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

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)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04659863

Acronym

ORION-13

Enrollment

Registered

2020-12-09

Start date

2021-02-16

Completion date

2024-11-18

Last updated

2026-01-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Familial Hypercholesterolemia - Homozygous

Keywords

Homozygous familial hypercholesterolemia (HoFH), LDL-cholesterol (LDL-C), adolescents, pediatric, small interfering ribonucleic acid (siRNA)

Brief summary

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).

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.

Interventions

DRUGInclisiran

Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL solution for subcutaneous injection

DRUGPlacebo

Sterile normal saline (0.9% sodium chloride in water for injection) for subcutaneous injection

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Masking description

Masked (Year 1) to No Masking (Year 2)

Intervention model description

Parallel (Year 1) to single-group (Year 2)

Eligibility

Sex/Gender

ALL

Age

12 Years to 17 Years

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 * 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

Design outcomes

Primary

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

Secondary

Measure	Time frame	Description
Percent Change in VLDL-C From Baseline up to Day 720	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.
Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 330 (Part 1/Year 1)	Baseline, after Day 90 up to Day 330	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
Percent Change in LDL-C From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in LDL-C from baseline to each assessment time up to Day 720.
Absolute Change in LDL-C From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in LDL-C from baseline to each assessment time up to Day 720.
Percent Change in Apo B From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in apolipoprotein B (Apo B) from baseline to each assessment time up to Day 720.
Absolute Change in Apo B From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in apolipoprotein B (Apo B) from baseline to each assessment time up to Day 720.
Percent Change in Lp(a) From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in lipoprotein (a) \[Lp(a)\] from baseline to each assessment time up to Day 720.
Absolute Change in Lp(a) From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in lipoprotein (a) \[Lp(a)\] from baseline to each assessment time up to Day 720.
Percent Change in Non-HDL-C From Baseline up to Day 720	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.
Absolute Change in Non-HDL-C From Baseline up to Day 720	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.
Absolute Change in HDL-C From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in high density lipoprotein cholesterol (HDL-C) from baseline to each assessment time up to Day 720.
Absolute Change in Total Cholesterol From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in total cholesterol from baseline to each assessment time up to Day 720.
Percent Change in Triglycerides From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in triglycerides from baseline to each assessment time up to Day 720.
Absolute Change in Triglycerides From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in triglycerides from baseline to each assessment time up to Day 720.
Percent Change in HDL-C From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in high density lipoprotein cholesterol (HDL-C) from baseline to each assessment time up to Day 720.
Absolut Change in VLDL-C From Baseline up to Day 720	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.
Percent Change in Apo A1 From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in apolipoprotein A1 (Apo A1) from baseline to each assessment time up to Day 720.
Absolute Change in Apo A1 From Baseline up to Day 720	Baseline, up to Day 720	Absolute change in apolipoprotein A1 (Apo A1) from baseline to each assessment time up to Day 720.
Percent Change in PCSK9 From Baseline up to Day 720	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.
Absolut Change in PCSK9 From Baseline up to Day 720	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.
Percent Change in Total Cholesterol From Baseline up to Day 720	Baseline, up to Day 720	Percentage change in total cholesterol from baseline to each assessment time up to Day 720.

Countries

Canada, France, Greece, Lebanon, Malaysia, Netherlands, Turkey (Türkiye), United States

Participant flow

Recruitment details

Thirteen participants were randomized from 9 study centers in 8 countries. The breakdown of countries and study centers for the randomized participants was as follows: Canada (1), France (1), Greece (1), Lebanon (1), Malaysia (1), Netherlands (1), Turkey (2), and United States (1).

Pre-assignment details

The study had an approximately 4-week screening/run-in period

Participants by arm

Arm	Count
Part 1- Inclisiran Inclisiran sodium 300 mg subcutaneous (sc) injection (given at Days 1, 90 and 270)	9
Part 1 - Placebo Placebo sc injection (given at Day 1, 90 and 270)	4
Total	13

Baseline characteristics

Characteristic	Part 1- Inclisiran	Part 1 - Placebo	Total
Age, Categorical <=18 years	9 Participants	4 Participants	13 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	0 Participants	0 Participants	0 Participants
Age, Continuous	14.6 years STANDARD_DEVIATION 1.54	15.1 years STANDARD_DEVIATION 2.66	14.8 years STANDARD_DEVIATION 1.85
Race/Ethnicity, Customized Asian	1 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized White	8 Participants	3 Participants	11 Participants
Sex: Female, Male Female	7 Participants	2 Participants	9 Participants
Sex: Female, Male Male	2 Participants	2 Participants	4 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 9	0 / 4	0 / 13
other Total, other adverse events	7 / 9	1 / 4	8 / 13
serious Total, serious adverse events	0 / 9	0 / 4	0 / 13

Outcome results

Primary

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)

Time frame: Baseline and Day 330

Population: Full Analysis Set (FAS) comprised all participants to whom study treatment had been assigned by randomization.

Arm	Measure	Value (MEAN)	Dispersion
Part 1- Inclisiran	Percentage Change in LDL-C From Baseline to Day 330 (Part 1/Year 1)	-21.6 percent change in LDL-C	Standard Deviation 13.36
Part 1 - Placebo	Percentage Change in LDL-C From Baseline to Day 330 (Part 1/Year 1)	11.7 percent change in LDL-C	Standard Deviation 30.52

95% CI: [-59.17, -7.34]

Secondary

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.

Time frame: Baseline, up to Day 720