Effectiveness and Safety Study of Early add-on of Ezetimibe With Atorvastatin in Very High-risk Patients (BETTER)

A Phase 4, Multicenter, Randomized, Open-label, Active-controlled Study to Evaluate the Effectiveness and Safety of Early add-on of Ezetimibe With Atorvastatin in Very High-risk Patients

This study aims to confirm the effectiveness of ezetimibe add-on therapy on LDL-C levels compared to atorvastatin monotherapy, especially in very high-risk patients. We intend to lay the foundation for a standard treatment for these patients through ezetimibe add on lipid-lowering therapy.

Study Overview

• Status: Completed
• Conditions: Atherosclerotic Cardiovascular Disease
• Intervention / Treatment: Drug: Atozet 10/40 mg or 10/80 mg; Drug: Lipitor 40 mg or 80 mg

Detailed Description

This is a phase 4, multicenter, randomized, open-label, active-controlled study to evaluate the effectiveness and safety of early add-on of ezetimibe with atorvastatin in very high-risk patients.

In Visit 1, screening is conducted for patients in the very high-risk group. LDL-C needs to be above 70 mg/dL in patients (a) who failed to achieve their target LDL-C goals with mild to moderate intensity statin; (b) who are statin-naive or have not been on a stable statin regimen for at least 4 weeks prior to enrollment. However, by tracking the registration status of patients, (b) patients should be enrolled not to exceed 40% of each group. All laboratory tests are performed in the local laboratory and the Visit 1 results may be substituted if available within 2 weeks prior to the screening visit. The study participation is determined through the inclusion/exclusion criteria based on the test results conducted for Visit 1. In the case of the lipid parameter, Visit 1 results are used as the baseline. Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened once.

In Visit 2, randomization is performed on patients who meet the inclusion criteria and do not meet any of the exclusion criteria and will be distributed 1:1 between test group (arm Eze/Ato) and control group (arm Ato). The results of laboratory tests at the Visit 2 are used as baseline except lipid parameters. Visit 1 and Visit 2 may be conducted on the same date.

In Visit 2 and Visit 3, the appropriate investigational medical product (IMP) is given to each group. In principle, IMPs are administered orally once a day from the day of distribution.

For participants whose LDL-C value has reached the target (LDL-C < 55 mg/dL) according to the lipid indicator test at Visit 3, they will continue treatment with the same dose for 6 weeks. If the LDL-C level has not reached target, the dose of atorvastatin should be increased to ezetimibe/atorvastatin 10/80 mg or atorvastatin 80 mg according to the group assigned. In principle, a morning visit is recommended so that the laboratory test results can be checked and the IMP can be prescribed and taken on the same day. However, if the test results are not confirmed on the same day, the investigator continues to prescribe the same dose of IMP(ezetimibe/atorvastatin 10/40 mg or atorvastatin 40 mg) the participant was taking for one more week, and an additional visit is made within 1 week to receive the new IMP. Visit 4 is the end of study visit, and tests for effectiveness and safety are conducted.

63 patients for each group and thus, a total of 126 patients will be randomized in this study.

• Study Type: Interventional
• Enrollment (Actual): 137
• Phase: Phase 4

Contacts and Locations

Study Locations

• South Korea
  • Seoul, South Korea, 03181
    • Kangbuk Samsung Hospital
  • Eunpyeong-gu
    • Seoul, Eunpyeong-gu, South Korea, 03312
      • Eunpyeong St. Mary's Hospital
  • Gyeonggi-do
    • Goyang-si, Gyeonggi-do, South Korea, 10380
      • Inje University Ilsan-Paik Hospital
    • Seongnam-si, Gyeonggi-do, South Korea, 13620
      • Seoul National University Bundang Hospital
  • Gyeongsangbuk-do
    • Daegu, Gyeongsangbuk-do, South Korea, 42601
      • Keimyung University Dongsan Medical Center
  • Gyeongsangnam-do
    • Ulsan, Gyeongsangnam-do, South Korea, 44033
      • Ulsan University Hospital
  • Jeollanam-do
    • Gwangju, Jeollanam-do, South Korea, 61469
      • Chonnam National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients who are ≥ 30 years old.
2. Patients with very high-risk*: clinical or unequivocal on imaging ASCVD. ASCVD includes previous ACS (MI or UA), stable angina, coronary revascularization (percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), and other arterial revascularization procedures), stroke and transient ischaemic attack (TIA), and peripheral arterial disease (Mach F 2020).

3. Patients (a) who failed to achieve their target LDL-C goals with low and/or moderate intensity statin mono therapy for ≥ 4 weeks or (b) who are statin-naïve or have not been on a stable (unchanged) statin regimen for at least 4 weeks prior to enrollment

   • rosuvastatin < 10 mg, atorvastatin < 40 mg, and all dose of pitavastatin, simvastatin, lovastatin, pravastatin, and fluvastatin (Team G 2020).
4. Patients with LDL-C levels ≥ 70 mg/dL
5. Patients who are willing to maintain TLC throughout the study.
6. Patients who are willing to provide written informed consent prior to study enrollment.

Exclusion Criteria:

1. Patients with hypersensitivity to ezetimibe, atorvastatin or any of its inactive ingredients.
2. Patients with active liver disease or unexplained persistent elevations of hepatic transaminase levels. (aspartate transaminase (AST) or alanine transaminase (ALT) > 3 x upper limit of normal (ULN)).
3. Patients who have predisposing conditions with muscle disease (i.e., rhabdomyolysis or myopathy) or neuromuscular disease.
4. Patients with myasthenia gravis.
5. Female patients who are pregnant or have a potential to be pregnant and nursing.
6. Patients who are taking glecaprevir and pibrentasvir.
7. Patients with hereditary problems of galactose intolerance, lapp lactase deficiency, or of glucose-galactose malabsorption.
8. Patients with disease known to influence serum lipids or lipoproteins excluding dyslipidemia.
9. Patients with a history of cancer within 5 years.
10. Patients whose life expectancy is less than 6 months due to their medical conditions.
11. Patients with any condition or situation that might pose a risk to the participant or interfere with participation in the study.
12. Patients who have received any investigational medicine within 12 weeks of written informed consent or are going to receive during the clinical trial period.
13. Patients who are judged to be difficult to conduct clinical trials according to the judgment of the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Eze/Ato: Ezetimibe/Atorvastatin; Participants will receive ezetimibe/atorvastatin 10/40 mg QD from Visit 2 (Day 1) to Visit 3 (Week 6). If the LDL-C target is reached (LDL-C < 55 mg/dL) at Visit 3, maintain the dose to Visit 4 (Week 12). If the LDL-C target level is not reached at Visit 3, dose is increased to ezetimibe/atorvastatin 10/80 mg QD from Visit 3 to Visit 4.	Drug: Atozet 10/40 mg or 10/80 mg; Atozet 10/40 mg or 10/80 mg Dosage Formulation: Tablet Dosing Instructions: oral. Take 1 tablet daily
Active Comparator: Ato: Atorvastatin; Participants will receive atorvastatin 40 mg QD from Visit 2 (Day 1) to Visit 3 (Week 6). If the LDL-C target is reached (LDL-C < 55 mg/dL) at Visit 3, maintain the dose to Visit 4 (Week 12). If the LDL-C target is not reached at Visit 3, dose is increased to atorvastatin 80 mg QD from Visit 3 to Visit 4.	Drug: Lipitor 40 mg or 80 mg; Lipitor 40 mg or 80 mg Dosage Formulation: Tablet Dosing Instructions: oral. Take 1 tablet daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change From Baseline in Low-Density Lipoprotein Cholesterol at Week 6	Blood samples were collected to determine the LDL-C values. The percentage change from baseline was defined as 100 x (LDL-C value at 6 weeks - LDL-C value at baseline)/LDL-C value at baseline. Baseline was defined as the last non-missing measurement taken prior to reference start date.	Baseline (Day 1) and Week 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved Low-Density Lipoprotein Cholesterol Goal of <55 mg/dL at Weeks 6 and 12	Blood samples were collected to determine the LDL-C values. Participants with LDL-C <55 mg/dL were identified. Percentages are rounded off to the hundredth decimal place.	Weeks 6 and 12
Percentage of Participants Who Achieved Low-Density Lipoprotein Cholesterol Goal of <70 mg/dL at Weeks 6 and 12	Blood samples were collected to determine the LDL-C values. Participants with LDL-C <70 mg/dL were identified. Percentages are rounded off to the hundredth decimal place.	Weeks 6 and 12
Percentage Change From Baseline in Low-Density Lipoprotein Cholesterol at Week 12	Blood samples were collected to determine the LDL-C values. The percentage change from baseline was defined as 100 x (LDL-C value at 12 weeks - LDL-C value at baseline)/LDL-C value at baseline. Baseline was defined as the last non-missing measurement taken prior to reference start date.	Baseline (Day 1) and Week 12
Percentage Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C), Non-High-Density Lipoprotein Cholesterol (Non-HDL-C), Triglycerides, and Total Cholesterol at Weeks 6 and 12	Blood samples were collected to determine the HDL-C, non-HDL-C, triglycerides, and total cholesterol values. The percentage change from baseline for HDL-C was defined as 100 x (HDL-C value at 6 or 12 weeks - HDL-C value at baseline)/HDL-C value at baseline. The percentage change from baseline for non-HDL-C was defined as 100 x (non-HDL-C value at 6 or 12 weeks - non-HDL-C value at baseline)/non-HDL-C value at baseline. The percentage change from baseline for triglycerides was defined as 100 x (triglycerides value at 6 or 12 weeks - triglycerides value at baseline)/triglycerides value at baseline. The percentage change from baseline for total cholesterol was defined as 100 x (total cholesterol value at 6 or 12 weeks - total cholesterol value at baseline)/total cholesterol value at baseline. Baseline was defined as the last non-missing measurement taken prior to reference start date.	Baseline (Day 1) and Weeks 6 and 12
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) at Weeks 6 and 12	An adverse event (AE) was defined as any untoward medical occurrence in a clinical study participant administered a medicinal product and which does not necessarily have a causal relationship with that product. An SAE was defined as any AE that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event. A TEAE was defined as AEs that first occurred or worsened in severity on or after the first administration of the study treatment during the treatment period.	From the first dose administration of the study treatment (Day 1) up to Week 6; From the first dose administration of the study treatment (Day 1) up to Week 12
Number of Participants With Treatment-Emergent Adverse Event Leading to the Premature Discontinuation of the Study	An AE was defined as any untoward medical occurrence in a clinical study participant administered a medicinal product and which does not necessarily have a causal relationship with that product. An SAE was defined as any AE that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event. A TEAE was defined as AEs that first occurred or worsened in severity on or after the first administration of the study treatment during the treatment period.	From the first dose administration of the study treatment (Day 1) up to Week 6; From the first dose administration of the study treatment (Day 1) up to Week 12

Collaborators and Investigators

• Sponsor: Organon and Co
• Collaborators: IQVIA Pty Ltd
• Investigators: Study Director: WonYoung Lee, Organon

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2023
• Primary Completion (Actual): September 4, 2024
• Study Completion (Actual): October 15, 2024

Study Registration Dates

• First Submitted: February 27, 2023
• First Submitted That Met QC Criteria: March 8, 2023
• First Posted (Actual): March 9, 2023

Study Record Updates

• Last Update Posted (Estimated): September 9, 2025
• Last Update Submitted That Met QC Criteria: August 20, 2025
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Very high-risk patients' Atherosclerotic cardiovascular disease (ASCVD)
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fatty Acids; Lipids; Azoles; Pyrroles; Heptanoic Acids; Atorvastatin
• Other Study ID Numbers: OG-KORATO-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No