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


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Verified May 2017 by Joo-Yong Hahn, Samsung Medical Center

Sponsor:

Collaborator:

Hanmi Pharm. Co., Ltd.

Information provided by (Responsible Party):

Joo-Yong Hahn, Samsung Medical Center

ClinicalTrials.gov Identifier:

NCT03169985

First received: May 24, 2017

Last updated: May 26, 2017

Last verified: May 2017

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.

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

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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

Masking: 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

Primary Outcome Measures:

  • Change in percent atheroma volume(PAV) in non-culprit lesions [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 12 months after index CAG ]

    In case that OCT is conducted

  • Change in fractional flow reserve(FFR) [ Time Frame: 12 months after index CAG ]

    Physiologic index

  • Change in coronary flow reserve(CFR) [ Time Frame: 12 months after index CAG ]

    Physiologic index

  • Change in index of microcirculatory resistance(IMR) [ Time Frame: 12 months after index CAG ]

    Physiologic index

  • Change in TAV in coronary computed tomography(CT) angiography [ Time Frame: 24 months after index CAG ]

    TAV which is measured in CT angiography

  • Major adverse cardiovascular events(MACE) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 6 and 12 months after index CAG ]

    For risk of developing diabetes mellitus by statin therapy

  • Change in hemoglobin A1c [ Time Frame: 6 and 12 months after index CAG ]

    For risk of developing diabetes mellitus by statin therapy

  • Change in lipid profile [ Time Frame: 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) [ Time Frame: 1 and 12 months after index CAG ]

    hs-CRP

  • Safety endpoint: Number of participants with abnormal laboratory values and adverse events [ Time Frame: 1 and 12 months after index CAG ]
    1. Creatine kinase(CK) elevation > 10 times upper limit of normal(ULN)
    2. CK elevation > 10 times ULN on two consecutive visits
    3. Hepatic transaminases > 3 times ULN
    4. Hepatic transaminases > 3 times ULN on two consecutive visits
    5. 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.

Estimated Enrollment: 280
Anticipated Study Start Date: June 1, 2017
Estimated Study Completion Date: December 31, 2023
Estimated Primary Completion Date: December 31, 2021 (Final data collection date for primary outcome measure)
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 Name: 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 Name: Crestor tablet 10 mg

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, we 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.

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

Exclusion Criteria:

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03169985

Samsung Medical Center
Seoul, Korea, Republic of, 06351

Samsung Medical Center

Hanmi Pharm. Co., Ltd.

Study Chair: Joo-Yong Hahn, MD, PhD Samsung Medical Center

Responsible Party: Joo-Yong Hahn, Professor, Samsung Medical Center
ClinicalTrials.gov Identifier: NCT03169985     History of Changes
Other Study ID Numbers: Rosuzet-IVUS16453143
Study First Received: May 24, 2017
Last Updated: May 26, 2017
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: After publication of first manuscript and trial results, the de-identified data will be shared by permission of principle investigator, when asked.

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Joo-Yong Hahn, Samsung Medical Center:

Rosuvastatin
Ezetimibe
Atherosclerotic plaque
Intravascular ultrasound

Additional relevant MeSH terms:

Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Plaque, Atherosclerotic
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Pathological Conditions, Anatomical
Rosuvastatin Calcium
Ezetimibe
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Lipid Regulating Agents

ClinicalTrials.gov processed this record on May 30, 2017