Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol

NCT03400800 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: MDCO-PCS-17-08
• Study Type: interventional
• Target: 1,617
• Locations: 7 countries
• Sites: 70

Brief Summary

This is a Phase III, placebo-controlled, double-blind, randomized study in participants with ASCVD or ASCVD-Risk equivalents and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) inclisiran injection(s). The study will be an international multicenter study (non-United States).

Conditions

ASCVD; Risk Factor, Cardiovascular; Elevated Cholesterol

Keywords

Inclisiran sodium; ASCVD; LDL-C

Outcome Measures

Primary Outcomes (2)

• Percentage Change in LDL-C From Baseline to Day 510

  Baseline, Day 510

• Time-adjusted Percent Change in LDL-C Levels From Baseline After Day 90 and up to Day 540

  Baseline, Day 90 to Day 540

Secondary Outcomes (6)

• Absolute Change In LDL-C From Baseline To Day 510

  Baseline, Day 510

• Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540

  Baseline, Day 90 to Day 540

• Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510

  Baseline, Day 510

• Percentage Change in Total Cholesterol From Baseline to Day 510

  Baseline, Day 510

• Percentage Change in Apolipoprotein B (ApoB) From Baseline to Day 510

  Baseline, Day 510

Study Arms (2)

Inclisiran

EXPERIMENTAL

Inclisiran sodium 300 milligrams (mg) (equivalent to 284 mg inclisiran) in 1.5 milliliters (mL) will be administered as a SC injection on Day 1, Day 90, and then every 6 months.

Drug: Inclisiran Sodium

Saline Solution

PLACEBO COMPARATOR

Placebo (1.5 mL) will be administered as a SC injection of saline solution on Day 1, Day 90, and then every 6 months.

Drug: Placebo

Interventions

Inclisiran Sodium DRUG

Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

Inclisiran

Placebo DRUG

Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).

Also known as: Saline Solution

Saline Solution

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female participants ≥18 years of age.
• History of ASCVD (coronary heart disease \[CHD\], cardiovascular disease \[CVD\], or peripheral arterial disease \[PAD\]).
• Serum LDL-C ≥1.8 millimole (mmol)/liter (L) (≥70 mg/dL).
• Fasting triglyceride \<4.52 mmol/L (\<400 mg/dL) at screening.
• Calculated glomerular filtration rate \>30 mL/min by estimated glomerular filtration rate (eGFR) using standardized clinical methodology
• Participants on statins should be receiving a maximally tolerated dose.
• Participants not receiving statins must have documented evidence of intolerance to all doses of at least 2 different statins.
• Subjects on lipid-lower therapies (such as a 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.
• Subjects were willing and able to give informed consent before initiation of any study-related procedures and willing to comply with all required study procedures

You may not qualify if:

• New York Heart Association (NYHA) class IV heart failure.
• Uncontrolled cardiac arrhythmia.
• Uncontrolled severe hypertension.
• Active liver disease.
• Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least 2 methods of highly effective contraception (failure rate less than 1% per year) (for example, combined oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, or intrauterine device) for the entire duration of the study. Exemptions from this criterion:
• Women \>2 years postmenopausal (defined as 1 year or longer since 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 randomization.
• Women who are surgically sterilized at least 3 months prior to enrollment.
• Males who are unwilling to use an acceptable method of birth control during the entire study period (such as condom with spermicide).
• Treatment with other investigational products or devices within 30 days or 5 half-lives of the screening visit, whichever is longer.
• Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9.
• The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Sponsors & Collaborators

• The Medicines Company: lead

Study Sites (70)

Research Site 11420-002

Chomutov, 43001, Czechia

Location

Research Site 11420-003

Uherské Hradiště, 68601, Czechia

Location

Research Site 11049-006

Berlin, 12567, Germany

Location

Research Site 11049-002

Bochum, 44787, Germany

Location

Research Site 11049-003

Frankfurt, 60313, Germany

Location

Research Site 11049-007

Heidelberg, 69120, Germany

Location

Research Site 11049-001

Leipzig, 4103, Germany

Location

Research Site 11036-001

Budapest, 1036, Hungary

Location

Research Site 11036-004

Debrecen, 4025, Hungary

Location

Research Site 11036-002

Hatvan, 3000, Hungary

Location

Research Site 11036-003

Zalaegerszeg, 8900, Hungary

Location

Research Site 11048-018

Bydgoszcz, Kuyavian-Pomeranian Voivodeship, 85-079, Poland

Location

Research Site 11048-016

Brzozów, Podkarpackie Voivodeship, 36-200, Poland

Location

Research Site 11048-019

Ruda Śląska, Silesian Voivodeship, 41-709, Poland

Location

Research Site 11048-011

Bydgoszcz, 85-231, Poland

Location

Research Site 11048-004

Gdansk, 80-382, Poland

Location

Research Site 11048-017

Gdansk, 80-542, Poland

Location

Research Site 11048-005

Gdynia, 81-537, Poland

Location

Research Site 11048-007

Katowice, 04-040, Poland

Location

Research Site 11048-012

Katowice, 40-648, Poland

Location

Research Site 11048-014

Krakow, 31-216, Poland

Location

Research Site 11048-003

Krakow, 31-501, Poland

Location

Research Site 11048-008

Lublin, 20-709, Poland

Location

Research Site 11048-001

Poznan, 60-702, Poland

Location

Research Site 11048-013

Rzeszów, 35-055, Poland

Location

Research Site 11048-015

Tarnów, 33-100, Poland

Location

Research Site 11048-009

Warsaw, 04-628, Poland

Location

Research Site 11048-006

Warszawice, 01-192, Poland

Location

Research Site 11048-002

Wroclaw, 50-381, Poland

Location

Research Site 11048-010

Wroclaw, 51-314, Poland

Location

Research Site 11027-003

Bloemfontein, Free State, 9301, South Africa

Location

Research Site 11027-005

Johannesburg, Gauteng, 1619, South Africa

Location

Research Site 11027-001

Cape Town, Western Cape, 7500, South Africa

Location

Research Site 11027-013

Cape Town, Western Cape, 7646, South Africa

Location

Research Site 11027-007

Kuils River, Western Cape, 7130, South Africa

Location

Research Site 11027-004

Somerset West, Western Cape, 7130, South Africa

Location

Research Site 11027-006

Pretoria, 184, South Africa

Location

Research Site 11027-011

Welkom, 9459, South Africa

Location

Research Site - 11380-005

Cherkasy, 18009, Ukraine

Location

Research Site - 11380-008

Kharkiv, 61444, Ukraine

Location

Research Site - 11380-004

Kiev, 3115, Ukraine

Location

Research Site - 11380-009

Kiev, 3115, Ukraine

Location

Research Site - 11380-001

Kyiv, 2002, Ukraine

Location

Research Site - 11380-002

Kyiv, 3037, Ukraine

Location

Research Site - 11380-003

Kyiv, 3049, Ukraine

Location

Research Site - 11380-007

Lviv, 79060, Ukraine

Location

Research Site - 11380-006

Uzhhorod, 8800, Ukraine

Location

Research Site - 11044-006

Edgbaston, Birmingham, B15 2SQ, United Kingdom

Location

Research Site - 11044-022

Sale, Cheshire, M33 2RH, United Kingdom

Location

Research Site - 11044-023

Sale, Cheshire, M33 4BR, United Kingdom

Location

Research Site - 11044-021

Timperley, Cheshire, WA14 5PF, United Kingdom

Location

Research Site - 11044-012

Liskeard, Cornwall, PL14 3XA, United Kingdom

Location

Research Site - 11044-009

Exeter, Devon, EX2 5DW, United Kingdom

Location

Research Site - 11044-019

Plymouth, Devon, PL5 3JB, United Kingdom

Location

Research Site - 11044-014

Chorley, Lancashire, PR7 7NA, United Kingdom

Location

Research Site - 11044-004

Waterloo, Liverpool, L22 0LG, United Kingdom

Location

Research Site - 11044-027

Davyhulme, Manchester, M41 7WJ, United Kingdom

Location

Research Site - 11044-028

Bollington, SK10 5JH, United Kingdom

Location

Research Site - 11044-026

Bury, BL9 ONJ, United Kingdom

Location

Research Site - 11044-007

Cardiff, CF15 9SS, United Kingdom

Location

Research Site - 11044-024

Cheadle Hulme, SK8 5LL, United Kingdom

Location

Research Site - 11044-010

Derby, S40 4AA, United Kingdom

Location

Research Site - 11044-001

Glasgow, G20 0SP, United Kingdom

Location

Research Site - 11044-008

Hexham, NE46 1QJ, United Kingdom

Location

Research Site - 11044-020

Macclesfield, SK11 6JL, United Kingdom

Location

Research Site - 11044-025

Manchester, M14 6WP, United Kingdom

Location

Research Site - 11044-005

Manchester, M15 6SX, United Kingdom

Location

Research Site - 11044-029

Manchester, M20 2RN, United Kingdom

Location

Research Site - 11044-003

Reading, RG2 0TG, United Kingdom

Location

Research Site - 11044-002

Stockton, TS19 8PE, United Kingdom

Location

Related Publications (4)

• Wright RS, Ray KK, Landmesser U, Koenig W, Raal FJ, Leiter LA, Conde LG, Han J, Schwartz GG. Effects of Inclisiran in Patients With Atherosclerotic Cardiovascular Disease: A Pooled Analysis of the ORION-10 and ORION-11 Randomized Trials. Mayo Clin Proc. 2024 Jul 5:S0025-6196(24)00167-8. doi: 10.1016/j.mayocp.2024.03.025. Online ahead of print.

  PMID: 39093262 DERIVED

• Dutta S, Shah R, Singhal S, Singh S, Piparva K, Katoch CDS. A systematic review and meta-analysis of tolerability, cardiac safety and efficacy of inclisiran for the therapy of hyperlipidemic patients. Expert Opin Drug Saf. 2024 Feb;23(2):187-198. doi: 10.1080/14740338.2023.2293201. Epub 2023 Dec 19.

  PMID: 38063346 DERIVED

• Ray KK, Wright RS. Plain language summary of results from ORION-10 and ORION-11: two studies to learn how well inclisiran works in people with high cholesterol. Future Cardiol. 2023 Mar;19(4):175-184. doi: 10.2217/fca-2022-0133. Epub 2023 Jun 6.

  PMID: 37282500 DERIVED

• Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, Bisch JA, Richardson T, Jaros M, Wijngaard PLJ, Kastelein JJP; ORION-10 and ORION-11 Investigators. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-1519. doi: 10.1056/NEJMoa1912387. Epub 2020 Mar 18.

  PMID: 32187462 DERIVED

MeSH Terms

Conditions

Hypercholesterolemia

Interventions

Saline Solution

Condition Hierarchy (Ancestors)

Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Vice-President, Regulatory Operations
• Organization: Novartis

frank.bosley@novartis.com

973-985-0597

Study Officials

• Ray Kausik, MD

  Imperial College of London

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2018
• First Posted: January 17, 2018
• Study Start: November 1, 2017
• Primary Completion: July 31, 2019
• Study Completion: August 27, 2019
• Last Updated: August 21, 2020
• Results First Posted: August 21, 2020

Record last verified: 2020-08

Locations

GB (23); CZ (2); DE (5); HU (4); PL (19); UA (9); ZA (8)