Study to Evaluate Efficacy and Safety of Inclisiran in Adolescents With Heterozygous Familial Hypercholesterolemia (ORION-16)

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)

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Familial Hypercholesterolemia - Heterozygous
• Intervention / Treatment: Drug: Inclisiran; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 141
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Formosa
    • Ciudad de Formosa, Formosa, Argentina, P3600
      • Novartis Investigative Site
• Brazil
  • Ceara
    • Fortaleza, Ceara, Brazil, 60430275
      • Unidade de pesquisa clinica - Hospital Universitario Walter Cantidio
  • RS
    • Porto Alegre, RS, Brazil, 90430-001
      • Nucleo de Pesquisa Clinica do Rio Grande do Sul
  • SP
    • Sao Paulo, SP, Brazil, 04023-900
      • Setor de Lípides, Aterosclerose e Biologia
    • Sao Paulo, SP, Brazil, 05403 000
      • Heart Institute (InCOr) HCMFUSP
• Canada
  • Quebec, Canada, G1V 4W2
    • Novartis Investigative Site
• Czechia
  • Praha 2, Czechia, 128 08
    • Novartis Investigative Site
  • Praha 5, Czechia, 150 06
    • Novartis Investigative Site
• France
  • Besancon Cedex, France, 25030
    • Novartis Investigative Site
  • Bron Cedex, France, 69677
    • Novartis Investigative Site
  • Toulouse Cedex, France, 31059
    • Novartis Investigative Site
• Germany
  • Frankfurt, Germany, 60590
    • KKIM UK Frankfurt/Main
  • Freiburg, Germany, 79106
    • Universitaetsklinikum Freiburg
  • Baden-Wuerttemberg
    • Mannheim, Baden-Wuerttemberg, Germany, 68305
      • UniversitaetsMedizin Mannheim
• Greece
  • Athens, Greece, 18547
    • Metropolitan Hospital
  • Athens, Greece, 115 27
    • Hippokrateion General Hospital of Athens Greece
  • GR
    • Ioannina, GR, Greece, 455 00
      • University General Hospital of Ioannina
• Hungary
  • Pecs, Hungary, 7623
    • Novartis Investigative Site
• Israel
  • Jerusalem, Israel, 9112001
    • Lipid Research
  • Ramat Gan, Israel, 52621
    • Lipids Center Sheba Medical Center, Israel
• Italy
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41124
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00165
      • Novartis Investigative Site
    • Roma, RM, Italy, 00100
      • Novartis Investigative Site
• Jordan
  • Irbid, Jordan, 22110
    • Novartis Investigative Site
• Lebanon
  • Ashrafieh, Lebanon, 166830
    • Hotel Dieu de France Hospital
• Malaysia
  • Selangor Darul Ehsan
    • Sungai Buloh, Selangor Darul Ehsan, Malaysia, 47000
      • UiTM Sungai Buloh
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Novartis Investigative Site
  • Zuid Holland
    • Rotterdam, Zuid Holland, Netherlands, 3015 GD
      • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0514
    • Novartis Investigative Site
• Poland
  • Gdansk, Poland, 80 952
    • Novartis Investigative Site
  • Lodz, Poland, 93-338
    • Novartis Investigative Site
• Russian Federation
  • Kemerovo, Russian Federation, 650002
    • Institute of the complex problems of cardiovascular disease
  • Moscow, Russian Federation, 127412
    • Novartis Investigative Site
  • Novosibirsk, Russian Federation, 630090
    • Institute of Internal Prev. Med.
• Slovakia
  • Poprad, Slovakia, 058 01
    • Novartis Investigative Site
• Slovenia
  • Ljubljana, Slovenia, 1000
    • University Medical Centre Ljubljana, Div. of Pediatric Dept. of Endocrinology, Diabetes and Metabolic Diseases
• South Africa
  • Cape Town, South Africa, 7925
    • Novartis Investigative Site
  • Free State
    • Bloemfontein, Free State, South Africa, 9301
      • Novartis Investigative Site
  • Gauteng
    • Pretoria, Gauteng, South Africa, 0184
      • Novartis Investigative Site
  • Western Cape
    • Somerset West, Western Cape, South Africa, 7130
      • Novartis Investigative Site
• Spain
  • A Coruna, Spain, 15001
    • Hospital Abente y Lago
  • Andalucia
    • Cordoba, Andalucia, Spain, 14004
      • Hospital Reina Sofia
    • Malaga, Andalucia, Spain, 29010
      • Hospital Virgen de la Vcitoria
  • Asturias
    • Oviedo, Asturias, Spain, 33011
      • Hospital Central de Asturias
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Novartis Investigative Site
• Switzerland
  • Geneve 14, Switzerland, 1211
    • Novartis Investigative Site
• Taiwan
  • New Taipei, Taiwan, 22060
    • Far Eastern Memorial Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
• Turkey
  • Adana, Turkey, 01250
    • Novartis Investigative Site
  • Ankara, Turkey, 06500
    • Gazi University Medical Faculty
  • Izmir, Turkey, 35040
    • Novartis Investigative Site
  • TUR
    • Istanbul, TUR, Turkey, 34098
      • Novartis Investigative Site
• United Kingdom
  • Middlesex, United Kingdom, UB9 6JH
    • Novartis Investigative Site
• United States
  • Arizona
    • Tucson, Arizona, United States, 85712
      • Tucson Medical Center
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest U of Health Sciences
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Childrens Hospital Pittsburgh of UPMC
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Medical Center

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inclisiran; 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; Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL solution for subcutaneous injection; Other Names: KJX839
Placebo Comparator: Placebo; 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; Sterile normal saline (0.9% sodium chloride in water for subcutaneous injection); 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

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.

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2021
• Primary Completion (Actual): November 9, 2023
• Study Completion (Estimated): December 2, 2024

Study Registration Dates

• First Submitted: December 2, 2020
• First Submitted That Met QC Criteria: December 2, 2020
• First Posted (Actual): December 3, 2020

Study Record Updates

• Last Update Posted (Actual): December 26, 2023
• Last Update Submitted That Met QC Criteria: December 22, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: pediatric; adolescents; Heterozygous familial hypercholesterolemia (HeFH); LDL-cholesterol (LDL-C); small interfering ribonucleic acid (siRNA)
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II
• Other Study ID Numbers: CKJX839C12301; 2020-002757-18 (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