Trial to Assess the Effect of Long Term Dosing of Inclisiran in Subjects With High CV Risk and Elevated LDL-C

Study Overview
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Brief Summary
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The purpose of this extension study is to evaluate the efficacy, safety, and tolerability of long-term dosing of Inclisiran. The study will be a global multicenter study.

Detailed Description
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This study will be an open label, long term extension study in subjects with atherosclerotic cardiovascular disease (ASCVD), ASCVD-risk equivalents (eg, diabetes and familial hypercholesterolemia), or heterozygous or homozygous familial hypercholesterolemia (HeFH or HoFH) and elevated low density lipoprotein cholesterol (LDL-C) despite maximum tolerated dose of LDL-C lowering therapies who have completed the inclisiran Phase II trial MDCO-PCS-16-01 (ORION-3), or any of the following Phase III lipid lowering studies: MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-4 (ORION-10), or MDCO-PCS-17-08 (ORION-11)

Official Title
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An Open-label Extension Trial of the Phase III Lipid-lowering Trials to Assess the Effect of Long Term Dosing of Inclisiran Given as Subcutaneous Injections in Subjects With High Cardiovascular Risk and Elevated LDL-C

Conditions
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ASCVD, Elevated Cholesterol, Heterozygous Familial Hypercholesterolemia, Homozygous Familial Hypercholesterolemia

Intervention / Treatment
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* Drug: Inclisiran Sodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Completion on a previously qualifying inclisiran Phase II trial MDCO-PCS-16-01 (ORION-3), or Phase III lipid lowering ORION feeder study [MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-4 (ORION-10), or MDCO-PCS-17-08 (ORION-11)] meaning the subject received the last dose of study drug and completed the final study visit per applicable protocol. On current lipid-lowering therapies (such as a statin and/or ezetimibe) from previous study with no planned medication or dose change during study participation. 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: Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with participation in the clinical study, and/or put the subject at significant risk [according to investigator's (or delegate's) judgment] if he/she participates in the clinical study. An underlying known disease, or surgical, physical, or medical condition that, in the opinion of the investigator (or delegate) might interfere with interpretation of the clinical study results. Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less than 3 years, Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or unexplained alanine aminotransferase (ALT), aspartate aminotransferase (AST), elevation >3x the upper limit of normal (ULN), or total bilirubin (TBIL) elevation >2x ULN at the last recorded visit in the feeder study prior to study entry visit. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least one method of acceptable effective contraception (eg, oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, 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. Planned use of other investigational medicinal products other than inclisiran or devices during the course of the study. Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to: Subjects who are unable to communicate or to cooperate with the investigator Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study (including subjects whose cooperation is doubtful due to drug abuse or alcohol dependency) Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study) Have any medical or surgical condition, which in the opinion of the investigator would put the subject at increased risk from participating in the study Persons directly involved in the conduct of the study. 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inclisiran<br>Inclisiran sodium 300 milligrams (mg) will be administered as a single SC injection on Day 1*, 90, then every 180 days to Day 990. *Subjects who received blinded placebo in the feeder study will receive blinded inclisiran and subjects who received blinded inclisiran in the feeder study will receive blinded placebo on Day 1 in ORION-8. Subjects from the open label ORION-3 study will not receive any injection of study drug on Day 1. Their first dose of study medication will be at day 90 | Drug: Inclisiran Sodium<br>* Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects achieving prespecified LDL-C targets. | A primary objective of the study is to evaluate the effect of inclisiran treatment on the proportion of subjects achieving prespecified LDL-C targets at end of study. | Day 1080 | 
| Incidence of Adverse Events and Serious Adverse Events | Safety assessments include adverse events and serious adverse events for long-term safety profile | Baseline, Day 1080 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute and percentage change in LDL-C from baseline. | A secondary objective of this study is to evaluate the effect of inclisiran on LDL-C levels. | Baseline, Day 1080 | 
| Absolute and percentage change in other lipids and lipoprotein from baseline. | A secondary objective of this study is to evaluate the effect of inclisiran on other lipids and lipoproteins. | Baseline, Day 1080 | 

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