Clinical trial NCT04659863: Study to Evaluate Efficacy and Safety of Inclisiran in Adolescents With Homozygous Familial Hypercholesterolemia
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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Familial Hypercholesterolemia - Homozygous
Keywords: Homozygous familial hypercholesterolemia (HoFH)
LDL-cholesterol (LDL-C)
adolescents
pediatric
small interfering ribonucleic acid (siRNA)
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-12-09
Enrollment: 13
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel (Year 1) to single-group (Year 2)
Primary purpose: TREATMENT

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.

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
* 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

Primary outcomes:
measure: Percentage Change in LDL-C From Baseline to Day 330 (Part 1/Year 1)
timeFrame: Baseline and Day 330
Secondary outcomes:
measure: Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 330 (Part 1/Year 1)
timeFrame: Baseline, after Day 90 up to Day 330
measure: Percent Change in LDL-C From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Absolute Change in LDL-C From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Percent Change in Apo B From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Absolute Change in Apo B From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Percent Change in Lp(a) From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Absolute Change in Lp(a) From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Percent Change in Non-HDL-C From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Absolute Change in Non-HDL-C From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Percent Change in Total Cholesterol From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Absolute Change in Total Cholesterol From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Percent Change in Triglycerides From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Absolute Change in Triglycerides From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Percent Change in HDL-C From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Absolute Change in HDL-C From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Percent Change in VLDL-C From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Absolut Change in VLDL-C From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Percent Change in Apo A1 From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Absolute Change in Apo A1 From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Percent Change in PCSK9 From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
measure: Absolut Change in PCSK9 From Baseline up to Day 720
timeFrame: Baseline, up to Day 720
Other outcomes:
Locations:
city: Boca Raton
country: United States
facility: Excel Medical Clinical Trials LLC
state: Florida
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Bron Cedex
country: France
facility: Novartis Investigative Site
city: Ioannina
country: Greece
facility: University General Hospital of Ioannina
state: GR
city: Athens
country: Greece
facility: Metropolitan Hospital
city: Ashrafieh
country: Lebanon
facility: Hotel Dieu de France Hospital
city: Beirut
country: Lebanon
facility: American University of Beirut Medical Center
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: TUR
city: Izmir
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
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.
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.