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

Primary Purpose

Familial Hypercholesterolemia - Heterozygous

Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Inclisiran
Placebo
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Familial Hypercholesterolemia - Heterozygous focused on measuring Heterozygous familial hypercholesterolemia (HeFH), LDL-cholesterol (LDL-C), adolescents, pediatric, small interfering ribonucleic acid (siRNA)

Eligibility Criteria

12 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Tucson Medical Center
  • Icahn School of Medicine at Mount Sinai
  • Wake Forest U of Health Sciences
  • Cincinnati Children's Hospital Medical Center
  • Childrens Hospital Pittsburgh of UPMC
  • Primary Children's Medical Center
  • Novartis Investigative Site
  • Unidade de pesquisa clinica - Hospital Universitario Walter Cantidio
  • Nucleo de Pesquisa Clinica do Rio Grande do Sul
  • Setor de Lípides, Aterosclerose e Biologia
  • Heart Institute (InCOr) HCMFUSP
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Universitaetsmedizin Mannheim
  • KKIM UK Frankfurt/Main
  • Universitaetsklinikum Freiburg
  • University General Hospital of Ioannina
  • Hippokrateion General Hospital of Athens Greece
  • Metropolitan Hospital
  • Novartis Investigative Site
  • Lipid Research
  • Lipids Center Sheba Medical Center, Israel
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Hotel Dieu de France Hospital
  • UiTM Sungai Buloh
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Institute of the complex problems of cardiovascular disease
  • Novartis Investigative Site
  • Institute of Internal Prev. Med.
  • Novartis Investigative Site
  • University Medical Centre Ljubljana, Div. of Pediatric Dept. of Endocrinology, Diabetes and Metabolic Diseases
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Hospital Reina Sofia
  • Hospital Virgen de la Vcitoria
  • Hospital Central de Asturias
  • Novartis Investigative Site
  • Hospital Abente y Lago
  • Novartis Investigative Site
  • Far Eastern Memorial Hospital
  • Taipei Veterans General Hospital
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Gazi University Medical Faculty
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Inclisiran

Placebo

Arm Description

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)

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)

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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
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)
% 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
% 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
% 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
% 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

Full Information

First Posted
December 2, 2020
Last Updated
August 22, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT04652726
Brief Title
Study to Evaluate Efficacy and Safety of Inclisiran in Adolescents With Heterozygous Familial Hypercholesterolemia
Acronym
ORION-16
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)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 27, 2021 (Actual)
Primary Completion Date
November 9, 2023 (Anticipated)
Study Completion Date
December 2, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Familial Hypercholesterolemia - Heterozygous
Keywords
Heterozygous familial hypercholesterolemia (HeFH), LDL-cholesterol (LDL-C), adolescents, pediatric, small interfering ribonucleic acid (siRNA)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Parallel (Year 1) to single-group (Year 2)
Masking
ParticipantInvestigator
Masking Description
Masked (Year 1) to No Masking (Year 2)
Allocation
Randomized
Enrollment
141 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Inclisiran
Arm Type
Experimental
Arm Description
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)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
Inclisiran
Other Intervention Name(s)
KJX839
Intervention Description
Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL solution for subcutaneous injection
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Saline solution
Intervention Description
Sterile normal saline (0.9% sodium chloride in water for subcutaneous injection)
Primary Outcome Measure Information:
Title
Percentage (%) change in low-density lipoprotein cholesterol (LDL-C) from baseline to Day 330
Description
Demonstrate superiority of inclisiran compared to placebo in reducing LDL-C [percent change] at Day 330 (Year 1)
Time Frame
Baseline and Day 330
Secondary Outcome Measure Information:
Title
Time-adjusted % change in LDL-C from baseline after Day 90 and up to Day 330
Description
Demonstrate superiority of inclisiran compared to placebo in reducing LDL-C [time-adjusted percent change] over Year 1
Time Frame
Baseline, after Day 90 up to Day 330
Title
Absolute change in LDL-C from baseline to Day 330
Description
Demonstrate superiority of inclisiran compared to placebo in reducing LDL-C [absolute change] at Day 330 (Year 1)
Time Frame
Baseline and Day 330
Title
% 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
Description
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
Time Frame
Baseline and Day 330
Title
% change and absolute change in LDL-C from baseline up to Day 720
Description
Evaluate the effect of inclisiran, compared to placebo (for Year 1) and long-term (up to Day 720), on lowering LDL-C over time
Time Frame
Baseline, up to Day 720
Title
% change and absolute change in other lipoproteins and lipid parameters from baseline up to Day 720
Description
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
Time Frame
Baseline, up to Day 720
Title
% change and absolute change in proprotein convertase subtilisin/kexin type 9 (PCSK9) from baseline up to Day 720
Description
Evaluate the effect of inclisiran, compared to placebo (for Year 1) and long-term (up to Day 720), on lowering PCSK9 over time
Time Frame
Baseline, up to Day 720

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Tucson Medical Center
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85712
Country
United States
Facility Name
Icahn School of Medicine at Mount Sinai
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Wake Forest U of Health Sciences
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229-3039
Country
United States
Facility Name
Childrens Hospital Pittsburgh of UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
Primary Children's Medical Center
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84113
Country
United States
Facility Name
Novartis Investigative Site
City
Ciudad de Formosa
State/Province
Formosa
ZIP/Postal Code
P3600
Country
Argentina
Facility Name
Unidade de pesquisa clinica - Hospital Universitario Walter Cantidio
City
Fortaleza
State/Province
Ceara
ZIP/Postal Code
60430275
Country
Brazil
Facility Name
Nucleo de Pesquisa Clinica do Rio Grande do Sul
City
Porto Alegre
State/Province
RS
ZIP/Postal Code
90430-001
Country
Brazil
Facility Name
Setor de Lípides, Aterosclerose e Biologia
City
Sao Paulo
State/Province
SP
ZIP/Postal Code
04023-900
Country
Brazil
Facility Name
Heart Institute (InCOr) HCMFUSP
City
Sao Paulo
State/Province
SP
ZIP/Postal Code
05403 000
Country
Brazil
Facility Name
Novartis Investigative Site
City
Quebec
ZIP/Postal Code
G1V 4W2
Country
Canada
Facility Name
Novartis Investigative Site
City
Praha 2
ZIP/Postal Code
128 08
Country
Czechia
Facility Name
Novartis Investigative Site
City
Praha 5
ZIP/Postal Code
150 06
Country
Czechia
Facility Name
Novartis Investigative Site
City
Besancon Cedex
ZIP/Postal Code
25030
Country
France
Facility Name
Novartis Investigative Site
City
Bron Cedex
ZIP/Postal Code
69677
Country
France
Facility Name
Novartis Investigative Site
City
Toulouse Cedex
ZIP/Postal Code
31059
Country
France
Facility Name
Universitaetsmedizin Mannheim
City
Mannheim
State/Province
Baden-Wuerttemberg
ZIP/Postal Code
68305
Country
Germany
Facility Name
KKIM UK Frankfurt/Main
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany
Facility Name
Universitaetsklinikum Freiburg
City
Freiburg
ZIP/Postal Code
79106
Country
Germany
Facility Name
University General Hospital of Ioannina
City
Ioannina
State/Province
GR
ZIP/Postal Code
455 00
Country
Greece
Facility Name
Hippokrateion General Hospital of Athens Greece
City
Athens
ZIP/Postal Code
115 27
Country
Greece
Facility Name
Metropolitan Hospital
City
Athens
ZIP/Postal Code
18547
Country
Greece
Facility Name
Novartis Investigative Site
City
Pecs
ZIP/Postal Code
7623
Country
Hungary
Facility Name
Lipid Research
City
Jerusalem
ZIP/Postal Code
9112001
Country
Israel
Facility Name
Lipids Center Sheba Medical Center, Israel
City
Ramat Gan
ZIP/Postal Code
52621
Country
Israel
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20162
Country
Italy
Facility Name
Novartis Investigative Site
City
Modena
State/Province
MO
ZIP/Postal Code
41124
Country
Italy
Facility Name
Novartis Investigative Site
City
Roma
State/Province
RM
ZIP/Postal Code
00100
Country
Italy
Facility Name
Novartis Investigative Site
City
Roma
State/Province
RM
ZIP/Postal Code
00165
Country
Italy
Facility Name
Novartis Investigative Site
City
Irbid
ZIP/Postal Code
22110
Country
Jordan
Facility Name
Hotel Dieu de France Hospital
City
Ashrafieh
ZIP/Postal Code
166830
Country
Lebanon
Facility Name
UiTM Sungai Buloh
City
Sungai Buloh
State/Province
Selangor Darul Ehsan
ZIP/Postal Code
47000
Country
Malaysia
Facility Name
Novartis Investigative Site
City
Rotterdam
State/Province
Zuid Holland
ZIP/Postal Code
3015 GD
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Oslo
ZIP/Postal Code
0514
Country
Norway
Facility Name
Novartis Investigative Site
City
Gdansk
ZIP/Postal Code
80 952
Country
Poland
Facility Name
Novartis Investigative Site
City
Lodz
ZIP/Postal Code
93-338
Country
Poland
Facility Name
Institute of the complex problems of cardiovascular disease
City
Kemerovo
ZIP/Postal Code
650002
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Moscow
ZIP/Postal Code
127412
Country
Russian Federation
Facility Name
Institute of Internal Prev. Med.
City
Novosibirsk
ZIP/Postal Code
630090
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Poprad
ZIP/Postal Code
058 01
Country
Slovakia
Facility Name
University Medical Centre Ljubljana, Div. of Pediatric Dept. of Endocrinology, Diabetes and Metabolic Diseases
City
Ljubljana
ZIP/Postal Code
1000
Country
Slovenia
Facility Name
Novartis Investigative Site
City
Bloemfontein
State/Province
Free State
ZIP/Postal Code
9301
Country
South Africa
Facility Name
Novartis Investigative Site
City
Pretoria
State/Province
Gauteng
ZIP/Postal Code
0184
Country
South Africa
Facility Name
Novartis Investigative Site
City
Somerset West
State/Province
Western Cape
ZIP/Postal Code
7130
Country
South Africa
Facility Name
Novartis Investigative Site
City
Cape Town
ZIP/Postal Code
7925
Country
South Africa
Facility Name
Hospital Reina Sofia
City
Cordoba
State/Province
Andalucia
ZIP/Postal Code
14004
Country
Spain
Facility Name
Hospital Virgen de la Vcitoria
City
Malaga
State/Province
Andalucia
ZIP/Postal Code
29010
Country
Spain
Facility Name
Hospital Central de Asturias
City
Oviedo
State/Province
Asturias
ZIP/Postal Code
33011
Country
Spain
Facility Name
Novartis Investigative Site
City
Pamplona
State/Province
Navarra
ZIP/Postal Code
31008
Country
Spain
Facility Name
Hospital Abente y Lago
City
A Coruna
ZIP/Postal Code
15001
Country
Spain
Facility Name
Novartis Investigative Site
City
Geneve 14
ZIP/Postal Code
1211
Country
Switzerland
Facility Name
Far Eastern Memorial Hospital
City
New Taipei
ZIP/Postal Code
22060
Country
Taiwan
Facility Name
Taipei Veterans General Hospital
City
Taipei
ZIP/Postal Code
11217
Country
Taiwan
Facility Name
Novartis Investigative Site
City
Istanbul
State/Province
TUR
ZIP/Postal Code
34098
Country
Turkey
Facility Name
Novartis Investigative Site
City
Adana
ZIP/Postal Code
01250
Country
Turkey
Facility Name
Gazi University Medical Faculty
City
Ankara
ZIP/Postal Code
06500
Country
Turkey
Facility Name
Novartis Investigative Site
City
Izmir
ZIP/Postal Code
35040
Country
Turkey
Facility Name
Novartis Investigative Site
City
Middlesex
ZIP/Postal Code
UB9 6JH
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
Citations:
PubMed Identifier
35175352
Citation
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.
Results Reference
derived
PubMed Identifier
33990512
Citation
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.
Results Reference
derived

Learn more about this trial

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

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