Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH) (ORION-9)

Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect of 300 mg of Inclisiran Sodium Given as Subcutaneous Injections in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH) and Elevated Low-Density Lipoprotein Cholesterol (LDL-C).

This is a Phase III, placebo-controlled, double-blind, randomized study in participants with HeFH and elevated LDL-C to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) injection(s) of inclisiran. The study will be multicenter and international.

Study Overview

• Status: Completed
• Conditions: Elevated Cholesterol; Heterozygous Familial Hypercholesterolemia
• Intervention / Treatment: Drug: Inclisiran; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 482
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Site 90011-005
    • Montréal, Quebec, Canada, H2W 1R7
      • Site 90011-001
    • Quebec City, Quebec, Canada, G1V 4W2
      • Site 90011-002
• Czechia
  • Prague, Czechia, 140 21
    • Site 90420-001
  • Prague, Czechia, 180 00
    • Site 90420-006
  • Trutnov, Czechia, 541 01
    • Site 90420-005
• Denmark
  • Aalborg, Denmark, DK-9000
    • Site 90045-001
  • Esbjerg, Denmark, DK-6700
    • Site 90045-004
  • Herning, Denmark, 7400
    • Site 90045-003
  • Hvidovre, Denmark, 2650
    • Site 90045-006
  • Roskilde, Denmark, DK-4000
    • Site 90045-002
  • Viborg, Denmark, DK-8800
    • Site 90045-005
• Netherlands
  • Amersfoort, Netherlands, 3813 TZ
    • Site 90031-001
  • Amsterdam, Netherlands, 1105 AZ
    • Site 90031-003
  • Hoorn, Netherlands, 1624 NP
    • Site 90031-009
  • Tilburg, Netherlands, 5042 AD
    • Site 90031-006
  • Utrecht, Netherlands, 3584 CX
    • Site 90031-005
• South Africa
  • Bloemfontein, South Africa, 9301
    • Site 90027-003
  • Cape Town, South Africa, 7130
    • Site 90027-005
  • Cape Town, South Africa, 7500
    • Site 90027-001
  • Cape Town, South Africa, 7530
    • Site 90027-008
  • Johannesburg, South Africa, 2193
    • Site 90027-010
  • Pretoria, South Africa, 0157
    • Site 90027-007
  • Pretoria, South Africa, 0184
    • Site 90027-006
  • Witbank, South Africa, 1035
    • Site 90027-009
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7130
      • Site 90027-004
• Spain
  • A Coruña, Spain, 15006
    • Site 90034-003
  • Barcelona, Spain
    • Site 90034-005
  • Córdoba, Spain, 14004
    • Site 90034-004
  • L'Hospitalet De Llobregat, Spain, 8907
    • Site 90034-006
  • Reus, Spain, 43204
    • Site 90034-001
  • Zaragoza, Spain, 50009
    • Site 90034-002
• Sweden
  • Göteborg, Sweden, SE-41345
    • Site 90046-002
  • Stockholm, Sweden, SE-11157
    • Site 90046-001
  • Stockholm, Sweden, SE-14186
    • Site 90046-003
• United States
  • California
    • Mission Viejo, California, United States, 92691
      • Site 90001-005
    • Newport Beach, California, United States, 92663
      • Site 90001-001
    • Stanford, California, United States, 94305
      • Site 90001-015
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Site 90001-047
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Site 90001-004
  • Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • Site 90001-056
  • Montana
    • Butte, Montana, United States, 59701
      • Site 90001-012
  • Nevada
    • Las Vegas, Nevada, United States, 89119
      • Site 90001-112
  • New Jersey
    • Summit, New Jersey, United States, 07901
      • Site 90001-014
  • Ohio
    • Cincinnati, Ohio, United States, 45227
      • Site 90001-002

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 HeFH with a diagnosis of HeFH by genetic testing; and/or a documented history of untreated LDL-C of >190 mg/dL, and a family history of familial hypercholesterolemia, elevated cholesterol or early heart disease that may indicate familial hypercholesterolemia.
3. Serum LDL-C ≥2.6 millimoles (mmol)/liter (L) (≥100 mg/dL) at screening.
4. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening.
5. Participants on statins should be receiving a maximally tolerated dose.
6. Participants not receiving statins must have documented evidence of intolerance to all doses of at least 2 different statins.
7. Participants on lipid-lowering 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.

Exclusion Criteria:

Participants will be excluded from the study if any of the following exclusion criteria apply immediately 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) (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 (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
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Inclisiran; Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90 then every 6 months.	Drug: Inclisiran; Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.
PLACEBO_COMPARATOR: Placebo; Placebo will be administered as SC injections of saline solution on Day 1, Day 90 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	Measure Description	Time Frame
Percent Change in LDL-C From Baseline To Day 510		Baseline, Day 510
Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 540	Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 90 reported	Baseline, Day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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	Assessments performed at Baseline, Day 90, Day 540, absolute change at Day 90 reported	Baseline, Day 90
Percent Change in Apolipoprotein B (Apo-B) From Baseline To Day 510		Baseline, Day 510
Percent Change in Non-high-density Lipoprotein (HDL)-C From Baseline To Day 510		Baseline, Day 510

Collaborators and Investigators

• Sponsor: The Medicines Company
• Investigators: Principal Investigator: Frederick J. Raal, MD, University of Witwatersrand, South Africa

Publications and helpful links

General Publications

• Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, Wijngaard PLJ, Curcio D, Jaros MJ, Leiter LA, Kastelein JJP; ORION-9 Investigators. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020 Apr 16;382(16):1520-1530. doi: 10.1056/NEJMoa1913805. Epub 2020 Mar 18.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 28, 2017
• Primary Completion (ACTUAL): August 27, 2019
• Study Completion (ACTUAL): September 17, 2019

Study Registration Dates

• First Submitted: January 2, 2018
• First Submitted That Met QC Criteria: January 5, 2018
• First Posted (ACTUAL): January 11, 2018

Study Record Updates

• Last Update Posted (ACTUAL): October 28, 2020
• Last Update Submitted That Met QC Criteria: October 6, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Inclisiran; LDL-C; HeFH
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II
• Other Study ID Numbers: MDCO-PCS-17-03; 2017-002472-30 (EUDRACT_NUMBER)

Drug and device information, study documents

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