Trial to Assess the Effect of Long Term Dosing of Inclisiran in Subjects With High CV Risk and Elevated LDL-C (ORION-8)
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| ClinicalTrials.gov Identifier: NCT03814187 |
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Recruitment Status :
Completed
First Posted : January 23, 2019
Results First Posted : March 6, 2024
Last Update Posted : March 6, 2024
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| ASCVD Elevated Cholesterol Heterozygous Familial Hypercholesterolemia Homozygous Familial Hypercholesterolemia | Drug: Inclisiran Sodium | Phase 3 |
This study was an open label, long term extension study in subjects with atherosclerotic cardiovascular disease (ASCVD), ASCVD-risk equivalents (eg, diabetes and familial hypercholesterolemia), or heterozygous familial hypercholesterolemia (HeFH) and elevated low density lipoprotein cholesterol (LDL-C) despite maximum tolerated dose of LDL-C lowering therapies who have completed the inclisiran Phase II trial MDCO-PCS-16-01 (ORION-3; NCT03060577), or any of the following Phase III lipid lowering studies: MDCO-PCS-17-03 (ORION-9; NCT03397121), MDCO-PCS-17-04 (ORION-10; NCT03399370), or MDCO-PCS-17-08 (ORION-11; NCT03400800).
The End of Study (EOS) visit in the previous feeder studies was Day 1 in this extension study.The duration that each subject participated in this study was a maximum of 3 years. However, for subjects from the Study ORION-3, the Sponsor decided to end the study prior to completion of their full 3-year of participation. It is recorded in the database as discontinuation was due to Sponsor's decision.
In this Phase III extension study, the same study drug of inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) was administered as a single subcutaneous (SC) dose every 180 days from the last dose in previous feeder study (except for subjects newly initiating inclisiran, who received the first two doses 90 days apart) until the end of the study.
On Day 1 (EOS visit in the feeder study), subjects from the previous feeder studies received blinded study medication except subjects from Study ORION-3. Subjects who received placebo in the previous Phase III feeder study received blinded inclisiran and subjects who received inclisiran in the previous feeder study received blinded placebo at this visit, so that subjects previously on placebo received the correct dosing regime, i.e. a dose at Day 1, Day 90 and every 180-days thereafter. Subjects previously treated with inclisiran did not need a dose of inclisiran to maintain every 180-dosing regime and therefore, were given placebo in order to maintain the blinding of the feeder study. Subjects that moved over from ORION-3 received the first study medication at Day 90, as this study was already open-label.
On Day 90, all subjects received inclisiran sodium 300 mg. This is 180 days after the last injection in the previous feeder study for subjects that received inclisiran and was the second dose of inclisiran for the subjects that received placebo in the feeder study. The EOS visit occurred at Day 1080.
This extension study allowed subjects continued access to inclisiran treatment and allowed the collection of additional efficacy and safety data for long-term use beyond the end of the feeder studies.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 3275 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 |
| Actual Primary Completion Date : | February 13, 2023 |
| Actual Study Completion Date : | February 13, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Inclisiran
Inclisiran sodium 300 milligrams (mg) was 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 received blinded inclisiran and subjects who received blinded inclisiran in the feeder study received blinded placebo on Day 1 in ORION-8. Subjects from the open label ORION-3 study did not receive any injection of study drug on Day 1. Their first dose of study medication was at day 90 |
Drug: Inclisiran Sodium
Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis. |
- Proportion of Subjects Achieving Global Lipid Targets for Their Level of ASCVD Risk [ Time Frame: From ORION-8 Day 1 to the end of study (up to 1080 days) ]
The primary objective of the study is to evaluate the effect of inclisiran treatment on the proportion of subjects achieving prespecified LDL-C targets at end of study (EOS).
Target is <70 mg/dL for atherosclerotic cardiovascular disease (ASCVD) subjects and <100 mg/dL for ASCVD risk equivalent subjects.
Risk equivalent subjects are defined as either type 2 diabetes, familial hypercholesterolemia or a 10-year risk of a cardiovascular event ≥20% as assessed by the Framingham Risk Score or equivalent; without a medical history of coronary heart disease , cerebrovascular disease or peripheral artery disease.
- Incidence of Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From ORION-8 Day 1 to the end of study (up to 1080 days) ]
Safety assessments include adverse events and serious adverse events until the end of study.
End of study visit occured at least 90 days following the last inclisiran dose once a decision was made to end the study (either by the subject, investigator or sponsor). For subjects prematurely and permanently discontinued from study treatment, who were not willing to return within the 90 day timeframe, the EOS visit was scheduled as soon as possible, or if decision to discontinue and not return was made at a specific visit, this visit became the EOS visit.
- Absolute Change in LDL-C From the Initial Feeder Study Baseline [ Time Frame: Feeder study baseline, ORION-8 baseline, Day 1080/EOS (ORION-8) (up to a maximum of 2340 days) ]Absolute change from baseline in low density lipoprotein cholesterol (LDL-C) was calculated to evaluate the effect of inclisiran on LDL-C levels.
- Percentage Change in LDL-C From the Initial Feeder Study Baseline [ Time Frame: Feeder study baseline, ORION-8 baseline, Day 1080/EOS (ORION-8) (up to a maximum of 2340 days) ]Percentage change from baseline in low density lipoprotein cholesterol (LDL-C) was calculated to evaluate the effect of inclisiran on LDL-C levels.
- Absolute Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C [ Time Frame: Feeder study baseline, ORION-8 baseline, Day 1080/EOS (ORION-8) (up to a maximum of 2340 days) ]Absolute change from baseline in total cholesterol, triglycerides and high density lipoprotein cholesterol (HDL-C) was calculated to evaluate the effect of inclisiran on other lipids and lipoproteins.
- Percentage Change From the Initial Feeder Study Baseline in Total Cholesterol, Triglycerides and HDL-C [ Time Frame: Feeder study baseline, ORION-8 baseline, Day 1080/EOS (ORION-8) (up to a maximum of 2340 days) ]Percentage change from baseline in total cholesterol (TC), triglycerides and high density lipoprotein cholesterol (HDL-C) was calculated to evaluate the effect of inclisiran on other lipids and lipoproteins.
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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:
- Completion on a previously qualifying inclisiran Phase II trial MDCO-PCS-16-01 (ORION-3), or Phase III lipid lowering ORION feeder study [MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-4 (ORION-10), or MDCO-PCS-17-08 (ORION-11)] meaning the subject received the last dose of study drug and completed the final study visit per applicable protocol.
- 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.
- 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:
- 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.
- 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.
- Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less than 3 years,
- 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.
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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:
- Women >2 years postmenopausal (defined as 1 year or longer since last menstrual period) and more than 55 years of age.
- Postmenopausal women (as defined above) and less than 55 years of age with a negative pregnancy test within 24 hours of randomization.
- Women who are surgically sterilized at least 3 months prior to enrollment.
- Planned use of other investigational medicinal products other than inclisiran or devices during the course of the study.
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Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to:
- Subjects who are unable to communicate or to cooperate with the investigator
- 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)
- 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)
- 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
- 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.
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): NCT03814187
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| Principal Investigator: | Scott Wright, MD | Mayo Clinic |
Documents provided by Novartis ( Novartis Pharmaceuticals ):
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT03814187 |
| Other Study ID Numbers: |
MDCO-PCS-17-05 CKJX839A12306B ( Other Identifier: Novartis Pharmaceuticals ) 2017-003092-55 ( EudraCT Number ) |
| First Posted: | January 23, 2019 Key Record Dates |
| Results First Posted: | March 6, 2024 |
| Last Update Posted: | March 6, 2024 |
| Last Verified: | February 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| 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 www.clinicalstudydatarequest.com |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Inclisiran sodium ASCVD LDL-C HeFH HoFH |
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Hyperlipoproteinemia Type II Homozygous Familial Hypercholesterolemia Hypercholesterolemia Hyperlipidemias Dyslipidemias Lipid Metabolism Disorders |
Metabolic Diseases Lipid Metabolism, Inborn Errors Metabolism, Inborn Errors Genetic Diseases, Inborn Hyperlipoproteinemias |