Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol

Study Overview
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Brief Summary
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This is a Phase III, placebo-controlled, double-blind, randomized study in participants with ASCVD or ASCVD-Risk equivalents and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) inclisiran injection(s). The study will be an international multicenter study (non-United States).

Official Title
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A Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect of 300 mg of Inclisiran Sodium Given as Subcutaneous Injections in Subjects With Atherosclerotic Cardiovascular Disease (ASCVD) or ACSVD Risk-Equivalents and Elevated Low-Density Lipoprotein Cholesterol (LDL-C)

Conditions
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ASCVD, Risk Factor, Cardiovascular, Elevated Cholesterol

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: Participants may be included if they meet all of the following inclusion criteria prior to randomization: Male or female participants ≥18 years of age. History of ASCVD (coronary heart disease [CHD], cardiovascular disease [CVD], or peripheral arterial disease [PAD]). Serum LDL-C ≥1.8 millimole (mmol)/liter (L) (≥70 mg/dL). Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening. Calculated glomerular filtration rate >30 mL/min by estimated glomerular filtration rate (eGFR) using standardized clinical methodology Participants on statins should be receiving a maximally tolerated dose. Participants not receiving statins must have documented evidence of intolerance to all doses of at least 2 different statins. Subjects on lipid-lower therapies (such as a statin and/or ezetimibe) should be on a stable dose for ≥30 days before screening with no planned medication or dose change during study participation. Subjects were 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: Participants will be excluded from the study if any of the following exclusion criteria apply prior to randomization: New York Heart Association (NYHA) class IV heart failure. Uncontrolled cardiac arrhythmia. Uncontrolled severe hypertension. Active liver disease. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least 2 methods of highly effective contraception (failure rate less than 1% per year) (for example, combined oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, or intrauterine device) for the entire duration of the study. Exemptions from this criterion: Women >2 years postmenopausal (defined as 1 year or longer since last menstrual period) and more than 55 years of age. Postmenopausal women (as defined above) and less than 55 years of age with a negative pregnancy test within 24 hours of randomization. Women who are surgically sterilized at least 3 months prior to enrollment. Males who are unwilling to use an acceptable method of birth control during the entire study period (such as condom with spermicide). Treatment with other investigational products or devices within 30 days or 5 half-lives of the screening visit, whichever is longer. Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inclisiran<br>Inclisiran sodium 300 milligrams (mg) (equivalent to 284 mg inclisiran) in 1.5 milliliters (mL) will be administered as a SC injection on Day 1, Day 90, and then every 6 months. | Drug: Inclisiran Sodium<br>* Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.<br>|
| Placebo Comparator: Saline Solution<br>Placebo (1.5 mL) will be administered as a SC injection of saline solution on Day 1, Day 90, and then every 6 months. | Drug: Placebo<br>* Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).<br>* Other names: Saline Solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in LDL-C From Baseline to Day 510 |  | Baseline, Day 510 | 
| Time-adjusted Percent Change in LDL-C Levels From Baseline After Day 90 and up to Day 540 |  | Baseline, Day 90 to Day 540 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change In LDL-C From Baseline To Day 510 |  | Baseline, Day 510 | 
| Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540 |  | Baseline, Day 90 to Day 540 | 
| Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510 |  | Baseline, Day 510 | 
| Percentage Change in Total Cholesterol From Baseline to Day 510 |  | Baseline, Day 510 | 
| Percentage Change in Apolipoprotein B (ApoB) From Baseline to Day 510 |  | Baseline, Day 510 | 
| Percentage Change in Non-HDL-C From Baseline to Day 510 |  | Baseline, Day 510 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inclisiran sodium, ASCVD, LDL-C