Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)

Study Overview
=================
Brief Summary
-----------------
This is a Phase III, placebo-controlled, double-blind, randomized study in participants with HeFH and elevated LDL-C to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) injection(s) of inclisiran. The study will be multicenter and international.

Official Title
-----------------
Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect of 300 mg of Inclisiran Sodium Given as Subcutaneous Injections in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH) and Elevated Low-Density Lipoprotein Cholesterol (LDL-C).

Conditions
-----------------
Heterozygous Familial Hypercholesterolemia, Elevated Cholesterol

Intervention / Treatment
-----------------
* Drug: Inclisiran
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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 HeFH with a diagnosis of HeFH by genetic testing; and/or a documented history of untreated LDL-C of >190 mg/dL, and a family history of familial hypercholesterolemia, elevated cholesterol or early heart disease that may indicate familial hypercholesterolemia. Serum LDL-C ≥2.6 millimoles (mmol)/liter (L) (≥100 mg/dL) at screening. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening. 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. Participants on lipid-lowering 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. Exclusion Criteria: Participants will be excluded from the study if any of the following exclusion criteria apply immediately 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) (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 (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
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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) will be administered as a SC injection on Day 1, Day 90 then every 6 months. | Drug: Inclisiran<br>* Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.<br>|
| Placebo Comparator: Placebo<br>Placebo will be administered as SC injections of saline solution on Day 1, Day 90 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?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in LDL-C From Baseline To Day 510 |  | Baseline, Day 510 | 
| Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 540 | Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 90 reported | Baseline, Day 90 | 

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 | Assessments performed at Baseline, Day 90, Day 540, absolute change at Day 90 reported | Baseline, Day 90 | 
| 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 | 
| Percent Change in Apolipoprotein B (Apo-B) From Baseline To Day 510 |  | Baseline, Day 510 | 
| Percent Change in Non-high-density Lipoprotein (HDL)-C From Baseline To Day 510 |  | Baseline, Day 510 | 

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