A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH)

NCT03851705 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: MDCO-PCS-17-02CKJX839A123022018-000893-31
• Study Type: interventional
• Target: 56
• Locations: 8 countries
• Sites: 13

Brief Summary

This study was a Phase III,A two-part (double-blind placebo-controlled/open-label) multicenter study to evaluate safety, tolerability, and efficacy of inclisiran in subjects with homozygous familial hypercholesterolemia (HoFH).

Conditions

Homozygous Familial Hypercholesterolemia

Keywords

HoFH

Outcome Measures

Primary Outcomes (1)

• Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150

  Percentage Change in LDL-C levels from Baseline to Day 150

  Baseline, Day 150

Secondary Outcomes (51)

• Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 150

  Baseline, Day 150

• Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 180

  Baseline, Days 90, 150, 180

• Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 720

  Baseline, Days 270, 330, 450, 510, 630, 690, and 720

• Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 180

  Baseline, Days 90, 150, 180

• Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Subsequent Visits up to Day 720

  Baseline, Days 270, 330, 450, 510, 630, 690, and 720

Study Arms (3)

Part 1 - Inclisiran

EXPERIMENTAL

Participants who received a dose of 300 milligram (mg) inclisiran sodium for injection administered by SC injection on Day 1 and Day 90.

Drug: Inclisiran Sodium for injection

Part 1 - Placebo

PLACEBO COMPARATOR

Participants who received a dose of placebos administered by SC injection on Day 1 and Day 90.

Drug: Placebo; Drug: Placebos

Part 2 - Inclisiran

EXPERIMENTAL

Participants who received a dose of 300 mg inclisiran sodium for injection administered by SC injection on Day 270, Day 450 and Day 630. In addition, participants who were assigned to the placebo arm in Part 1 will receive a dose of 300 mg inclisiran sodium administered by SC injection on Day 180 after completion of Part 1.

Drug: Inclisiran Sodium for injection

Interventions

Inclisiran Sodium for injection DRUG

Inclisiran is a synthetic, chemically modified small interfering ribonucleic acid (siRNA) targeting proprotein convertase subtilisin kexin type 9 (PCSK9) messenger ribonucleic acid (mRNA) with a covalently attached triantennary N-acetylgalactosamine (GalNAc) ligand.

Also known as: ALN-PCSSC; KJX839, ALN-PCSSC

Part 1 - Inclisiran; Part 2 - Inclisiran

Placebo DRUG

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

Part 1 - Placebo

Placebos DRUG

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

Part 1 - Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of HoFH by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration \>500 mg/dL (13 mmol/L) together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents
• Stable on a low-fat diet.
• Subjects on statins should be receiving a maximally tolerated dose. Maximum tolerated dose is defined as the maximum dose of statin that can be taken on a regular basis without intolerable adverse events.
• Subjects not receiving statins must have documented evidence of intolerance to at least two different statins.
• Subjects on lipid-lower therapies (such as statin and/or ezetimibe) should be on a stable dose for ≥30 days before screening with no planned medication or dose change during study participation.
• Fasting central laboratory LDL-C concentration ≥130 mg/dL (3.4 mmol/L).
• Triglyceride concentration \<400 mg/dL (4.5 mmol/L)
• No current or planned renal dialysis or renal transplantation
• Subjects on a documented regimen of LDL or plasma apheresis will be allowed to continue the apheresis during the study, if needed.
• Subjects must be willing and able to give written informed consent before initiation of any study-related procedures. The subject should be willing to comply with all required study procedures.
• Willing to follow all study procedures including adherence to dietary guidelines, study visits, fasting blood draws, and compliance with study treatment regimens.

You may not qualify if:

• Use of Mipomersen or Lomitapide therapy within 5 months of screening
• Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9
• New York Heart Association (NYHA) class IV heart failure or last known left ventricular ejection fraction \<25%
• Major adverse cardiovascular event within 3 months prior to randomization
• Planned cardiac surgery or revascularization
• Uncontrolled severe hypertension: systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg prior to randomization despite anti-hypertensive therapy
• Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or unexplained alanine aminotransferase (ALT), aspartate aminotransferase (AST), elevation \>3x ULN, or total bilirubin \>2x upper limit of normal (ULN) at screening confirmed by a repeat measurement at least 1 week apart
• Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less than the duration of the trial
• History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy and/or commencement of systemic therapy as treatment during the 3 years prior to randomization
• Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least one acceptable effective method of contraception (eg, oral contraceptives, barrier methods, approved contraceptive implant, long- term injectable contraception, intrauterine device) for the entire duration of the study. Exemptions from this criterion:
• Women \>2 years postmenopausal (defined as 1 year or longer since their last menstrual period) AND more than 55 years of age
• Postmenopausal women (as defined above) and less than 55 years of age with a negative pregnancy test within 24 hours of enrolment
• Women who are surgically sterilized at least 3 months prior to enrolment
• Known history of alcohol and/or drug abuse within 5 years
• Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to:

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (13)

(50852-001) Queen Mary Hospital

Hong Kong, Hong Kong

Location

(50972-001) Hadassah Hospital Lipid Research Ein Kerem

Jerusalem, 91120, Israel

Location

(50007-001) Research Institute of Complex Issues of Cardiovascular Diseases

Kemerovo, 650002, Russia

Location

(50007-003) National Medical Research Centre of Cardiology

Moscow, 121552, Russia

Location

(50007-002) Hospital for War Veterans

Saint Petersburg, 193079, Russia

Location

(50381-001) Clinical Center of Serbia

Belgrade, 11000, Serbia

Location

(50027-001) Johannesburg Hospital

Johannesburg, 2193, South Africa

Location

(50886-001) Taipei Veterans General Hospital

Taipei, 11217, Taiwan

Location

(50090-002) University of Health Sciences

Etlik, 06010, Turkey (Türkiye)

Location

(50090-003) Istanbul University

Istanbul, 34093, Turkey (Türkiye)

Location

(50090-001) Ege Universitesi

Izmir, 35040, Turkey (Türkiye)

Location

(50380-002) IMunicipal Non-commercial Enterprise "Ivano-Frankivsk Regional Clinical Cardiology Center Ivano-Frankivsk Regional Council"

Ivano-Frankivsk, 76018, Ukraine

Location

(50380-001) National Scientific Center

Kyiv, 03680, Ukraine

Location

Related Publications (2)

• Raal F, Durst R, Bi R, Talloczy Z, Maheux P, Lesogor A, Kastelein JJP; ORION-5 Study Investigators. Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial. Circulation. 2024 Jan 30;149(5):354-362. doi: 10.1161/CIRCULATIONAHA.122.063460. Epub 2023 Oct 18.

  PMID: 37850379 DERIVED

• 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.

  PMID: 33990512 DERIVED

Related Links

• A Plain Language Trial Summary is available on novctrd.com

MeSH Terms

Conditions

Homozygous Familial Hypercholesterolemia

Interventions

Injections; ALN-PCS

Condition Hierarchy (Ancestors)

Hyperlipoproteinemia Type II; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hyperlipoproteinemias; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Drug Administration Routes; Drug Therapy; Therapeutics

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Double-blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 7, 2019
• First Posted: February 22, 2019
• Study Start: February 6, 2019
• Primary Completion: March 2, 2020
• Study Completion: September 9, 2021
• Last Updated: January 30, 2023
• Results First Posted: November 10, 2022

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will share

Locations

ZA (1); RU (3); HK (1); IL (1); TU (3); TW (1); SE (1); UA (2)