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

Primary Purpose

Coronary Artery Disease

Status
Recruiting
Phase
Phase 4
Locations
Korea, Republic of
Study Type
Interventional
Intervention
Rosuvastatin 10 mg plus ezetimibe 10 mg orally once a day
Rosuvastatin 20 mg orally once a day
Sponsored by
Samsung Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Coronary Artery Disease focused on measuring Rosuvastatin, Ezetimibe, Atherosclerotic plaque, Intravascular ultrasound

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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)

Sites / Locations

  • Samsung Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Rosuvastatin plus ezetimibe arm

High-dose rosuvastatin monotherapy arm

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Change in percent atheroma volume(PAV) in non-culprit lesions
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
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
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)
In case that OCT is conducted
Change in fractional flow reserve(FFR)
Physiologic index
Change in coronary flow reserve(CFR)
Physiologic index
Change in index of microcirculatory resistance(IMR)
Physiologic index
Change in TAV in coronary computed tomography(CT) angiography
TAV which is measured in CT angiography
Major adverse cardiovascular events(MACE)
MACE is defined as a composite of death, myocardial infarction, stroke and revascularization.
Change in homeostatic model assessment(HOMA) index
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
For risk of developing diabetes mellitus by statin therapy
Change in hemoglobin A1c
For risk of developing diabetes mellitus by statin therapy
Change in lipid profile
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)
hs-CRP
Safety endpoint: Number of participants with abnormal laboratory values and adverse events
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.

Full Information

First Posted
May 24, 2017
Last Updated
November 10, 2021
Sponsor
Samsung Medical Center
Collaborators
Hanmi Pharmaceutical co., ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT03169985
Brief Title
Usual Dose Rosuvastatin Plus Ezetimibe Versus High-dose Rosuvastatin on Coronary Atherosclerotic Plaque
Acronym
Rosuzet-IVUS
Official Title
The Effect of Usual Dose Rosuvastatin Plue Ezetimibe Versus High-dose Rosuvastatin on Coronary Atherosclerotic Plaque: A Randomized Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
November 2021
Overall Recruitment Status
Recruiting
Study Start Date
July 12, 2017 (Actual)
Primary Completion Date
December 31, 2022 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Samsung Medical Center
Collaborators
Hanmi Pharmaceutical co., ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Coronary Artery Disease
Keywords
Rosuvastatin, Ezetimibe, Atherosclerotic plaque, Intravascular ultrasound

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
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.
Allocation
Randomized
Enrollment
280 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Rosuvastatin plus ezetimibe arm
Arm Type
Active Comparator
Arm Description
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.
Arm Title
High-dose rosuvastatin monotherapy arm
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Rosuvastatin 10 mg plus ezetimibe 10 mg orally once a day
Other Intervention Name(s)
Rosuzet tablet 10/10 mg
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Rosuvastatin 20 mg orally once a day
Other Intervention Name(s)
Crestor tablet 10 mg
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in percent atheroma volume(PAV) in non-culprit lesions
Description
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
Time Frame
12 months after index coronary angiography(CAG)
Secondary Outcome Measure Information:
Title
Change in normalized TAV in non-culprit lesions
Description
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
Time Frame
12 months after index CAG
Title
Change in indexed TAV
Description
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
Time Frame
12 months after index CAG
Title
Change in fibrous cap thickness by OCT(optical coherence tomography)
Description
In case that OCT is conducted
Time Frame
12 months after index CAG
Title
Change in fractional flow reserve(FFR)
Description
Physiologic index
Time Frame
12 months after index CAG
Title
Change in coronary flow reserve(CFR)
Description
Physiologic index
Time Frame
12 months after index CAG
Title
Change in index of microcirculatory resistance(IMR)
Description
Physiologic index
Time Frame
12 months after index CAG
Title
Change in TAV in coronary computed tomography(CT) angiography
Description
TAV which is measured in CT angiography
Time Frame
24 months after index CAG
Title
Major adverse cardiovascular events(MACE)
Description
MACE is defined as a composite of death, myocardial infarction, stroke and revascularization.
Time Frame
12, 24 and 36 months after index CAG
Title
Change in homeostatic model assessment(HOMA) index
Description
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
Time Frame
6 months after index CAG
Title
Change in fasting glucose
Description
For risk of developing diabetes mellitus by statin therapy
Time Frame
6 and 12 months after index CAG
Title
Change in hemoglobin A1c
Description
For risk of developing diabetes mellitus by statin therapy
Time Frame
6 and 12 months after index CAG
Title
Change in lipid profile
Description
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.
Time Frame
1, 6 and 12 months after index CAG
Title
Change in high-sensitivity C-reactive protein(hs-CRP)
Description
hs-CRP
Time Frame
1 and 12 months after index CAG
Title
Safety endpoint: Number of participants with abnormal laboratory values and adverse events
Description
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.
Time Frame
1 and 12 months after index CAG

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Joo-Yong Hahn, MD, PhD
Phone
82-2-3410-6653
Email
ichjy1@gmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Joo Myung Lee, MD, PhD
Phone
82-2-3410-1246
Email
Drone80@hanmail.net
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joo-Yong Hahn, MD, PhD
Organizational Affiliation
Samsung Medical Center
Official's Role
Study Chair
Facility Information:
Facility Name
Samsung Medical Center
City
Seoul
ZIP/Postal Code
06351
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joo-Yong Hahn, MD, PhD
Phone
82-2-3410-6653
Email
ichjy1@gmail.com
First Name & Middle Initial & Last Name & Degree
Joo Myung Lee, MD, MPH
Phone
82-2-3410-1246
Email
drone80@hanmail.net

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
After publication of first manuscript and trial results, the de-identified data will be shared by permission of principle investigator, when asked.

Learn more about this trial

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

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