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Trial to Assess the Effect of Long Term Dosing of Inclisiran in Subjects With High CV Risk and Elevated LDL-C (ORION-8)

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. Identifier: NCT03814187
Recruitment Status : Active, not recruiting
First Posted : January 23, 2019
Last Update Posted : September 24, 2020
Information provided by (Responsible Party):

Brief Summary:
The purpose of this extension study is to evaluate the efficacy, safety, and tolerability of long-term dosing of Inclisiran. The study will be a global multicenter study.

Condition or disease Intervention/treatment Phase
ASCVD Elevated Cholesterol Heterozygous Familial Hypercholesterolemia Homozygous Familial Hypercholesterolemia Drug: Inclisiran Sodium Phase 3

Detailed Description:
This study will be an open label, long term extension study in subjects with atherosclerotic cardiovascular disease (ASCVD), ASCVD-risk equivalents (eg, diabetes and familial hypercholesterolemia), or heterozygous or homozygous familial hypercholesterolemia (HeFH or HoFH) and elevated low density lipoprotein cholesterol (LDL-C) despite maximum tolerated dose of LDL-C lowering therapies who have completed any of the following inclisiran Phase III lipid lowering studies: MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-04 (ORION-10), MDCO-PCS-17-08 (ORION-11) or MDCO-PCS-17-02 (ORION-5).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2991 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label Extension Trial of the Phase III Lipid-lowering Trials to Assess the Effect of Long Term Dosing of Inclisiran Given as Subcutaneous Injections in Subjects With High Cardiovascular Risk and Elevated LDL-C
Actual Study Start Date : April 16, 2019
Estimated Primary Completion Date : August 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Inclisiran

Inclisiran sodium 300 milligrams (mg) will be administered as a single SC injection on Day 1*, 90, then every 180 days to Day 990.

*Subjects who received blinded placebo in the feeder study will receive blinded inclisiran and subjects who received blinded inclisiran in the feeder study will receive blinded placebo on Day 1 in ORION-8. Subjects from the open label ORION-5 study will not receive any injection of study drug/placebo on Day 1.

Drug: Inclisiran Sodium
Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

Primary Outcome Measures :
  1. Proportion of subjects reaching on treatment LDL-C targets of <70 mg/dL [ Time Frame: Day 1080 ]
    Proportion of subjects who attain global lipid targets (entry criterion from respective previous study) for their level of ASCVD risk at EOS.

  2. Proportion of subjects reaching on treatment LDL-C targets of <100 mg/dL [ Time Frame: Day 1080 ]
    Proportion of subjects who attain global lipid targets (entry criterion from respective previous study) for their level of ASCVD risk at EOS.

Secondary Outcome Measures :
  1. Evaluate the effect of inclisiran on LDL-C levels [ Time Frame: Baseline, Day 1080 ]
  2. Evaluate the effect of inclisiran on total cholesterol (TC), triglycerides, LDL-C, and high density lipoprotein cholesterol (HDL-C) [ Time Frame: Baseline, Day 1080 ]

Other Outcome Measures:
  1. Safety assessments including adverse events, serious adverse events, ECGs, concomitant medications, and safety laboratory parameters will be performed. The formation and further characterization of anti-drug antibodies will also be evaluated. [ Time Frame: Baseline, Day 1080 ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Completion of a previously qualifying Phase III lipid-lowering ORION feeder study [MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-04 (ORION-10), MDCO-PCS-17-08 (ORION-11) or MDCO-PCS-17-02 (ORION-5)] meaning the subject received the last dose of study drug and completed the final study visit per applicable protocol.
  2. On current lipid-lowering therapies (such as a statin and/or ezetimibe) from previous study with no planned medication or dose change during study participation.
  3. 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:

  1. 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's) judgment] if he/she participates in the clinical study.
  2. An underlying known disease, or surgical, physical, or medical condition that, in the opinion of the investigator (or delegate) might interfere with interpretation of the clinical study results.
  3. Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less than 3 years,
  4. 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 the upper limit of normal (ULN), or total bilirubin (TBIL) elevation >2x ULN at the last recorded visit in the feeder study prior to study entry visit.
  5. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least one method of acceptable effective 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 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. Planned use of other investigational medicinal products other than inclisiran or devices during the course of the study.
  7. 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.

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 identifier (NCT number): NCT03814187

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Sponsors and Collaborators
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Principal Investigator: Scott Wright, MD Mayo Clinic
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Responsible Party: Novartis Identifier: NCT03814187    
Other Study ID Numbers: MDCO-PCS-17-05
CKJX839A12306B ( Other Identifier: Novartis )
First Posted: January 23, 2019    Key Record Dates
Last Update Posted: September 24, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis:
Inclisiran sodium
Additional relevant MeSH terms:
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Hyperlipoproteinemia Type II
Lipid Metabolism Disorders
Metabolic Diseases
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn