Randomized, Double-Blind, Multicenter Study Evaluating Inclisiran Versus Placebo in Pediatric Patients with Heterozygous Familial Hypercholesterolemia

The primary objective of this study is to demonstrate the **superiority** of inclisiran compared to placebo in reducing low-density lipoprotein cholesterol (LDL-C) by percent change at Day 330 (Year 1) in children aged 6 to less than 12 years with heterozygous familial hypercholesterolemia (HeFH) and elevated LDL-C. This objective is clinically relevant as it addresses the need for effective treatment options in pediatric patients with HeFH, a condition associated with increased cardiovascular risk due to elevated LDL-C levels.

Secondary objectives include: - Demonstrating the superiority of inclisiran compared to placebo in reducing LDL-C by time-adjusted percent change over Year 1. - Demonstrating the superiority of inclisiran compared to placebo in reducing LDL-C by absolute change at Day 330 (Year 1). - Demonstrating the superiority of inclisiran compared to placebo in reducing proprotein convertase subtilisin/kexin type 9 (PCSK9), total cholesterol, apolipoprotein B (Apo B), and non-high density lipoprotein cholesterol (non-HDL-C) by percent change at Day 330 (Year 1). - Evaluating the effect of inclisiran compared to placebo on lowering LDL-C, other lipoprotein and lipid parameters, and PCSK9 over time for Year 1 and long-term up to Day 720. - Evaluating the safety and tolerability profile of inclisiran compared to placebo for Year 1 and long-term up to Day 720 in children with HeFH.

The clinical trial involves a total of **24 participants** diagnosed with **Heterozygous Familial Hypercholesterolemia** (HeFH). The study population comprises both male and female children aged 6 to less than 12 years. Participants were selected based on specific criteria, including a diagnosis of HeFH confirmed by genetic testing or phenotypic criteria, and a fasting LDL-C level greater than 130 mg/dL at screening. The trial includes children who are either on an optimal dose of statin therapy or are statin intolerant, with or without additional lipid-lowering treatments such as ezetimibe. Participants on lipid-lowering therapies must have been on a stable dose for at least 30 days prior to screening, with no planned changes in medication or dosage during the study. The trial population is considered vulnerable due to the age group involved. The study does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the general health status of the participants.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study followed by an open-label phase. It aims to evaluate the safety, tolerability, and efficacy of **inclisiran** in children aged 6 to less than 12 years with **heterozygous familial hypercholesterolemia** and elevated LDL-cholesterol. The trial is structured in two parts: the first year involves a double-blind comparison of inclisiran versus placebo, and the second year is an open-label phase where all participants receive inclisiran. The primary objective is to demonstrate the superiority of inclisiran compared to placebo in reducing LDL-C percentage change at Day 330 of Year 1.

Participants will be involved in the study for an estimated duration of two years, with the trial expected to conclude by January 2030. The study begins with a screening visit to confirm eligibility based on criteria such as age, diagnosis of heterozygous familial hypercholesterolemia, and LDL-C levels. Participants must be on a stable dose of lipid-lowering therapies, if applicable, for at least 30 days before screening. The trial includes multiple follow-up visits to monitor the primary and secondary endpoints, which include changes in LDL-C, PCSK9, total cholesterol, and other lipid parameters, as well as the incidence of adverse events.

The end-of-study visit will assess the long-term effects of inclisiran on lipid levels and safety parameters. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial's design ensures rigorous monitoring and data collection to evaluate the therapeutic potential of inclisiran in the pediatric population with heterozygous familial hypercholesterolemia.

The clinical trial involves the administration of **Inclisiran**, marketed under the product code KJX839, which is a **solution for injection**. Inclisiran is a nucleic acid-based therapeutic agent developed by Novartis Pharma AG. The pharmaceutical form is a solution for injection, and it is administered via **subcutaneous use**. The dosing regimen includes a maximum daily dose of 300 mg and a total maximum dose of 1500 mg over a treatment period of 630 days. The trial is designed to evaluate the safety, tolerability, and efficacy of Inclisiran in children aged 6 to less than 12 years with heterozygous familial hypercholesterolemia and elevated LDL-cholesterol. Participant compliance with the dosing schedule will be monitored throughout the study.

The study also includes a **placebo** comparator, which is a 0 mg/1.5 mL solution for injection in a vial, designed to match the appearance and administration route of Inclisiran. The placebo is administered subcutaneously, following the same schedule as the active treatment, to maintain the double-blind nature of the trial during the first year. The placebo is used to assess the efficacy of Inclisiran by providing a baseline for comparison in reducing LDL-C levels in the target population. The placebo does not contain any active pharmaceutical ingredients and is intended solely for use in the control group to ensure the validity of the study results.

The efficacy of inclisiran in the clinical trial will be assessed primarily by evaluating the **percentage change in LDL-C** from baseline to Day 330 (Year 1) in children aged 6 to less than 12 years with heterozygous familial hypercholesterolemia (HeFH) and elevated LDL-cholesterol (LDL-C). Secondary endpoints include the time-adjusted percent change in LDL-C from baseline after Day 90 up to Day 330, absolute change in LDL-C from baseline to Day 330, and percent change in PCSK9, total cholesterol, Apo B, and non-HDL-C from baseline to Day 330. Additionally, the trial will assess percent and absolute changes in LDL-C, PCSK9, total cholesterol, Apo B, non-HDL-C, lipoprotein (a) [Lp(a)], triglycerides, high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol (VLDL-C), and apolipoprotein A1 (Apo A1) from baseline to each assessment time up to Day 720 (Year 2).

Measurements will be collected at specified timepoints, including Day 330 and up to Day 720, using validated laboratory tests. The trial will also monitor the incidence, severity, and relationship to the study drug of treatment-emergent adverse events (AEs) and serious adverse events (SAEs), as well as vital signs, laboratory parameters, anti-drug antibodies (ADA) measurement, growth (height, weight, body mass index (BMI)), and pubertal development (sexual hormones and Tanner staging). These assessments will provide comprehensive data on the efficacy and safety of inclisiran in the pediatric population with HeFH.