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

Primary Purpose

Familial Hypercholesterolemia - Homozygous

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 - Homozygous focused on measuring Homozygous familial hypercholesterolemia (HoFH), 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:

  • 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
  • Estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 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
  • Major adverse cardiovascular events within 1 month prior to randomization
  • 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

Other protocol-defined inclusion/exclusion criteria may apply

Sites / Locations

  • Excel Medical Clinical Trials LLC
  • Novartis Investigative Site
  • Novartis Investigative Site
  • University General Hospital of Ioannina
  • Metropolitan Hospital
  • Hotel Dieu de France Hospital
  • American University of Beirut Medical Center
  • Novartis Investigative Site
  • Novartis Investigative Site
  • 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
Evaluate the effect of inclisiran compared to placebo on reducing LDL-C [percent change] at Day 330 (Year 1)

Secondary Outcome Measures

Time-adjusted percent change in LDL-C from baseline after Day 90 and up to Day 330
Evaluate the effect of inclisiran compared to placebo on reducing LDL-C [time-adjusted percent change] over Year 1
% 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 lipoprotein and lipid parameters from baseline up to Day 720
Evaluate the effect of inclisiran compared to placebo (up to Day 330) and long-term (up to Day 720), on lowering apolipoprotein B (Apo B), lipoprotein (a) [Lp(a)], non-high density lipoprotein cholesterol (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 (up to Day 330) and long-term (up to Day 720), on lowering PCSK9 over time

Full Information

First Posted
December 2, 2020
Last Updated
October 24, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT04659863
Brief Title
Study to Evaluate Efficacy and Safety of Inclisiran in Adolescents With Homozygous Familial Hypercholesterolemia
Acronym
ORION-13
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 Homozygous Familial Hypercholesterolemia and Elevated LDL-cholesterol (ORION-13)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 16, 2021 (Actual)
Primary Completion Date
November 6, 2023 (Anticipated)
Study Completion Date
November 30, 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 homozygous familial hypercholesterolemia (HoFH) 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 homozygous familial hypercholesterolemia (HoFH) and elevated low density lipoprotein cholesterol (LDL-C) on stable standard of care background lipid-lowering therapy. The primary objective is to evaluate the effect 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 - Homozygous
Keywords
Homozygous familial hypercholesterolemia (HoFH), 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
13 (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 injection) for subcutaneous injection
Primary Outcome Measure Information:
Title
Percentage (%) change in low-density lipoprotein cholesterol (LDL-C) from baseline to Day 330
Description
Evaluate the effect of inclisiran compared to placebo on reducing LDL-C [percent change] at Day 330 (Year 1)
Time Frame
Baseline and Day 330
Secondary Outcome Measure Information:
Title
Time-adjusted percent change in LDL-C from baseline after Day 90 and up to Day 330
Description
Evaluate the effect of inclisiran compared to placebo on reducing LDL-C [time-adjusted percent change] over Year 1
Time Frame
Baseline, after Day 90 up to 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 lipoprotein and lipid parameters from baseline up to Day 720
Description
Evaluate the effect of inclisiran compared to placebo (up to Day 330) and long-term (up to Day 720), on lowering apolipoprotein B (Apo B), lipoprotein (a) [Lp(a)], non-high density lipoprotein cholesterol (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
Baselne, 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 (up to Day 330) 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: 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 Estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 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 Major adverse cardiovascular events within 1 month prior to randomization 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 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
Excel Medical Clinical Trials LLC
City
Boca Raton
State/Province
Florida
ZIP/Postal Code
33434
Country
United States
Facility Name
Novartis Investigative Site
City
Quebec
ZIP/Postal Code
G1V 4W2
Country
Canada
Facility Name
Novartis Investigative Site
City
Bron Cedex
ZIP/Postal Code
69677
Country
France
Facility Name
University General Hospital of Ioannina
City
Ioannina
State/Province
GR
ZIP/Postal Code
455 00
Country
Greece
Facility Name
Metropolitan Hospital
City
Athens
ZIP/Postal Code
18547
Country
Greece
Facility Name
Hotel Dieu de France Hospital
City
Ashrafieh
ZIP/Postal Code
166830
Country
Lebanon
Facility Name
American University of Beirut Medical Center
City
Beirut
ZIP/Postal Code
1107 2020
Country
Lebanon
Facility Name
Novartis Investigative Site
City
Kuala Lumpur
ZIP/Postal Code
59100
Country
Malaysia
Facility Name
Novartis Investigative Site
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Istanbul
State/Province
TUR
ZIP/Postal Code
34098
Country
Turkey
Facility Name
Novartis Investigative Site
City
Izmir
ZIP/Postal Code
35040
Country
Turkey

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

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

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