Study to Evaluate Efficacy and Safety of Inclisiran in Adolescents With Homozygous Familial Hypercholesterolemia (ORION-13)

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 Homozygous Familial Hypercholesterolemia and Elevated LDL-cholesterol (ORION-13)

This was a pivotal phase III study designed to evaluate safety, tolerability, and efficacy of inclisiran in adolescents with homozygous familial hypercholesterolemia (HoFH) and elevated low density lipoprotein cholesterol (LDL-C).

Study Overview

• Status: Completed
• Conditions: Familial Hypercholesterolemia - Homozygous
• Intervention / Treatment: Drug: Inclisiran; Drug: Placebo

Detailed Description

This was a two-part (double-blind, inclisiran versus placebo [Year 1] followed by open-label inclisiran [Year 2]) multicenter study in adolescents (aged 12 to < 18 years) with HoFH and elevated LDL-C (> 130 mg/dL; 3.4 mmol/L) on stable, individualized, optimal standard of care (SoC) background lipid-lowering therapy (including maximally tolerated statin treatment, at the Investigator's discretion) to evaluate the safety, tolerability, and efficacy of inclisiran in this pediatric patient population.

Following an approximately 4-week screening/run-in period, the study had 2 sequential parts as follows:

Part 1/Year 1: 12 months double-blind, parallel group period, in which participants were randomized in a 2:1 ratio to receive either inclisiran sodium 300 mg subcutaneous (s.c.) or placebo. The primary endpoint was assessed at Day 330.

Part 2/Year 2: 12 months single arm, open-label follow-up period, with all participants receiving inclisiran sodium 300 mg s.c.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Québec, Quebec, Canada, G1V 4W2
      • Novartis Investigative Site
• France
  • Bron, France, 69677
    • Novartis Investigative Site
• Greece
  • Athens, Greece, 18547
    • Metropolitan Hospital
  • GR
    • Ioannina, GR, Greece, 455 00
      • University General Hospital of Ioannina
• Lebanon
  • Beirut, Lebanon, 1107 2020
    • American University of Beirut Medical Center
  • El Achrafiyé, Lebanon, 166830
    • Hotel Dieu de France Hospital
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Novartis Investigative Site
• Turkey (Türkiye)
  • Izmir, Turkey (Türkiye), 35100
    • Novartis Investigative Site
  • TUR
    • Istanbul, TUR, Turkey (Türkiye), 34098
      • Novartis Investigative Site
• United States
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Excel Medical Clinical Trials LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Homozygous Familial Hypercholesterolemia (HoFH) diagnosed by genetic confirmation
• Fasting LDL-C >130 mg/dL (3.4 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
• Male or female participants >=12 to <18 years of age at screening

Exclusion Criteria:

• Documented evidence of a null (negative) mutation in both LDLR alleles
• Heterozygous familial hypercholesterolemia (HeFH)
• Active liver disease
• Secondary hypercholesterolemia, e.g. hypothyroidism or nephrotic syndrome
• Previous treatment with monoclonal antibodies directed towards PCSK9 (within 90 days of screening)
• Treatment with mipomersen or lomitapide (within 5 months of screening)
• Recent and/or planned use of other investigational medicinal products or devices

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 - Inclisiran; Inclisiran sodium 300 mg subcutaneous (sc) injection (given at Days 1, 90 and 270)	Drug: Inclisiran; Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL solution for subcutaneous injection; Other Names: KJX839
Placebo Comparator: Part 1 - Placebo; Placebo sc injection (given at Day 1, 90 and 270)	Drug: Placebo; Sterile normal saline (0.9% sodium chloride in water for injection) for subcutaneous injection; Other Names: Saline solution
Experimental: Part 2 - Inclisiran (Total); Inclisiran sodium 300 mg sc injection (given at Days 450 and 630). In addition, participants assigned to placebo in Part 1 received inclisiran sodium 300 mg sc injection on Day 360, while participants assigned to inclisiran in Part 1 received placebo sc injection on Day 360.	Drug: Inclisiran; Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL solution for subcutaneous injection; Other Names: KJX839

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change in LDL-C From Baseline to Day 330 (Part 1/Year 1)	Percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to Day 330 (Year 1)	Baseline and Day 330

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 330 (Part 1/Year 1)	Time-adjusted percent change in LDL-C (after Day 90 and up to Day 330), calculated as the average of percent changes from baseline to Days 150, 270 and 330	Baseline, after Day 90 up to Day 330
Percent Change in LDL-C From Baseline up to Day 720	Percentage change in LDL-C from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Absolute Change in LDL-C From Baseline up to Day 720	Absolute change in LDL-C from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Percent Change in Apo B From Baseline up to Day 720	Percentage change in apolipoprotein B (Apo B) from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Absolute Change in Apo B From Baseline up to Day 720	Absolute change in apolipoprotein B (Apo B) from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Percent Change in Lp(a) From Baseline up to Day 720	Percentage change in lipoprotein (a) [Lp(a)] from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Absolute Change in Lp(a) From Baseline up to Day 720	Absolute change in lipoprotein (a) [Lp(a)] from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Percent Change in Non-HDL-C From Baseline up to Day 720	Percentage change in non-high density lipoprotein cholesterol (non-HDL-C) from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Absolute Change in Non-HDL-C From Baseline up to Day 720	Absolute change in non-high density lipoprotein cholesterol (non-HDL-C) from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Percent Change in Total Cholesterol From Baseline up to Day 720	Percentage change in total cholesterol from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Absolute Change in Total Cholesterol From Baseline up to Day 720	Absolute change in total cholesterol from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Percent Change in Triglycerides From Baseline up to Day 720	Percentage change in triglycerides from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Absolute Change in Triglycerides From Baseline up to Day 720	Absolute change in triglycerides from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Percent Change in HDL-C From Baseline up to Day 720	Percentage change in high density lipoprotein cholesterol (HDL-C) from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Absolute Change in HDL-C From Baseline up to Day 720	Absolute change in high density lipoprotein cholesterol (HDL-C) from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Percent Change in VLDL-C From Baseline up to Day 720	Percentage change in very low density lipoprotein cholesterol (VLDL-C) from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Absolut Change in VLDL-C From Baseline up to Day 720	Absolute change in very low density lipoprotein cholesterol (VLDL-C) from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Percent Change in Apo A1 From Baseline up to Day 720	Percentage change in apolipoprotein A1 (Apo A1) from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Absolute Change in Apo A1 From Baseline up to Day 720	Absolute change in apolipoprotein A1 (Apo A1) from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Percent Change in PCSK9 From Baseline up to Day 720	Percentage change in proprotein convertase subtilisin/kexin type 9 (PCSK9) from baseline to each assessment time up to Day 720.	Baseline, up to Day 720
Absolut Change in PCSK9 From Baseline up to Day 720	Absolute change in proprotein convertase subtilisin/kexin type 9 (PCSK9) from baseline to each assessment time up to Day 720.	Baseline, up to Day 720

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Reijman MD, Schweizer A, Peterson ALH, Bruckert E, Stratz C, Defesche JC, Hegele RA, Wiegman A. Rationale and design of two trials assessing the efficacy, safety, and tolerability of inclisiran in adolescents with homozygous and heterozygous familial hypercholesterolaemia. Eur J Prev Cardiol. 2022 Jul 20;29(9):1361-1368. doi: 10.1093/eurjpc/zwac025.
• Warden BA, Duell PB. Inclisiran: A Novel Agent for Lowering Apolipoprotein B-containing Lipoproteins. J Cardiovasc Pharmacol. 2021 Aug 1;78(2):e157-e174. doi: 10.1097/FJC.0000000000001053.
• Wiegman A, Peterson AL, Hegele RA, Bruckert E, Schweizer A, Lesogor A, Wang Y, Defesche J. Efficacy and Safety of Inclisiran in Adolescents With Genetically Confirmed Homozygous Familial Hypercholesterolemia: Results From the Double-Blind, Placebo-Controlled Part of the ORION-13 Randomized Trial. Circulation. 2025 Jun 24;151(25):1758-1766. doi: 10.1161/CIRCULATIONAHA.124.073233. Epub 2025 May 20.

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com
• A Pediatric Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2021
• Primary Completion (Actual): October 30, 2023
• Study Completion (Actual): November 18, 2024

Study Registration Dates

• First Submitted: December 2, 2020
• First Submitted That Met QC Criteria: December 2, 2020
• First Posted (Actual): December 9, 2020

Study Record Updates

• Last Update Posted (Estimated): January 13, 2026
• Last Update Submitted That Met QC Criteria: December 18, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: pediatric; adolescents; LDL-cholesterol (LDL-C); small interfering ribonucleic acid (siRNA); Homozygous familial hypercholesterolemia (HoFH)
• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Hyperlipoproteinemia Type II; Homozygous Familial Hypercholesterolemia; Pharmaceutical Preparations; Crystalloid Solutions; Isotonic Solutions; Solutions; Saline Solution; ALN-PCS
• Other Study ID Numbers: CKJX839C12302; 2020-002755-38 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No