmi Pharmaceutical co., ltd. (Other)

280

Enrollment

Location

Arms

89.7

Anticipated Duration (Months)

3.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of this prospective, open-label, randomized, single center study is to compare the effect of usual dose rosuvastatin plus ezetimibe and high-dose rosuvastatin on modifying atherosclerotic plaque.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease	Drug: Rosuvastatin 10 mg plus ezetimibe 10 mg orally once a day Drug: Rosuvastatin 20 mg orally once a day	Phase 4

Detailed Description

High-intensity statin therapy have shown improved clinical outcomes compared to placebo or moderate-intensity statin therapy. Based on these results, 2013 American College of Cardiology/American Heart Association(ACC/AHA) guideline on treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults recommended high-intensity statin therapy to patient with coronary artery disease for secondary prevention. However, high-intensity statin therapy was known to increase risk of diabetes mellitus and complication such as hepatotoxicity and myalgia. An alternative to high-intensity statin therapy is reducing the dose of statin and using drug that can improve blood cholesterol level by a different mechanism than statin. Ezetimibe acts on Niemann-Pick C1-like protein then inhibits cholesterol absorption in the intestine, which can reduce low-density lipoprotein(LDL) cholesterol more effectively when administered with statin. In IMPROVE-IT study, simvastatin plus ezetimibe decreased ischemic events more than simvastatin alone in patients with acute coronary syndrome. Although this study could confirm the additional effect of ezetimibe by using the same amount of simvastatin in both groups, it could not compare the effect of statin plus ezetimibe and high dose statin monotherapy. Moreover, there were few data on the efficacy of ezetimibe added to rosuvastatin which is one of the effective statin recommended by various guidelines. One study reported that rosuvastatin 2.5 mg plus ezetimibe 10 mg was superior to rosuvastatin 5 mg monotherapy in reducing LDL cholesterol. Another study reported that adding rosuvastatin 5 mg to ezetimibe 10 mg was more effective than rosuvastatin 5 mg alone in reducing coronary atherosclerotic lesions as measured by intravascular ultrasound. However, the previous studies did not compare the efficacy of combination therapy of usual dose rosuvastatin and ezetimibe to high-dose statin monotherapy. Therefore, investigators aimed to compare the effect of rosuvastatin 10 mg plus ezetimibe 10 mg to rosuvastatin 20 mg alone on the reduction of coronary atherosclerosis in patient with coronary artery disease. If this study shows that the combination of usual dose rosuvastatin and ezetimibe is not inferior to high dose rosuvastatin monotherapy in anti-atherosclerotic effect and safety, it would provide a basis for effective and safe cholesterol treatment.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

280 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Prospective, open label, two-arm, randomized controlled trialProspective, open label, two-arm, randomized controlled trial

Masking:

Single (Outcomes Assessor)

Masking Description:

The obtained intravascular ultrasound(IVUS) data will be stored through the storage device in the core lab of Heart Center of Heart Vascular Stroke Institute in Samsung Medical Center, and the treatment group to which the patient belongs would not be known. Subsequent baseline and follow-up IVUS data will be analyzed together by independent experts without knowledge of the patient's treatment group.

Primary Purpose:

Treatment

Official Title:

The Effect of Usual Dose Rosuvastatin Plue Ezetimibe Versus High-dose Rosuvastatin on Coronary Atherosclerotic Plaque: A Randomized Controlled Trial

Actual Study Start Date :

Jul 12, 2017

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Dec 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Rosuvastatin plus ezetimibe arm In patients who have moderate stenosis(30-70%) in coronary artery and deferred to medical treatment by intracoronary physiologic or radiologic test, this arm will be received rosuvastatin 10 mg plus ezetimibe 10 mg qd during 12 months after randomization.	Drug: Rosuvastatin 10 mg plus ezetimibe 10 mg orally once a day After the initial 12 months, randomized intervention will be stopped and then this arm will be received either usual dose rosuvastatin plus ezetimibe or high-dose rosuvastatin during the next 24 months by clinical judgement. Other Names: Rosuzet tablet 10/10 mg
Active Comparator: High-dose rosuvastatin monotherapy arm In patients who have moderate stenosis(30-70%) in coronary artery and deferred to medical treatment by intracoronary physiologic or radiologic test, this arm will be received rosuvastatin 20 mg qd during 12 months after randomization.	Drug: Rosuvastatin 20 mg orally once a day After the initial 12 months, randomized intervention will be stopped and then this arm will be received either usual dose rosuvastatin plus ezetimibe or high-dose rosuvastatin during the next 24 months based by clinical judgement. Other Names: Crestor tablet 10 mg

Arm

Intervention/Treatment

Active Comparator: Rosuvastatin plus ezetimibe arm

In patients who have moderate stenosis(30-70%) in coronary artery and deferred to medical treatment by intracoronary physiologic or radiologic test, this arm will be received rosuvastatin 10 mg plus ezetimibe 10 mg qd during 12 months after randomization.

Drug: Rosuvastatin 10 mg plus ezetimibe 10 mg orally once a day

After the initial 12 months, randomized intervention will be stopped and then this arm will be received either usual dose rosuvastatin plus ezetimibe or high-dose rosuvastatin during the next 24 months by clinical judgement.

Other Names:

Rosuzet tablet 10/10 mg

Active Comparator: High-dose rosuvastatin monotherapy arm

Drug: Rosuvastatin 20 mg orally once a day

Other Names:

Crestor tablet 10 mg

Outcome Measures

Primary Outcome Measures

Change in percent atheroma volume(PAV) in non-culprit lesions [12 months after index coronary angiography(CAG)]
PAV is calculated as the percentage of the sum of external elastic membrane(EEM) cross sectional areas(CSA) occupied by total atheroma volume(TAV). TAV was determined by summation of the plaque area, defined as the difference between EEM and lumen CSA, for all evaluable images. These values could be expressed as follows: TAV = ∑(EEM CSA - lumen CSA), PAV = 100 X ∑(EEM CSA - lumen CSA) / ∑EEM CSA

Secondary Outcome Measures

Change in normalized TAV in non-culprit lesions [12 months after index CAG]
The TAV is normalized to the length corresponding to the median number of comparable slices for each treatment group in view of the variability in the length of pullback analyzed between subjects. This value could be expressed as follows: normalized TAV = [∑(EEM CSA - lumen CSA) / number of images in pullback] X median number of images in cohort
Change in indexed TAV [12 months after index CAG]
Indexed TAV is calculated as TAV divided by the length of plaque in each subject. This value could be expressed as follows: Indexed TAV = ∑(EEM CSA - lumen CSA) / plaque length
Change in fibrous cap thickness by OCT(optical coherence tomography) [12 months after index CAG]
In case that OCT is conducted
Change in fractional flow reserve(FFR) [12 months after index CAG]
Physiologic index
Change in coronary flow reserve(CFR) [12 months after index CAG]
Physiologic index
Change in index of microcirculatory resistance(IMR) [12 months after index CAG]
Physiologic index
Change in TAV in coronary computed tomography(CT) angiography [24 months after index CAG]
TAV which is measured in CT angiography
Major adverse cardiovascular events(MACE) [12, 24 and 36 months after index CAG]
MACE is defined as a composite of death, myocardial infarction, stroke and revascularization.
Change in homeostatic model assessment(HOMA) index [6 months after index CAG]
HOMA index is a method used to quantify insulin resistance. This values could be calculated with fasting plasma glucose and insulin, as follows: HOMA index = glucose X insulin (mg/dL) / 405
Change in fasting glucose [6 and 12 months after index CAG]
For risk of developing diabetes mellitus by statin therapy
Change in hemoglobin A1c [6 and 12 months after index CAG]
For risk of developing diabetes mellitus by statin therapy
Change in lipid profile [1, 6 and 12 months after index CAG]
Fasting plasma triglyceride(TG), high-density lipoprotein(HDL), LDL and total cholesterol. These items will be compared separately, and described as a group of lipid profile.
Change in high-sensitivity C-reactive protein(hs-CRP) [1 and 12 months after index CAG]
hs-CRP
Safety endpoint: Number of participants with abnormal laboratory values and adverse events [1 and 12 months after index CAG]
Creatine kinase(CK) elevation > 10 times upper limit of normal(ULN) CK elevation > 10 times ULN on two consecutive visits Hepatic transaminases > 3 times ULN Hepatic transaminases > 3 times ULN on two consecutive visits Document reason for discontinuation of study medication These items will be described together as a group of safety endpoint, such as number of participants with abnormal laboratory values and adverse events.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Among patients who undergo CAG for suspected ischemic heart disease and meet all of the followings:
Moderate stenosis (30-70%) in coronary artery
Deferred to medical treatment based on physiologic (FFR, CFR, IMR) or radiologic (IVUS with or without OCT) evaluation.
Agreement obtained by participant

Exclusion Criteria:

Severe renal failure(glomerular filtration rate < 30 ml/min/1.73m2, hemodialysis or peritoneal dialysis)
Active liver disease
Patient taking Niacin or fibrate(if possible, patient can be enrolled to the study after stopping those medication)
Medical or family history of myositis, unexplained CK elevation > 3 times ULN at first visit
Life expectancy < 2 years (judged by investigator)
Coadministration of cyclosporine
Untreated hypothyroidism
Patient with poor compliance including alcohol abuse
History of hypersensitivity including myotoxicity for either statin or ezetimibe
Pregnant or breast-feeding woman
Other conditions inappropriate for enrollment by investigator
- Eligible patients will be randomly assigned to treatment arms, stratified by diagnosis on admission(acute coronary syndrome or stable ischemic heart disease) and presence of chronic statin use (more than one month)