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

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ClinicalTrials.gov Identifier: NCT03397121
Recruitment Status : Completed
First Posted : January 11, 2018
Results First Posted : October 28, 2020
Last Update Posted : October 28, 2020
Sponsor:
Information provided by (Responsible Party):
The Medicines Company

Tracking Information
First Submitted Date  ICMJE January 2, 2018
First Posted Date  ICMJE January 11, 2018
Results First Submitted Date  ICMJE August 27, 2020
Results First Posted Date  ICMJE October 28, 2020
Last Update Posted Date October 28, 2020
Actual Study Start Date  ICMJE November 28, 2017
Actual Primary Completion Date August 27, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 6, 2020)
  • Percent Change in LDL-C From Baseline To Day 510 [ Time Frame: Baseline, Day 510 ]
  • Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 540 [ Time Frame: Baseline, Day 90 ]
    Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 90 reported
Original Primary Outcome Measures  ICMJE
 (submitted: January 5, 2018)
  • Percentage Change In LDL-C From Baseline To Day 510 [ Time Frame: Baseline, Day 510 ]
  • Time-adjusted Percentage Change In LDL-C From Baseline Between Day 90 And Day 540 [ Time Frame: Baseline, Day 90 to Day 540 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 6, 2020)
  • Absolute Change in LDL-C From Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
  • Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540 [ Time Frame: Baseline, Day 90 ]
    Assessments performed at Baseline, Day 90, Day 540, absolute change at Day 90 reported
  • Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
  • Percentage Change in Total Cholesterol From Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
  • Percent Change in Apolipoprotein B (Apo-B) From Baseline To Day 510 [ Time Frame: Baseline, Day 510 ]
  • Percent Change in Non-high-density Lipoprotein (HDL)-C From Baseline To Day 510 [ Time Frame: Baseline, Day 510 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: January 5, 2018)
  • Absolute Change in LDL-C from Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
  • Time-adjusted Absolute Change in LDL-C from Baseline Between Day 90 and Day 540 [ Time Frame: Baseline, Day 540 ]
  • Percentage Change in Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) from Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
  • Percentage Change in Total Cholesterol from Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
  • Percentage Change in Apolipoprotein B (ApoB) from Baseline To Day 510 [ Time Frame: Baseline, Day 510 ]
  • Percentage Change in Non-high-density Lipoprotein (HDL)-C from Baseline To Day 510 [ Time Frame: Baseline, Day 510 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)
Official Title  ICMJE 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).
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Condition  ICMJE
  • Heterozygous Familial Hypercholesterolemia
  • Elevated Cholesterol
Intervention  ICMJE
  • Drug: Inclisiran
    Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.
  • Drug: Placebo
    Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).
    Other Name: Saline Solution
Study Arms  ICMJE
  • Experimental: Inclisiran
    Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90 then every 6 months.
    Intervention: Drug: Inclisiran
  • Placebo Comparator: Placebo
    Placebo will be administered as SC injections of saline solution on Day 1, Day 90 then every 6 months.
    Intervention: Drug: Placebo
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 6, 2018)
482
Original Estimated Enrollment  ICMJE
 (submitted: January 5, 2018)
400
Actual Study Completion Date  ICMJE September 17, 2019
Actual Primary Completion Date August 27, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Czechia,   Denmark,   Netherlands,   South Africa,   Spain,   Sweden,   United States
Removed Location Countries Israel,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT03397121
Other Study ID Numbers  ICMJE MDCO-PCS-17-03
2017-002472-30 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party The Medicines Company
Original Responsible Party Same as current
Current Study Sponsor  ICMJE The Medicines Company
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Frederick J. Raal, MD University of Witwatersrand, South Africa
PRS Account The Medicines Company
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP