Study of Efficacy and Safety of Inclisiran in Asian Participants With Atherosclerotic Cardiovascular Disease (ASCVD) or ASCVD High Risk and Elevated Low Density Lipoprotein Cholesterol (LDL-C)

Study Overview
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Brief Summary
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A multicenter study to evaluate safety and efficacy of inclisiran in Asian patients with ASCVD or ASCVD high risk and elevated LDL-C

Detailed Description
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The purpose of the study is to demonstrate the efficacy and safety of inclisiran sodium 300mg to support the indication for LDL-C reduction of inclisiran in Asian patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-high risk patients with elevated LDL-C as an adjunct to diet and maximally tolerated dose statins with or without additional lipid-lowering therapy. A core part (2-week screening period and a 12-month double-blinded treatment period), and an extension part (until reasonable access to the IMP post product launch provided for the participants)

Official Title
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A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Study to Evaluate the Efficacy and Safety of Inclisiran in Asian Patients With ASCVD or ASCVD High Risk and Elevated Low-density Lipoprotein Cholesterol as an Adjunct to Diet and Maximally Tolerated Statins With or Without Additional Lipid-lowering Therapy (ORION-18)

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: inclisiran sodium
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -At screening participants with: ASCVD (including acute coronary syndrome (ACS), stable coronary heart disease, post revascularization, ischemic cardiomyopathy, ischemic stroke, transient ischemic attack (TIA), and peripheral atherosclerosis) and Serum LDL-C ≥1.8 mmol/L (≥70 mg/dL) OR ASCVD high risk (LDL-C ≥4.9 mmol/L, diabetes, high 10-year ASCVD risk assessed by Chinese ASCVD Risk Assessment Flow Chart , or high risk per local guidelines with a target LDL-C of <100 mg/dL) and Serum LDL-C ≥2.6 mmol/L (≥100 mg/dL) Fasting triglyceride < 400 mg/dL (< 4.52 mmol/L) at screening. Participants on statins should be receiving a maximally tolerated dose . Maximum tolerated dose is defined as the maximum dose of statin that can be taken on a regular basis without intolerable AE. Intolerance to any dose of statin must be documented as historical AEs attributed to the statin in question on the source documentation and on the Medical history page of the eCRF Participants not receiving statin must have a documented evidence of intolerance to all doses of at least 2 different statins(or the corresponding local definition of complete intolerance to statins) Participants following lifestyle modification should be on the therapy of LDL-C lowering (such as statin monotherapy, or statin incombination with ezetimibe) with a stable dose for ≥30 days before screening and have no planned medication or dose change during study participation. Participants are willing and able to give informed consent before initiation of any study related procedures and willing to comply with all required study procedures. Exclusion Criteria: New York Heart Association (NYHA) class IV heart failure or last known left ventricular ejection fraction <25%. Cardiac arrhythmia with clinical significance within 3 months prior to randomization that is not controlled by medication or via ablation. Major adverse cardiovascular event within 3 months prior to randomization. Uncontrolled severe hypertension: systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg prior to randomization despite antihypertensive therapy. Calculated glomerular filtration rate ≤30 mL/min by estimated glomerular filtration rate (eGFR) using standardized clinical methodology. Severe concomitant non-cardiovascular disease that carries the risk of reducing life expectancy to less than 2 years. History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy and/or systemic therapy during the three years prior to randomization. Barrier method: Condom or Occlusive cap (e.g. diaphragm or cervical/vault caps). Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: inclisiran sodium 300 mg<br>Subcutaneous injection | Drug: inclisiran sodium<br>* Subcutaneously injected on Day 1, 90 and 270 (Core Part). Subcutaneously injected on Day 360 and every 6 months thereafter until EOS visit (Extension Part)<br>* Other names: KJX839;|
| Placebo Comparator: Placebo<br>Subcutaneous injection | Drug: Placebo<br>* Subcutaneously injected on Day 1, 90, and 270.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core: Percentage change in low- density lipoprotein cholesterol (LDL-C) | Superiority of inclisiran compared to placebo in reducing LDL-C from baseline to Day 330 | Baseline, Day 330 | 
| Extension: Number of participants with Adverse Events | Evaluation of the safety and tolerability of inclisiran, treatment emergent Adverse events and Serious Adverse Events | Day 360 until study completion, an average of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core: Time adjusted percentage change in LDL-C | The superiority of inclisiran compared to placebo in reducing LDL-C from baseline to Day 330 and over time | From baseline after Day 90 and up to Day 360 | 
| Core: Absolute change in LDL-C | The superiority of inclisiran compared to placebo in reducing LDL-C from baseline to Day 330 and over time | From baseline to Day 330 | 
| Core: Time adjusted absolute change in LDL-C | The superiority of inclisiran compared to placebo in reducing LDL-C from baseline to Day 330 and over time | From baseline after Day 90 and up to Day 360 | 
| Core: Percentage change in PCSK9 | The superiority of inclisiran compared to placebo in reducing PCSK9 from baseline to Day 330 | From baseline to Day 330 | 
| Core: Absolute change in PCSK9 | The superiority of inclisiran compared to placebo in reducing PCSK9 from baseline to Day 330 | From baseline to Day 330 | 
| Core: Proportion of participants reaching LDL-C levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL | The superiority of inclisiran compared to placebo in individual response rate for lipid controlling | Day 330 | 
| Core: Proportion of participants in each group with ≥ 50% LDL-C reduction | The superiority of inclisiran compared to placebo in individual response rate for lipid controlling | From baseline to Day 330 | 
| Core: Proportion of participants in each group who attain global lipid targets for their level of ASCVD risk (55mg/dl for ASCVD patients, 70mg/dl for ASCVD high risk patients) | The superiority of inclisiran compared to placebo in individual response rate for lipid controlling | Day 330 | 
| Core: Percentage change in total cholesterol, ApoB, non-HDL-C, ApoA1, HDL-C, Lp(a) and triglycerides | The superiority of inclisiran compared to placebo in reducing other lipids, lipoproteins and apolipoproteins | From baseline to Day 330 | 
| Core: Absolute change in total cholesterol, ApoB, non-HDL-C, ApoA1, HDL-C, Lp(a) and triglycerides | The superiority of inclisiran compared to placebo in reducing other lipids, lipoproteins and apolipoproteins | From baseline to Day 330 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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inclisiran, siRNA, dyslipidemia, KJX839