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

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ClinicalTrials.gov Identifier: NCT03851705
Recruitment Status : Recruiting
First Posted : February 22, 2019
Last Update Posted : February 22, 2019
Sponsor:
Information provided by (Responsible Party):
The Medicines Company

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).

Condition or disease Intervention/treatment Phase
Renal Impairment Drug: Inclisiran for injection Drug: Placebos Phase 2 Phase 3

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description: Double-blind
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : February 6, 2019
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
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

Placebo Comparator: Part 1 - Placebo
Participants will receive a dose of placebos administered by SC injection on Day 1 and Day 90.
Drug: Placebos
Sterile normal saline (0.9% sodium chloride in water for injection)

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.
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




Primary Outcome Measures :
  1. Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) from Baseline to Day 150 [ Time Frame: Baseline, Day 150 ]

Secondary Outcome Measures :
  1. 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

  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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 ]
  8. 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 ]
  9. 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 ]
  10. 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 ]
  11. 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 ]
  12. 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

  13. 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

  14. 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

  15. 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 ]
  16. 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 ]
  17. 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 ]
  18. 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 ]
  19. 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 ]
  20. 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 ]
  21. 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 ]
  22. 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 ]
  23. 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 ]
  24. 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 ]
  25. 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 ]
  26. 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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03851705


Contacts
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Contact: Global Health Science Center 1-888-977-6326 medical.information@themedco.com

Locations
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Czechia
(50042-001) Fakultni nemocnice Hradec Králové Not yet recruiting
Hradec Králové, Czechia, 500 05
Hong Kong
(50852-001) Queen Mary Hospital Not yet recruiting
Hong Kong, Hong Kong
Russian Federation
(50007-001) Research Institute of Complex Issues of Cardiovascular Diseases Not yet recruiting
Kemerovo, Russian Federation, 650002
(50007-003) National Medical Research Centre of Cardiology Not yet recruiting
Moscow, Russian Federation, 121552
(50007-002) Hospital for War Veterans Not yet recruiting
Saint Petersburg, Russian Federation, 193079
Serbia
(50381-001) Clinical Center of Serbia Recruiting
Belgrad, Serbia, 11000
Taiwan
(50886-001) Taipei Veterans General Hospital Not yet recruiting
Taipei, Taiwan, 11217
Ukraine
(50380-002) lvano-Frankivsk Regional Clinical Cardiology Center Not yet recruiting
Ivano-Frankivs'k, Ukraine, 76018
(50380-003) National Institute of Therapy Not yet recruiting
Kharkiv, Ukraine, 61039
(50380-001) National Scientific Center Not yet recruiting
Kyiv, Ukraine, 03680
Sponsors and Collaborators
The Medicines Company
Investigators
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Principal Investigator: John P. Kastelein, MD The Familial Hypercholesterolemia Foundation

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Responsible Party: The Medicines Company
ClinicalTrials.gov Identifier: NCT03851705     History of Changes
Other Study ID Numbers: MDCO-PCS-17-02
First Posted: February 22, 2019    Key Record Dates
Last Update Posted: February 22, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hyperlipoproteinemia Type II
Renal Insufficiency
Hypercholesterolemia
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Kidney Diseases
Urologic Diseases
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Hyperlipoproteinemias