In Silico Study Assessing the Impact of Inclisiran on Major Adverse Cardiovascular Events in Patients With Established Cardiovascular Disease

Study Overview
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Brief Summary
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Study CKJX839B1FR01 in an In silico trial to predict the efficacy of Inclisiran therapy on major adverse cardiovascular events (MACE) and cardiovascular (CV) death in virtual patients with atherosclerotic cardiovascular disease (ASCVD) and elevated LDL-C.

Detailed Description
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Purpose of this study is to predict the size of efficacy of inclisiran 300 mg s.c., administered on Day 1, Month 3 (Day 90), and every 6 months thereafter in addition to currently available lipid lowering therapies (LLTs) on a 3-Point-Major Adverse Cardiovascular Events (3P-MACE) defined as a composite of CV death, non-fatal myocardial infarction (MI) or non-fatal ischemic stroke, and on CV death, in a secondary prevention cohort of ASCVD virtual patients with a LDL-C ≥ 70 mg/dL. This will be compared to 1) placebo in adjunct to high-intensity statin therapy with or without ezetimibe, 2) ezetimibe in adjunct to high-intensity statin therapy, 3) Evolocumab in adjunct to high-intensity statin therapy and ezetimibe.

Official Title
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In Silico Non Interventional Secondary Use of Data Study Assessing the Impact of Inclisiran on Major Adverse Cardiovascular Events in Patients With Established Cardiovascular Disease

Conditions
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Atherosclerotic Cardiovascular Disease

Intervention / Treatment
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* Drug: Inclisiran sodium
* Drug: Placebo
* Drug: Ezetimibe
* Drug: Evolocumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria : Patients with atherosclerotic CV disease, defined as any of the following i. Previous MI ii. Previous ischemic stroke iii. Previous symptomatic peripheral arterial disease (PAD) as evidenced by either intermittent claudication with ABI <0.85, prior peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease Fasting LDL-C ≥ 70 mg/dL Under stable (≥ 4 weeks) well-tolerated high-intensity statin with or without ezetimibe. Exclusion Criteria : Patients with acute coronary syndrome, ischemic stroke, peripheral arterial revascularization procedure or amputation due to atherosclerotic disease <4 weeks prior to the first study visit

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Virtual Patient with ASCVD<br>Virtual Patient with ASCVD and LDL-C ≥ 70 mg/dL despite receiving a well-tolerated high-intensity statin with or without ezetimibe. Each virtual patient is his own control. | Drug: Inclisiran sodium<br>* Drug: Inclisiran sodium 300 mg virtually subcutaneously administered on Day 1, Month 3 (Day 90) and every 6 months thereafter until end of simulation.<br>Drug: Placebo<br>* Drug: Placebo virtually subcutaneously administered on Day 1, Month 3 (Day 90) and every 6 months thereafter until end of simulation.<br>Drug: Ezetimibe<br>* Drug: Ezetimibe 10 mg virtually orally once a day until end of simulation.<br>Drug: Evolocumab<br>* Drug: Evolocumab 140 mg virtually subcutaneously administered every two weeks until end of simulation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the first occurrence between trial start and end of follow-up of any component of 3P-MACE (composite of CV death, non-fatal MI or non-fatal ischemic stroke) | 3P-MACE is a confirmed composite endpoint which includes cardiovascular death, non-fatal myocardial infarction and non-fatal ischemic stroke. | 5 years of follow-up | 
| Time to the first occurrence between trial start and end of follow-up of CV death | CV death is defined as death due to cardiovascular events | 5 years of follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the first occurrence between trial start and end of follow-up of MI (non-fatal or fatal) | Myocardial infarction (MI) | 5 years of follow-up | 
| Time to the first occurrence between trial start and end of follow-up of ischemic stroke (non-fatal or fatal) |  | 5 years of follow-up | 
| Time to the first occurrence between trial start and end of follow-up of Major Adverse Limb events (MALE) | MALE include acute lower limb ischemia, lower limb amputation due to ischemia, or urgent lower limb revascularization for ischemia | 5 years of follow-up | 
| Change in LDL-C from baseline to specified time points | Low density lipoprotein cholesterol (LDL-C) | baseline, day 1, 30, 90 and every 6 months afterwards will be presented and additional time points could be added if deemed necessary. | 
| Time adjusted percentage change in LDL-C | This is the average percentage change in LDL-C from baseline over period from Day 90 and the end of follow-up period. | From baseline between Day 90 and the end of follow-up period (up to 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atherosclerotic cardiovascular disease, Hypercholesterolemia, Dyslipidemia, High cholesterol, Hyperlipidemia, Inclisiran, siRNA, KJX839, Myocardial infarction, Ischemic stroke, Peripheral arterial disease, In silico model, In silico simulation, PCSK9 inhibitors, Arteriosclerosis, Atherosclerosis, Arterial Occlusive Diseases, Vascular Diseases, Cardiovascular Diseases