The ULTRA-CKD trial is a prospective, randomized, open-label, multicenter trial designed to compare the efficacy and safety of moderate-intensity statin plus ezetimibe combination therapy versus high-intensity statin monotherapy in patients with chronic kidney disease (CKD) and concomitant atherosclerotic cardiovascular disease (ASCVD). Patients with CKD are at very high risk for ASCVD. In this population, it is important to establish a lipid-lowering strategy that optimizes cardiovascular outcomes while ensuring long-term safety. While high-intensity statins are generally considered as initial treatment option for secondary prevention, the optimal strategy for CKD patients remains to be clinicaly defined. This study aims to evaluate whether the combination of moderate-intensity statin and ezetimibe is non-inferior to high-intensity statin monotherapy in terms of 3-year composite of major adverse cardiovascular events.
All eligible patients with chronic kidney disease (CKD) and concomitant atherosclerotic cardiovascular disease (ASCVD) will be enrolled according to inclusion/exclusion criteria after voluntary agreement with informed consent. At the time of enrollment, we will stratify the patients according to diabetes mellitus and dialysis status, and randomly assign them in two groups according to lipid-lowering regimen with a 1:1 ratio: "Moderate-intensity statin plus ezetimibe group" vs. "High-intensity statin monotherapy group". In this study, the combination therapy strategy will utilize Pitavastatin 1-4 mg plus Ezetimibe 10 mg once daily or Atorvastatin 10-20 mg plus Ezetimibe 10 mg once daily. The monotherapy strategy will utilize Atorvastatin 40 mg once daily. Study visits are scheduled at 4 weeks and at 6, 12, 18, 24, 30, and 36 months. The primary outcome is the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary outcome is CKD progression defined as a ≥40% decline in eGFR confirmed on at least two consecutive measurements
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,952
Participants will receive moderate-intensity statin plus ezetimibe (pitavastatin 1-4 mg + ezetimibe 10 mg once daily or atorvastatin 10-20 mg + ezetimibe 10 mg once daily), with 36-month follow-up.
Participants will receive high-intensity statin monotherapy (atorvastatin 40 mg once daily), with 36-month follow-up.
Severance Hospital
Seoul, South Korea
RECRUITINGMajor adverse cardiovascular events
Composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.
Time frame: 3 years
CKD progression
CKD progression: ≥40% decline in eGFR from baseline, confirmed on at least two consecutive measurements during follow-up.
Time frame: 3 years
Cardiovascular death.
Death due to cardiovascular causes during follow-up.
Time frame: 3 years
Myocardial infarction.
Occurrence of myocardial infarction during follow-up.
Time frame: 3 years
Stroke.
Occurrence of stroke during follow-up
Time frame: 3 years
Hospitalization for unstable angina.
Hospitalization due to unstable angina during follow-up.
Time frame: 3 years
Coronary revascularization.
Any coronary revascularization procedure, including percutaneous coronary intervention or coronary artery bypass graft surgery, during follow-up.
Time frame: 3 years
Composite of cardiovascular death, myocardial infarction, and stroke.
First occurrence of cardiovascular death, myocardial infarction, or stroke during follow-up.
Time frame: 3 years
Composite of cardiovascular death, myocardial infarction, stroke, and hospitalization for unstable angina
First occurrence of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina during follow-up
Time frame: 3 years
Composite of cardiovascular death, myocardial infarction, stroke, and coronary revascularization.
First occurrence of cardiovascular death, myocardial infarction, stroke, or coronary revascularization during follow-up.
Time frame: 3 years
Composite of all-cause death, myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization.
First occurrence of all-cause death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization during follow-up.
Time frame: 3 years
Proportion of participants achieving the LDL-C <70 mg/dL in each group.
Proportion of participants achieving a low-density lipoprotein cholesterol (LDL-C) level below 70 mg/dL in each treatment group during follow-up.
Time frame: 3 years
Proportion of participants achieving LDL-C <55 mg/dL in each group.
Proportion of participants achieving a low-density lipoprotein cholesterol (LDL-C) level below 55 mg/dL in each treatment group during follow-up.
Time frame: 3 years
Proportion of participants crossing over to the non-assigned treatment group in each group.
Proportion of participants who crossed over from the assigned treatment group to the non-assigned treatment group during follow-up.
Time frame: 3 years
New-onset diabetes mellitus.
Occurrence of new-onset diabetes mellitus during follow-up.
Time frame: 3 years
New-onset diabetes mellitus requiring initiation of antidiabetic medication.
Occurrence of new-onset diabetes mellitus requiring initiation of antidiabetic medication during follow-up.
Time frame: 3 years
Worsening glycemic control.
Occurrence of worsening glycemic control during follow-up
Time frame: 3 years
Marked decline in kidney function
eGFR \<10 mL/min/1.73 m², confirmed on at least two consecutive measurements during follow-up.
Time frame: 3 years
Initiation of dialysis or kidney transplantation.
Initiation of maintenance dialysis or receipt of kidney transplantation during follow-up.
Time frame: 3 years
Statin-associated muscle symptoms requiring a change in regimen or dose.
Occurrence of statin-associated muscle symptoms requiring a change in statin regimen or dose during follow-up.
Time frame: 3 years
Rhabdomyolysis.
Occurrence of rhabdomyolysis during follow-up.
Time frame: 3 years
Elevated creatine phosphokinase (CK >4 × the upper limit of normal)
Elevation of creatine phosphokinase greater than 4 times the upper limit of normal during follow-up.
Time frame: 3 years
Elevated liver enzymes (AST and/or ALT ≥3 × the upper limit of normal)
Elevation of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) equal to or more than 3 times the upper limit of normal during follow-up.
Time frame: 3 years
Cancer diagnosis
New diagnosis of cancer during follow-up.
Time frame: 3 years
Cataract surgery.
Occurrence of cataract surgery during follow-up.
Time frame: 3 years
Hemorrhagic stroke.
Occurrence of hemorrhagic stroke during follow-up.
Time frame: 3 years
Major bleeding (BARC type 2, 3, or 5 bleeding), assessed among participants who underwent percutaneous coronary intervention with new stent implantation at study enrollment.
Major bleeding defined as BARC type 2, 3, or 5 bleeding, assessed among participants who underwent percutaneous coronary intervention with new stent implantation at study enrollment.
Time frame: 3 years
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