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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Atherosclerotic Cardiovascular Disease

Intervention / Treatment
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* Drug: Atozet 10/40 mg or 10/80 mg
* Drug: Lipitor 40 mg or 80 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who are ≥ 30 years old. 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). 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). Patients with LDL-C levels ≥ 70 mg/dL Patients who are willing to maintain TLC throughout the study. Patients who are willing to provide written informed consent prior to study enrollment. Exclusion Criteria: Patients with hypersensitivity to ezetimibe, atorvastatin or any of its inactive ingredients. 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)). Patients who have predisposing conditions with muscle disease (i.e., rhabdomyolysis or myopathy) or neuromuscular disease. Patients with myasthenia gravis. Female patients who are pregnant or have a potential to be pregnant and nursing. Patients who are taking glecaprevir and pibrentasvir. Patients with hereditary problems of galactose intolerance, lapp lactase deficiency, or of glucose-galactose malabsorption. Patients with disease known to influence serum lipids or lipoproteins excluding dyslipidemia. Patients with a history of cancer within 5 years. Patients whose life expectancy is less than 6 months due to their medical conditions. Patients with any condition or situation that might pose a risk to the participant or interfere with participation in the study. Patients who have received any investigational medicine within 12 weeks of written informed consent or are going to receive during the clinical trial period. Patients who are judged to be difficult to conduct clinical trials according to the judgment of the investigator.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eze/Ato: Ezetimibe/Atorvastatin<br>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<br>* Atozet 10/40 mg or 10/80 mg Dosage Formulation: Tablet Dosing Instructions: oral. Take 1 tablet daily<br>|
| Active Comparator: Ato: Atorvastatin<br>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<br>* Lipitor 40 mg or 80 mg Dosage Formulation: Tablet Dosing Instructions: oral. Take 1 tablet daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effectiveness of early add-on of ezetimibe with atorvastatin in very high-risk patients - Percentage change in LDL-C from baseline to week 6 | All laboratory tests are performed in the local laboratory , percentage change in LDL-C from baseline to 6 weeks. | Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the clinical effectiveness of early add-on of ezetimibe with atorvastatin in very high-risk patients - Proportion of patients achieving LDL-C goal of <55 mg/dL after 6 weeks and 12 weeks of treatment | All laboratory tests are performed in the local laboratory, Proportion of patients achieving LDL-C goal of <55 mg/dL after 6 weeks and 12 weeks of treatment | Week 12 | 
| Proportion of patients achieving LDL-C goal of <70 mg/dL after 6 weeks and 12 weeks of treatment. | All laboratory tests are performed in the local laboratory, Proportion of patients achieving LDL-C goal of <70 mg/dL after 6 weeks and 12 weeks of treatment | Week 12 | 
| : Percentage change in LDL-C from baseline to week 12 | All laboratory tests are performed in the local laboratory, Percentage change in LDL-C from baseline to week 12 | Week 12 | 
| Percentage change in HDL-C, non-HDL-C, triglycerides, and total cholesterol from baseline to week 6 and week 12 | All laboratory tests are performed in the local laboratory, Percentage change in HDL-C, non-HDL-C, from baseline to week 6 and week 12 | Week 12 | 
| To evaluate the safety of early add-on of ezetimibe with atorvastatin in very high-risk patients - Treatment-emergent adverse events (TEAEs) at 6 weeks and 12 weeks | The number and percentage of patients experiencing TEAEs, treatment-emergent serious adverse events (TESAE)s, Treatment-related adverse events (TRAEs) and TEAEs leading to the premature discontinuation of the study at 6 weeks and 12 weeks will be presented by treatment group and tested using Chi-square test or Fisher's exact test as appropriate. The difference in the percentages will be presented with its corresponding 95% CI and p-value. | Week 12 | 
| Dropout rate due to TEAEs at 6 weeks and 12 weeks | The number and percentage of patients experiencing TEAEs, treatment-emergent serious adverse events (TESAE)s, Treatment-related adverse events (TRAEs) and TEAEs leading to the premature discontinuation of the study at 6 weeks and 12 weeks will be presented by treatment group and tested using Chi-square test or Fisher's exact test as appropriate. The difference in the percentages will be presented with its corresponding 95% CI and p-value. | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Very high-risk patients' Atherosclerotic cardiovascular disease (ASCVD)