Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol (ORION-11)

A Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect of 300 mg of Inclisiran Sodium Given as Subcutaneous Injections in Subjects With Atherosclerotic Cardiovascular Disease (ASCVD) or ACSVD Risk-Equivalents and Elevated Low-Density Lipoprotein Cholesterol (LDL-C)

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).

Study Overview

• Status: Completed
• Conditions: Risk Factor, Cardiovascular; Elevated Cholesterol; ASCVD
• Intervention / Treatment: Drug: Inclisiran Sodium; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 1617
• Phase: Phase 3

Contacts and Locations

Study Locations

• Czechia
  • Chomutov, Czechia, 43001
    • Research Site 11420-002
  • Uherské Hradiště, Czechia, 68601
    • Research Site 11420-003
• Germany
  • Berlin, Germany, 12567
    • Research Site 11049-006
  • Bochum, Germany, 44787
    • Research Site 11049-002
  • Frankfurt, Germany, 60313
    • Research Site 11049-003
  • Heidelberg, Germany, 69120
    • Research Site 11049-007
  • Leipzig, Germany, 4103
    • Research Site 11049-001
• Hungary
  • Budapest, Hungary, 1036
    • Research Site 11036-001
  • Debrecen, Hungary, 4025
    • Research Site 11036-004
  • Hatvan, Hungary, 3000
    • Research Site 11036-002
  • Zalaegerszeg, Hungary, 8900
    • Research Site 11036-003
• Poland
  • Bydgoszcz, Poland, 85-231
    • Research Site 11048-011
  • Gdańsk, Poland, 80-382
    • Research Site 11048-004
  • Gdańsk, Poland, 80-542
    • Research Site 11048-017
  • Gdynia, Poland, 81-537
    • Research Site 11048-005
  • Katowice, Poland, 04-040
    • Research Site 11048-007
  • Katowice, Poland, 40-648
    • Research SIte 11048-012
  • Kraków, Poland, 31-216
    • Research SIte 11048-014
  • Kraków, Poland, 31-501
    • Research Site 11048-003
  • Lublin, Poland, 20-709
    • Research Site 11048-008
  • Poznań, Poland, 60-702
    • Research Site 11048-001
  • Rzeszów, Poland, 35-055
    • Research SIte 11048-013
  • Tarnów, Poland, 33-100
    • Research SIte 11048-015
  • Warsaw, Poland, 04-628
    • Research Site 11048-009
  • Warszawice, Poland, 01-192
    • Research Site 11048-006
  • Wrocław, Poland, 50-381
    • Research Site 11048-002
  • Wrocław, Poland, 51-314
    • Research Site 11048-010
  • Kujawsko-pomorskie
    • Bydgoszcz, Kujawsko-pomorskie, Poland, 85-079
      • Research Site 11048-018
  • Podkarpackie
    • Brzozów, Podkarpackie, Poland, 36-200
      • Research SIte 11048-016
  • Slaskie
    • Ruda Śląska, Slaskie, Poland, 41-709
      • Research Site 11048-019
• South Africa
  • Pretoria, South Africa, 184
    • Research Site 11027-006
  • Welkom, South Africa, 9459
    • Research Site 11027-011
  • Free State
    • Bloemfontein, Free State, South Africa, 9301
      • Research Site 11027-003
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 1619
      • Research Site 11027-005
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7500
      • Research Site 11027-001
    • Cape Town, Western Cape, South Africa, 7646
      • Research Site 11027-013
    • Kuilsrivier, Western Cape, South Africa, 7130
      • Research Site 11027-007
    • Somerset West, Western Cape, South Africa, 7130
      • Research Site 11027-004
• Ukraine
  • Cherkasy, Ukraine, 18009
    • Research Site - 11380-005
  • Kharkiv, Ukraine, 61444
    • Research Site - 11380-008
  • Kiev, Ukraine, 3115
    • Research Site - 11380-004
  • Kiev, Ukraine, 3115
    • Research Site - 11380-009
  • Kyiv, Ukraine, 2002
    • Research Site - 11380-001
  • Kyiv, Ukraine, 3037
    • Research Site - 11380-002
  • Kyiv, Ukraine, 3049
    • Research Site - 11380-003
  • Lviv, Ukraine, 79060
    • Research Site - 11380-007
  • Uzhhorod, Ukraine, 8800
    • Research Site - 11380-006
• United Kingdom
  • Bollington, United Kingdom, SK10 5JH
    • Research Site - 11044-028
  • Bury, United Kingdom, BL9 ONJ
    • Research Site - 11044-026
  • Cardiff, United Kingdom, CF15 9SS
    • Research Site - 11044-007
  • Cheadle Hulme, United Kingdom, SK8 5LL
    • Research Site - 11044-024
  • Derby, United Kingdom, S40 4AA
    • Research Site - 11044-010
  • Glasgow, United Kingdom, G20 0SP
    • Research Site - 11044-001
  • Hexham, United Kingdom, NE46 1QJ
    • Research Site - 11044-008
  • Macclesfield, United Kingdom, SK11 6JL
    • Research Site - 11044-020
  • Manchester, United Kingdom, M14 6WP
    • Research Site - 11044-025
  • Manchester, United Kingdom, M15 6SX
    • Research Site - 11044-005
  • Manchester, United Kingdom, M20 2RN
    • Research Site - 11044-029
  • Reading, United Kingdom, RG2 0TG
    • Research Site - 11044-003
  • Stockton, United Kingdom, TS19 8PE
    • Research Site - 11044-002
  • Birmingham
    • Edgbaston, Birmingham, United Kingdom, B15 2SQ
      • Research Site - 11044-006
  • Cheshire
    • Sale, Cheshire, United Kingdom, M33 2RH
      • Research Site - 11044-022
    • Sale, Cheshire, United Kingdom, M33 4BR
      • Research Site - 11044-023
    • Timperley, Cheshire, United Kingdom, WA14 5PF
      • Research Site - 11044-021
  • Cornwall
    • Liskeard, Cornwall, United Kingdom, PL14 3XA
      • Research Site - 11044-012
  • Devon
    • Exeter, Devon, United Kingdom, EX2 5DW
      • Research Site - 11044-009
    • Plymouth, Devon, United Kingdom, PL5 3JB
      • Research Site - 11044-019
  • Lancashire
    • Chorley, Lancashire, United Kingdom, PR7 7NA
      • Research Site - 11044-014
  • Liverpool
    • Waterloo, Liverpool, United Kingdom, L22 0LG
      • Research Site - 11044-004
  • Manchester
    • Davyhulme, Manchester, United Kingdom, M41 7WJ
      • Research Site - 11044-027

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Participants may be included if they meet all of the following inclusion criteria prior to randomization:

1. Male or female participants ≥18 years of age.
2. History of ASCVD (coronary heart disease [CHD], cardiovascular disease [CVD], or peripheral arterial disease [PAD]).
3. Serum LDL-C ≥1.8 millimole (mmol)/liter (L) (≥70 mg/dL).
4. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening.
5. Calculated glomerular filtration rate >30 mL/min by estimated glomerular filtration rate (eGFR) using standardized clinical methodology
6. Participants on statins should be receiving a maximally tolerated dose.
7. Participants not receiving statins must have documented evidence of intolerance to all doses of at least 2 different statins.
8. 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.
9. 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

Exclusion Criteria:

Participants will be excluded from the study if any of the following exclusion criteria apply prior to randomization:

1. New York Heart Association (NYHA) class IV heart failure.
2. Uncontrolled cardiac arrhythmia.
3. Uncontrolled severe hypertension.
4. Active liver disease.

5. 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:

   1. Women >2 years postmenopausal (defined as 1 year or longer since last menstrual period) and more than 55 years of age.
   2. Postmenopausal women (as defined above) and less than 55 years of age with a negative pregnancy test within 24 hours of randomization.
   3. Women who are surgically sterilized at least 3 months prior to enrollment.
6. Males who are unwilling to use an acceptable method of birth control during the entire study period (such as condom with spermicide).
7. Treatment with other investigational products or devices within 30 days or 5 half-lives of the screening visit, whichever is longer.
8. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inclisiran; 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; Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.
Placebo Comparator: Saline Solution; 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; Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).; Other Names: Saline Solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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 Outcome Measures

Outcome Measure	Time Frame
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
Percentage Change in Non-HDL-C From Baseline to Day 510	Baseline, Day 510

Collaborators and Investigators

• Sponsor: The Medicines Company
• Investigators: Principal Investigator: Ray Kausik, MD, Imperial College of London

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2017
• Primary Completion (Actual): July 31, 2019
• Study Completion (Actual): August 27, 2019

Study Registration Dates

• First Submitted: January 9, 2018
• First Submitted That Met QC Criteria: January 9, 2018
• First Posted (Actual): January 17, 2018

Study Record Updates

• Last Update Posted (Actual): August 21, 2020
• Last Update Submitted That Met QC Criteria: August 3, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: LDL-C; ASCVD; Inclisiran sodium
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia
• Other Study ID Numbers: MDCO-PCS-17-08

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No