Study to Evaluate Efficacy and Safety of Inclisiran in Adolescents With Heterozygous Familial Hypercholesterolemia

Study Overview
=================
Brief Summary
-----------------
This is a pivotal phase III study designed to evaluate safety, tolerability, and efficacy of inclisiran in adolescents with heterozygous familial hypercholesterolemia (HeFH) and elevated low density lipoprotein cholesterol (LDL-C).

Detailed Description
-----------------
This is a two-part (1 year double-blind inclisiran versus placebo / 1 year open-label inclisiran) multicenter study designed to evaluate safety, tolerability, and efficacy of inclisiran in adolescents with heterozygous familial hypercholesterolemia (HeFH) and elevated low density lipoprotein cholesterol (LDL-C) on stable standard of care background lipid-lowering therapy. The primary objective is to demonstrate superiority of inclisiran compared to placebo in reducing LDL-C (percent change) at Day 330.

Official Title
-----------------
Two Part (Double-blind Inclisiran Versus Placebo [Year 1] Followed by Open-label Inclisiran [Year 2]) Randomized Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of Inclisiran in Adolescents (12 to Less Than 18 Years) With Heterozygous Familial Hypercholesterolemia and Elevated LDL-cholesterol (ORION-16)

Conditions
-----------------
Familial Hypercholesterolemia - Heterozygous

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Heterozygous Familial Hypercholesterolemia (HeFH) diagnosed either by genetic testing or on phenotypic criteria Fasting LDL-C >130 mg/dL (3.4 mmol/L) at screening Fasting triglycerides <400 mg/dL (4.5 mmol/L) at screening On maximally tolerated dose of statin (investigator's discretion) with or without other lipid-lowering therapy; stable for ≥ 30 days before screening Estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 at screening Exclusion Criteria: Homozygous familial hypercholesterolemia (HoFH) Active liver disease Secondary hypercholesterolemia, e.g. hypothyroidism or nephrotic syndrome Major adverse cardiovascular events within 3 months prior to randomization Previous treatment with monoclonal antibodies directed towards PCSK9 (within 90 days of screening) Recent and/or planned use of other investigational medicinal products or devices Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 17 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
Interventional Model Description: Parallel (Year 1) to single-group (Year 2)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inclisiran<br>Year 1 - inclisiran sodium 300 mg subcutaneous injection (given at Days 1, 90, and 270) Day 360 only - placebo subcutaneous injection Year 2 - inclisiran sodium 300 mg subcutaneous injection (given at Days 450 and 630) | Drug: Inclisiran<br>* Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL solution for subcutaneous injection<br>* Other names: KJX839;|
| Placebo Comparator: Placebo<br>Year 1 - placebo subcutaneous injection (given at Days 1, 90 and 270) Year 2 - inclisiran sodium 300 mg subcutaneous injection (given at Days 360, 450, and 630) | Drug: Placebo<br>* Sterile normal saline (0.9% sodium chloride in water for subcutaneous injection)<br>* Other names: Saline solution;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage (%) change in low-density lipoprotein cholesterol (LDL-C) from baseline to Day 330 | Demonstrate superiority of inclisiran compared to placebo in reducing LDL-C [percent change] at Day 330 (Year 1) | Baseline and Day 330 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-adjusted % change in LDL-C from baseline after Day 90 and up to Day 330 | Demonstrate superiority of inclisiran compared to placebo in reducing LDL-C [time-adjusted percent change] over Year 1 | Baseline, after Day 90 up to Day 330 | 
| Absolute change in LDL-C from baseline to Day 330 | Demonstrate superiority of inclisiran compared to placebo in reducing LDL-C [absolute change] at Day 330 (Year 1) | Baseline and Day 330 | 
| % change in apolipoprotein B (Apo B), lipoprotein (a) [Lp(a)], non-high density lipoprotein cholesterol (non-HDL-C), and total cholesterol from baseline to Day 330 | Demonstrate superiority of inclisiran compared to placebo in reducing Apo B, lipoprotein (a) [Lp(a)], non-high density lipoprotein cholesterol (non-HDL-C), and total cholesterol [percent change] at Day 330 (Year 1) - Hierarchical testing | Baseline and Day 330 | 
| % change and absolute change in LDL-C from baseline up to Day 720 | Evaluate the effect of inclisiran, compared to placebo (for Year 1) and long-term (up to Day 720), on lowering LDL-C over time | Baseline, up to Day 720 | 
| % change and absolute change in other lipoproteins and lipid parameters from baseline up to Day 720 | Evaluate the effect of inclisiran, compared to placebo (for Year 1) and long-term (up to Day 720), on lowering Apo B, Lp(a), non-HDL-C, total cholesterol, triglycerides, high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C), apolipoprotein A1 (Apo A1) over time | Baseline, up to Day 720 | 
| % change and absolute change in proprotein convertase subtilisin/kexin type 9 (PCSK9) from baseline up to Day 720 | Evaluate the effect of inclisiran, compared to placebo (for Year 1) and long-term (up to Day 720), on lowering PCSK9 over time | Baseline, up to Day 720 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Heterozygous familial hypercholesterolemia (HeFH), LDL-cholesterol (LDL-C), adolescents, pediatric, small interfering ribonucleic acid (siRNA)