Clinical trial NCT04652726: Study to Evaluate Efficacy and Safety of Inclisiran in Adolescents With Heterozygous 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 Heterozygous Familial Hypercholesterolemia and Elevated LDL-cholesterol (ORION-16)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Familial Hypercholesterolemia - Heterozygous
Keywords: Heterozygous familial hypercholesterolemia (HeFH)
LDL-cholesterol (LDL-C)
adolescents
pediatric
small interfering ribonucleic acid (siRNA)
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-12-03
Enrollment: 141
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 heterozygous familial hypercholesterolemia (HeFH) and elevated low density lipoprotein cholesterol (LDL-C).

Detailed description: This was 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 was to demonstrate superiority of inclisiran compared to placebo in reducing LDL-C (percent change) at Day 330.

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

Exclusion Criteria:

* Homozygous familial hypercholesterolemia (HoFH)
* Active liver disease
* Secondary hypercholesterolemia, e.g. hypothyroidism or nephrotic syndrome
* 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

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: Absolute Change in LDL-C From Baseline to up Day 330 (Part 1/Year 1)
timeFrame: Baseline and Day 330
measure: Percent Change in Apo B From Baseline up to Day 330 (Part 1/Year 1)
timeFrame: Baseline and Day 330
measure: Percent Change in Lp(a) From Baseline up to Day 330 (Part 1/Year 1)
timeFrame: Baseline and Day 330
measure: Percent Change in Non-HDL-C From Baseline up to Day 330 (Part 1/Year 1)
timeFrame: Baseline and Day 330
measure: Percent Change in Total Cholesterol From Baseline up to Day 330 (Part 1/Year 1)
timeFrame: Baseline and 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: Tucson
country: United States
facility: Tucson Medical Center
state: Arizona
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest U of Health Sciences
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: Childrens Hospital Pittsburgh of UPMC
state: Pennsylvania
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Ciudad de Formosa
country: Argentina
facility: Novartis Investigative Site
state: Formosa
city: Fortaleza
country: Brazil
facility: Unidade de pesquisa clinica - Hospital Universitario Walter Cantidio
state: Ceara
city: Porto Alegre
country: Brazil
facility: Nucleo de Pesquisa Clinica do Rio Grande do Sul
state: RS
city: Sao Paulo
country: Brazil
facility: Setor de Lípides, Aterosclerose e Biologia
state: SP
city: Sao Paulo
country: Brazil
facility: Heart Institute (InCOr) HCMFUSP
state: SP
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Praha 5
country: Czechia
facility: Novartis Investigative Site
city: Praha
country: Czechia
facility: Novartis Investigative Site
city: Besancon Cedex
country: France
facility: Novartis Investigative Site
city: Bron Cedex
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex
country: France
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Universitaetsmedizin Mannheim
state: Baden-Wuerttemberg
city: Frankfurt
country: Germany
facility: KKIM UK Frankfurt/Main
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Ioannina
country: Greece
facility: University General Hospital of Ioannina
state: GR
city: Athens
country: Greece
facility: Hippokrateion General Hospital of Athens Greece
city: Athens
country: Greece
facility: Metropolitan Hospital
city: Pecs
country: Hungary
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Lipid Research
city: Ramat Gan
country: Israel
facility: Lipids Center Sheba Medical Center, Israel
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Irbid
country: Jordan
facility: Novartis Investigative Site
city: Ashrafieh
country: Lebanon
facility: Hotel Dieu de France Hospital
city: Sungai Buloh
country: Malaysia
facility: UiTM Sungai Buloh
state: Selangor Darul Ehsan
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
state: Zuid Holland
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Gdansk
country: Poland
facility: Novartis Investigative Site
city: Lodz
country: Poland
facility: Novartis Investigative Site
city: Kemerovo
country: Russian Federation
facility: Institute of the complex problems of cardiovascular disease
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Novosibirsk
country: Russian Federation
facility: Institute of Internal Prev. Med.
city: Poprad
country: Slovakia
facility: Novartis Investigative Site
city: Ljubljana
country: Slovenia
facility: University Medical Centre Ljubljana, Div. of Pediatric Dept. of Endocrinology, Diabetes and Metabolic Diseases
city: Bloemfontein
country: South Africa
facility: Novartis Investigative Site
state: Free State
city: Somerset West
country: South Africa
facility: Novartis Investigative Site
state: Western Cape
city: Cape Town
country: South Africa
facility: Novartis Investigative Site
city: Cordoba
country: Spain
facility: Hospital Reina Sofia
state: Andalucia
city: Malaga
country: Spain
facility: Hospital Virgen de la Vcitoria
state: Andalucia
city: Oviedo
country: Spain
facility: Hospital Central de Asturias
state: Asturias
city: Pamplona
country: Spain
facility: Novartis Investigative Site
state: Navarra
city: A Coruna
country: Spain
facility: Hospital Abente y Lago
city: Geneve 14
country: Switzerland
facility: Novartis Investigative Site
city: New Taipei
country: Taiwan
facility: Far Eastern Memorial Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: TUR
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Gazi University Medical Faculty
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Middlesex
country: United Kingdom
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.