Evaluation of Inclisiran Versus Placebo in Pediatric Patients with Homozygous Familial Hypercholesterolemia: A Randomized, Double-Blind, Multicenter Study

The primary objective of this study is to evaluate the effect of **inclisiran** compared to placebo on reducing low-density lipoprotein cholesterol (LDL-C) [percent change] at Day 330 (Year 1) in children aged 2 to less than 12 years with homozygous familial hypercholesterolemia (HoFH) and elevated LDL-C. This is clinically relevant as reducing LDL-C levels is crucial in managing HoFH, a condition characterized by extremely high cholesterol levels that increase the risk of cardiovascular disease from an early age.

Secondary objectives include:

• Evaluating the effect of inclisiran compared to placebo on reducing LDL-C [time-adjusted percent change] over Year 1.
• Assessing the effect of inclisiran, compared to placebo (for Year 1) and long-term (up to Day 720), on lowering LDL-C, other lipoprotein and lipid parameters, and proprotein convertase subtilisin/kexin type 9 (PCSK9) over time.
• Evaluating the safety and tolerability profile of inclisiran, compared to placebo (for Year 1) and long-term (up to Day 720), in children with HoFH.

The clinical trial involves a total of **7 participants** diagnosed with **homozygous familial hypercholesterolemia** (HoFH). The study population consists of both male and female children aged 2 to less than 12 years, who have been genetically confirmed to have HoFH. Participants are required to have elevated LDL-C levels, specifically fasting LDL-C greater than 130 mg/dL at screening. The trial includes individuals who are on an optimal dose of statins, unless statin intolerant, and may also be on other lipid-lowering therapies such as ezetimibe. It is essential that these therapies have been stable for at least 30 days prior to screening, with no planned changes during the study. Additionally, participants who are on a documented regimen of LDL-apheresis for at least 3 months before screening are permitted to continue this treatment during the trial, provided the schedule and settings remain unchanged during the double-blind period. The trial population was selected based on these criteria to ensure a consistent and reliable assessment of the primary objective, which is to evaluate the effect of inclisiran compared to placebo on reducing LDL-C levels at Day 330 (Year 1).

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 2 to less than 12 years with **homozygous 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 assess the percentage change in LDL-C from baseline to Day 330 in the first year. Secondary endpoints include time-adjusted percent change in LDL-C and other lipid parameters up to Day 720, as well as the incidence and severity of treatment-emergent adverse events.

Participants will be involved in the study for a maximum of 630 days. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to conclude participation. The inclusion criteria require participants to be on a stable dose of lipid-lowering therapies for at least 30 days before screening, with no planned changes during the study. Participants on LDL-apheresis must have a stable regimen prior to and during the double-blind period. Conditions for early termination from the study include significant protocol deviations, adverse events, or withdrawal of consent.

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. It is administered via **subcutaneous injection**. The dosing regimen for Inclisiran involves a maximum daily dose of 300 mg, with a total maximum dose of 1500 mg over the treatment period. The trial is designed to evaluate the safety, tolerability, and efficacy of Inclisiran in children aged 2 to less than 12 years with homozygous familial hypercholesterolemia (HoFH) and elevated LDL-cholesterol. The treatment period extends up to 630 days, with compliance monitored through scheduled visits and assessments.

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 serves as a control to evaluate the effect of Inclisiran on reducing LDL-C levels in the target population. Compliance with the placebo administration is similarly monitored to ensure adherence to the study protocol.

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). This primary endpoint will provide a direct measure of the drug's impact on lowering LDL-cholesterol levels in children aged 2 to less than 12 years with homozygous familial hypercholesterolemia (HoFH) and elevated LDL-C. Secondary endpoints will include the time-adjusted percent change in LDL-C from baseline after Day 90 and up to Day 330, as well as percent and absolute changes in various lipid parameters such as PCSK9, total cholesterol, Apo B, non-HDL-C, Lp(a), triglycerides, HDL-C, VLDL-C, and Apo A1 from baseline to each assessment time up to Day 720 (Year 2).

These efficacy parameters will be measured and collected at specified timepoints throughout the study, utilizing validated laboratory tests to ensure accuracy and reliability. The analysis will include the incidence, severity, and relationship to the study drug of treatment-emergent adverse events (AEs) and serious adverse events (SAEs), as well as assessments of vital signs, laboratory parameters, anti-drug antibody (ADA) measurement, growth metrics (height, weight, BMI), and pubertal development (sexual hormones and Tanner staging). The study is designed to provide comprehensive data on the efficacy and safety of inclisiran in the pediatric population with HoFH.