Effects of Ezetimibe Combination Therapy for Patients With Atherosclerotic Cardiovascular Disease; Randomized Comparison of LDL-cholesterol Targeting <70 Versus <55mg/dL; Ez-PAVE Trial

Sponsor

Yonsei University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04626973

Collaborator

(none)

3,048

Enrollment

Location

Arms

55.5

Anticipated Duration (Months)

54.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Although the clinical efficacy of LDL-cholesterol lowering therapy has been proven with strong evidences and emphasized, there are also growing concerns that intensive lipid-lowering therapy would be related to increased risk of adverse effects. In addition, statin potency from recent guidelines was set from the studies composed of mainly Caucasian population, although there is an inconsistency of statin effect according to ethnicity. Asian population showed more profound LDL reduction not only from high potent statin but also from moderate to low potent statin. Conventional strategies for lowering LDL-cholesterol focused on statins, therefore doubling of previously described dose of statin would be common way in patients with inadequate LDL-cholesterol levels. Adding ezetimibe will be an alternative strategy not only to lower LDL-cholesterol level and also to reduce the need of dosage of high-intensity statin to achieve sufficient LDL-cholesterol lowering effect. However, studies regarding the effect of intensive-targeting of lipid-lowering therapy and therapy regimens are lacking. Thus, on these basis, we sought to evaluate whether intensive-targeting of lipid-lowering therapy will have more prominent beneficial effect compared to conventional-targeting in patients with documented ASCVD with either an ezetimibe/statin combination therapy or a statin monotherapy.

Condition or Disease	Intervention/Treatment	Phase
Atherosclerotic Cardiovascular Disease	Drug: Ezetimibe/Statin Combination therapy Drug: Statin monotherapy Drug: Ezetimibe/Statin Combination therapy Drug: Statin monotherapy	N/A

Detailed Description

All eligible patients who have documented ASCVD will be enrolled according to inclusion/exclusion criteria after voluntary agreement with informed consent. At the time of enrollment, we will stratify all patients according to LDL-cholesterol <100mg/dL, DM, and acute coronary syndrome, and randomly assign them in two groups according to LDL-cholesterol targeting level with a 1:1 ratio: "Intensive-targeting group" vs. "Conventional-targeting group". In addition, patients in each group will be randomly assigned to receive two lipid-lowering therapy regimen with a 1:1 ratio: "Ezetimibe/Statin combination therapy" vs. "Statin monotherapy". Patients allocated to each treatment group will receive lipid-lowering therapy with following protocols.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

3048 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Intervention Model Description:

At the time of enrollment, we will stratify all patients according to LDL-cholesterol <100mg/dL, DM, and acute coronary syndrome, and randomly assign them in two groups according to LDL-cholesterol targeting level with a 1:1 ratio: "Intensive-targeting group" vs. "Conventional-targeting group". In addition, patients in each group will be randomly assigned to receive two lipid-lowering therapy regimen with a 1:1 ratio: "Ezetimibe/Statin combination therapy" vs. "Statin monotherapy".At the time of enrollment, we will stratify all patients according to LDL-cholesterol <100mg/dL, DM, and acute coronary syndrome, and randomly assign them in two groups according to LDL-cholesterol targeting level with a 1:1 ratio: "Intensive-targeting group" vs. "Conventional-targeting group". In addition, patients in each group will be randomly assigned to receive two lipid-lowering therapy regimen with a 1:1 ratio: "Ezetimibe/Statin combination therapy" vs. "Statin monotherapy".

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Effects of Ezetimibe Combination Therapy for Patients With Atherosclerotic Cardiovascular Disease; Randomized Comparison of LDL-cholesterol Targeting <70 Versus <55mg/dL; Ez-PAVE Trial

Actual Study Start Date :

Jan 15, 2021

Anticipated Primary Completion Date :

Sep 1, 2025

Anticipated Study Completion Date :

Sep 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intensive-targeting group	Drug: Ezetimibe/Statin Combination therapy For statin naive patients, patients would initially receive Ezetimibe 10 mg plus Rosuvastatin 10 mg , For non-statin naive patients, regimens are to be changed to the equivalent dose of ezetimibe+rosuvastatin combination in case of already achieved LDL-cholesterol target (<55 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target. Drug: Statin monotherapy For statin naive patients, patients would initially receive Ezetimibe 10 mg plus Rosuvastatin 10 mg , For non-statin native patients, regimens are to be change to equivalent dose of atorvastatin or rosuvastatin in case of already achieved LDL-cholesterol target (<55 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.
Active Comparator: Conventional-targeting group	Drug: Ezetimibe/Statin Combination therapy For statin naive patients, patients would initially receive Ezetimibe 10 mg plus Rosuvastatin 10 mg , For non-statin naive patients, regimens are to be changed to the equivalent dose of ezetimibe+rosuvastatin combination in case of already achieved LDL-cholesterol target (<70 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target. Drug: Statin monotherapy For statin naive patients, patients would initially receive Ezetimibe 10 mg plus Rosuvastatin 10 mg , For non-statin native patients, regimens are to be change to equivalent dose of atorvastatin or rosuvastatin in case of already achieved LDL-cholesterol target (<70 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.

Arm

Intervention/Treatment

Experimental: Intensive-targeting group

Drug: Ezetimibe/Statin Combination therapy

For statin naive patients, patients would initially receive Ezetimibe 10 mg plus Rosuvastatin 10 mg , For non-statin naive patients, regimens are to be changed to the equivalent dose of ezetimibe+rosuvastatin combination in case of already achieved LDL-cholesterol target (<55 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.

Drug: Statin monotherapy

For statin naive patients, patients would initially receive Ezetimibe 10 mg plus Rosuvastatin 10 mg , For non-statin native patients, regimens are to be change to equivalent dose of atorvastatin or rosuvastatin in case of already achieved LDL-cholesterol target (<55 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.

Active Comparator: Conventional-targeting group

Drug: Ezetimibe/Statin Combination therapy

For statin naive patients, patients would initially receive Ezetimibe 10 mg plus Rosuvastatin 10 mg , For non-statin naive patients, regimens are to be changed to the equivalent dose of ezetimibe+rosuvastatin combination in case of already achieved LDL-cholesterol target (<70 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.

Drug: Statin monotherapy

For statin naive patients, patients would initially receive Ezetimibe 10 mg plus Rosuvastatin 10 mg , For non-statin native patients, regimens are to be change to equivalent dose of atorvastatin or rosuvastatin in case of already achieved LDL-cholesterol target (<70 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.

Outcome Measures

Primary Outcome Measures

Clinical outcomes by different lipid-lowering therapy [Within 3 years after the enrollment]
Composite of cardiovascular death, non-fatal MI, non-fatal stroke, any revascularization, and hospitalization for angina

Secondary Outcome Measures

Each component of primary endpoint within 3 years [Within 3 years after the enrollment]
A. Rate of Cardiovascular death B. Rate of non-fatal MI C. Rate of non-fatal stroke D. Rate of any revascularization E. Rate of hospitalization for angina
Various composite outcomes within 3 years [Within 3 years after the enrollment]
A. Rate of composite of cardiovascular death, non-fatal MI, and non-fatal stroke B. Rate of composite of cardiovascular death, non-fatal MI, non-fatal stroke, and any revascularization C. Rate pf composite of cardiovascular death, non-fatal MI, and any revascularization D. Rate of composite of all-cause death, non-fatal MI, non-fatal stroke, any revascularization, and hospitalization for angina
Proportion of subjects achieving target LDL-cholesterol level [Within 3 years after the enrollment]
Rate of cross-over into the non-allocated therapy regimen in order to achieve target LDL-cholesterol level [Within 3 years after the enrollment]
Proportions of subjects requiring proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to achieve target LDL-cholesterol level [Within 3 years after the enrollment]
Difference in rate of primary outcome according to sex [Within 3 years after the enrollment]
Difference in rate of primary outcome according to body mass index [Within 3 years after the enrollment]
Rate of New-onset diabetes mellitus [Within 3 years after the enrollment]
Rate of worsening of glycemic control or homeostatic model assessment (HOMA)-index [Within 3 years after the enrollment]
Occurrence of statin-associated muscle symptoms (SAMS) requiring change of therapy regimen or dosage [Within 3 years after the enrollment]
Occurence of elevation of muscle enzymes (CPK > 4 x UNL) [Within 3 years after the enrollment]
Occurence of elevation of hepatic enzymes (AST, ALT, or both ≥ 3 x UNL) [Within 3 years after the enrollment]
Occurence of elevation of serum creatinine level (>50% from baseline) [Within 3 years after the enrollment]
Change of proteinuria [Within 3 years after the enrollment]
Rate of cancer diagnosis [Within 3 years after the enrollment]
Rate of operation due to cataract [Within 3 years after the enrollment]

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 19-80 years
Documented atherosclerotic cardiovascular disease (ASCVD)

Previous acute coronary syndrome (myocardial infarction [MI] or unstable angina),
Or stable angina with imaging or functional studies
Or coronary revascularization (percutaneous coronary intervention [PCI], coronary artery bypass graft [CABG], and other arterial revascularization procedures)
Or stroke and transient ischemic attack (TIA)
Or peripheral artery disease

Exclusion Criteria:

LDL-cholesterol level less than 70 mg/dL without statin therapyAllergy or hypersensitive to ezetimibe or statin
Active liver disease or persistent unexplained serum AST/ALT elevation more than 2 times the upper limit of normal range
Allergy or hypersensitivity to any statin or ezetimibe
Solid organ transplantation recipient
Pregnant women, women with potential childbearing, or lactating women
Life expectancy less than 3 years
Inability to follow the patient over the period of 1 year after enrollment, as assessed by the investigator
Inability to understand or read the informed content