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A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH) (ORION-5)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03851705
Recruitment Status : Active, not recruiting
First Posted : February 22, 2019
Last Update Posted : June 4, 2020
Sponsor:
Information provided by (Responsible Party):
The Medicines Company

Tracking Information
First Submitted Date  ICMJE February 7, 2019
First Posted Date  ICMJE February 22, 2019
Last Update Posted Date June 4, 2020
Actual Study Start Date  ICMJE February 6, 2019
Actual Primary Completion Date March 2, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 20, 2019)
Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) from Baseline to Day 150 [ Time Frame: Baseline, Day 150 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 20, 2019)
  • Absolute Change in Low-Density Lipoprotein Cholesterol (LDL-C) from Baseline to Day 150 [ Time Frame: Baseline, Day 150 ]
    Change in LDL-C levels (mg/dL) from baseline to Day 150
  • Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 90, 150, 180, 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 720 [ Time Frame: Baseline, Days 90, 150, 180, 270, 330, 450, 510, 630, 690, and 720 ]
  • Percent Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 90, 150, 180, 330, 510, 690, and 720 ]
  • Absolute Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 90, 150, 180, 330, 510, 690, and 720 ]
  • Percent Change in Total Cholesterol from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline to Days 150, 180, 330, 510, 690, and 720 ]
  • Absolute Change in Total Cholesterol from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline to Days 150, 180, 330, 510, 690, and 720 ]
  • Percent Change in Apolipoprotein B (apoB) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline to Days 150, 180, 330, 510, 690, and 720 ]
  • Absolute Change in Apolipoprotein B (apoB) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline to Days 150, 180, 330, 510, 690, and 720 ]
  • Percent Change in non-HDL Cholesterol (non-HDL-C) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline to Days 150, 180, 330, 510, 690, and 720 ]
  • Absolute Change in non-HDL Cholesterol (non-HDL-C) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline to Days 150, 180, 330, 510, 690, and 720 ]
  • Individual Responsiveness of Subjects [ Time Frame: Baseline, Days 150, 180, 330, 510, 690 and 720 ]
    Subjects defined as the number of subjects reaching on treatment LDL-C levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL at Days 150, 180, 330, 510, 690, and 720
  • Proportional Responsiveness of Subjects [ Time Frame: Baseline, Days 150, 180, 330, 510, 690 and 720 ]
    Proportion of subjects of subjects in each group who attain global lipid targets for their indication
  • LDL-C reduction ≥ 20% or ≥30% [ Time Frame: Baseline, Days 150, 180, 330, 510, 690, and 720 ]
    Proportion of subjects in each group with ≥ 20% or ≥30% LDL-C reduction from baseline at Days 150, 180, 330, 510, 690, and 720
  • Percent Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 150, 180, 330, 510, 690, and 720 ]
  • Absolute Change in High-Density Lipoprotein Cholesterol Levels (HDL-C) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 150, 180, 330, 510, 690, and 720 ]
  • Percent Change in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 150, 180, 330, 510, 690, and 720 ]
  • Absolute Change in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 150, 180, 330, 510, 690, and 720 ]
  • Percent Change in Apolipoprotein A-1 (Apo-A1) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 150, 180, 330, 510, 690, and 720 ]
  • Absolute Change in Apolipoprotein A-1 (Apo-A1) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 150, 180, 330, 510, 690, and 720 ]
  • Percent Change in Lipoprotein(a) [Lp(a)] from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 150, 180, 330, 510, 690, and 720 ]
  • Absolute Change in Lipoprotein(a) [Lp(a)] from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 150, 180, 330, 510, 690, and 720 ]
  • Percent Change in High-Sensitivity C-Reactive Protein (hsCRP) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 150, 180, 330, 510, 690, and 720 ]
  • Absolute Change in High-Sensitivity C-Reactive Protein (hsCRP) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 150, 180, 330, 510, 690, and 720 ]
  • Percent Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 150, 180, 330, 510, 690, and 720 ]
  • Absolute Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) from Baseline to Subsequent Visits up to Day 720 [ Time Frame: Baseline, Days 150, 180, 330, 510, 690, and 720 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH)
Official Title  ICMJE 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) (ORION-5)
Brief Summary This study is 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).
Detailed Description

This study has two sequential parts:

  • Part 1: 6-month double-blind period in which subjects will be randomized to receive either inclisiran or placebo
  • Part 2: 18-month open-label follow-up period; placebo-treated subjects from Part 1 will be transitioned to inclisiran at Day 180 and all subjects will participate in an open-label follow-up period of inclisiran only
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description:
Double-blind
Primary Purpose: Treatment
Condition  ICMJE Homozygous Familial Hypercholesterolemia
Intervention  ICMJE
  • Drug: Inclisiran for injection
    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.
    Other Name: ALN-PCSSC
  • Drug: Placebos
    Sterile normal saline (0.9% sodium chloride in water for injection)
Study Arms  ICMJE
  • Experimental: Part 1 - Inclisiran
    Participants will receive a dose of 300 milligram (mg) Inclisiran for injection administered by SC injection on Day 1 and Day 90.
    Intervention: Drug: Inclisiran for injection
  • Placebo Comparator: Part 1 - Placebo
    Participants will receive a dose of placebos administered by SC injection on Day 1 and Day 90.
    Intervention: Drug: Placebos
  • Experimental: Part 2 - Inclisiran
    All participants will receive a dose of 300 mg inclisiran for injection administered by SC injection on Day 270, Day 450 and Day 630.
    Intervention: Drug: Inclisiran for injection
Publications * Not Provided

*   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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 12, 2020)
56
Original Estimated Enrollment  ICMJE
 (submitted: February 20, 2019)
45
Estimated Study Completion Date  ICMJE September 2021
Actual Primary Completion Date March 2, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. 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
  2. Stable on a low-fat diet.
  3. 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.
  4. Subjects not receiving statins must have documented evidence of intolerance to at least two different statins.
  5. 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.
  6. Fasting central laboratory LDL-C concentration ≥130 mg/dL (3.4 mmol/L).
  7. Triglyceride concentration <400 mg/dL (4.5 mmol/L)
  8. No current or planned renal dialysis or renal transplantation
  9. Subjects on a documented regimen of LDL or plasma apheresis will be allowed to continue the apheresis during the study, if needed.
  10. 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.
  11. Willing to follow all study procedures including adherence to dietary guidelines, study visits, fasting blood draws, and compliance with study treatment regimens.

Exclusion Criteria:

  1. Use of Mipomersen or Lomitapide therapy within 5 months of screening
  2. Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9
  3. New York Heart Association (NYHA) class IV heart failure or last known left ventricular ejection fraction <25%
  4. Major adverse cardiovascular event within 3 months prior to randomization
  5. Planned cardiac surgery or revascularization
  6. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg prior to randomization despite anti-hypertensive therapy
  7. 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
  8. Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less than the duration of the trial
  9. 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
  10. 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:

    1. Women >2 years postmenopausal (defined as 1 year or longer since their 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 enrolment
    3. Women who are surgically sterilized at least 3 months prior to enrolment
  11. Known history of alcohol and/or drug abuse within 5 years
  12. Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to:

    1. Subjects who are unable to communicate or to cooperate with the investigator.
    2. Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study (including subjects whose cooperation is doubtful due to drug abuse or alcohol dependency)
    3. Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study)
    4. Have any medical or surgical condition, which in the opinion of the investigator would put the subject at increased risk from participating in the study
    5. Persons directly involved in the conduct of the study
  13. Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with participation in the clinical study, and/or put the subject at significant risk (according to investigator's [or delegate] judgment) if he/she participates in the clinical study
  14. Any underlying known disease, or surgical, physical, or medical condition that, in the opinion of the Investigator, might interfere with the interpretation of clinical study results
  15. Treatment with other investigational medicinal products or devices within 30 days or 5 half-lives of the screening visit, whichever is longer
  16. Previous participation in the study
  17. Hypersensitivity to any of the ingredients of Inclisiran

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 to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Hong Kong,   Israel,   Russian Federation,   Serbia,   South Africa,   Taiwan,   Turkey,   Ukraine
Removed Location Countries Czechia
 
Administrative Information
NCT Number  ICMJE NCT03851705
Other Study ID Numbers  ICMJE MDCO-PCS-17-02
Has Data Monitoring Committee No
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
Plan to Share IPD: No
Responsible Party The Medicines Company
Study Sponsor  ICMJE The Medicines Company
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: John P. Kastelein, MD The Familial Hypercholesterolemia Foundation
PRS Account The Medicines Company
Verification Date June 2020

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