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Atherosclerotic Cardiovascular DiseasePhase 2ORION-3NCT03060577

An Extension Trial of Inclisiran in Participants With Cardiovascular Disease and High Cholesterol

A Phase 2 study testing Inclisiran and Evolocumab in people with Atherosclerotic Cardiovascular Disease and Symptomatic Atherosclerosis, run by Novartis Pharmaceuticals at 52 sites in 5 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This clinical study was designed to assess the efficacy, safety, and tolerability of long-term dosing of inclisiran and evolocumab given as subcutaneous injections in participants with high cardiovascular risk and elevated low-density lipoprotein cholesterol (LDL-C). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Inclisiran and Evolocumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
382 participants
Where
52 sitesin 5 countries
Study dates
27 Apr 2017to 17 Dec 2021
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Completion of Study MDCO-PCS-15-01 and no contraindication to receiving inclisiran or evolocumab.
  • Willing and able to give written and informed consent before initiation of any study related procedures and willing to comply with all required study procedures.
  • Willing to self-inject.

Who cannot join

  • 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 participant at significant risk (according to investigator's [or delegate's] judgment).
  • 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.
  • Serious comorbid disease in which the life expectancy of the participant is shorter than the duration of the trial (for example, acute systemic infection, cancer, or other serious illnesses).
  • Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver; unexplained alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation greater than 2 times upper limit of normal (ULN); or total bilirubin elevation greater than 1.5 times ULN at study entry visit.
  • Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least two methods of contraception (for example, oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device) for the entire duration of the study. Exemptions from this criterion are
  • Women >2 years postmenopausal (defined as 1 year or longer since their last menstrual period) AND more than 55 years of age
Show all 19Show fewer
  • Postmenopausal women (as defined above) and less than 55 years old with a negative pregnancy test within 24 hours of enrollment
  • Women who are surgically sterilized at least 3 months prior to enrollment
  • Males who are unwilling to use an acceptable method of birth control during the entire study period (that is, condom with spermicide).
  • Treatment with investigational medicinal products other than inclisiran or devices within 30 days or five half˗lives, whichever is longer.
  • Planned use of investigational medicinal products other than inclisiran or devices during the course of the study.
  • Participants with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients
  • Previous or current treatment (within 90 days of study entry) with monoclonal antibodies directed towards PCSK9.
  • Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to:
  • Inappropriate for this study, including participants 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 participants whose cooperation is doubtful due to drug abuse or alcohol dependency).
  • Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (for example, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study).
  • Involved with, or a relative of, someone directly involved in the conduct of the study.
  • Any known cognitive impairment (for example, Alzheimer's Disease).

Trial locations and contacts

52 sites in 5 countries.

52 sites in 5 countries

Netherlands14 sites

  • Novartis Investigative Site

    Amsterdam, 1105 AZ

  • Novartis Investigative Site

    Deventer, 7416 SE

  • Novartis Investigative Site

    Eindhoven, 5611NJ

  • Novartis Investigative Site

    Goes, 4462 RA

  • Novartis Investigative Site

    Hoogeveen, 7909 AA

  • Novartis Investigative Site

    Hoogezand, 9603 AE

  • Novartis Investigative Site

    Hoorn, 1624 NP

  • Novartis Investigative Site

    Leiden, South Holland, 2333 ZA

  • Novartis Investigative Site

    Rotterdam, The Netherlands, 3021 HC

  • Novartis Investigative Site

    The Hague, 2545 CH

  • Novartis Investigative Site

    Utrecht, 3582 KE

  • Novartis Investigative Site

    Utrecht, 3584 CX

  • Novartis Investigative Site

    Venlo, 5912 BL

  • Novartis Investigative Site

    Zwijndrecht, 3331 LZ

Other trials in Netherlands

United Kingdom14 sites

  • Novartis Investigative Site

    Birmingham, B15 2TH

  • Novartis Investigative Site

    Edinburgh, ED16 4SA

  • Novartis Investigative Site

    Exeter, EX2 5DW

  • Novartis Investigative Site

    Fowey, Cornwall, PL23 1DT

  • Novartis Investigative Site

    High Wycombe, HP16 9QJ

  • Novartis Investigative Site

    Liskeard, Cornwall, PL14 3XA

  • Novartis Investigative Site

    London, NW3 2QG

  • Novartis Investigative Site

    Manchester, M13 9WL

  • Novartis Investigative Site

    Newcastle Upon Tyme, NE4 4LP

  • Novartis Investigative Site

    Penzance, Cornwall, TR18 AJH

  • Novartis Investigative Site

    Plymouth, PL5 3JB

  • Novartis Investigative Site

    St Austell, Cornwall, PL26 7RL

  • Novartis Investigative Site

    Torpoint, Cornwall, PL11 2TB

  • Novartis Investigative Site

    Worcester, WR5 1DD

Other trials in United Kingdom

Canada11 sites

  • Novartis Investigative Site

    Brampton, Ontario, L6Z 4N5

  • Novartis Investigative Site

    Chicoutimi, Quebec, G7H 7K9

  • Novartis Investigative Site

    London, Ontario, N6A 4G5

  • Novartis Investigative Site

    Montreal, Quebec, H2W 1R7

  • Novartis Investigative Site

    Québec, G1V 4G5

  • Novartis Investigative Site

    Québec, G1V 4W2

  • Novartis Investigative Site

    Sherbrooke, Quebec, J1H 5N4

  • Novartis Investigative Site

    St. Johns, A1B 3V6

  • Novartis Investigative Site

    Toronto, Ontario, M5C 2T2

  • Novartis Investigative Site

    Vancouver, British Columbia, V6Z 1Y6

  • Novartis Investigative Site

    Winnipeg, Manitoba, R2H 2A6

Other trials in Canada

United States8 sites

  • Novartis Investigative Site

    Amarillo, Texas, 79106

  • Novartis Investigative Site

    Cincinnati, Ohio, 45229

  • Novartis Investigative Site

    Cincinnati, Ohio, 45246

  • Novartis Investigative Site

    Greenville, Tennessee, 37745

  • Novartis Investigative Site

    Indianapolis, Indiana, 46260

  • Novartis Investigative Site

    Jacksonville, Florida, 32216

  • Novartis Investigative Site

    New York, New York, 10029

  • Novartis Investigative Site

    Richmond, Virginia, 23294

Other trials in United States

Germany5 sites

  • Novartis Investigative Site

    Berlin, 12203

  • Novartis Investigative Site

    Essen, 45355

  • Novartis Investigative Site

    Frankfurt, 60590

  • Novartis Investigative Site

    Heidelberg, 69120

  • Novartis Investigative Site

    Munich, 80636

Other trials in Germany

About this study

Official title: An Open Label, Active Comparator Extension Trial to Assess the Effect of Long Term Dosing of Inclisiran and Evolocumab Given as Subcutaneous Injections in Participants With High Cardiovascular Risk and Elevated LDL-C (ORION-3)

This clinical study was designed to assess the efficacy, safety, and tolerability of long-term dosing of inclisiran and evolocumab given as subcutaneous injections in participants with high cardiovascular risk and elevated low-density lipoprotein cholesterol (LDL-C).

Read the detailed description

MDCO-PCS-16-01 (ORION-3) was a Phase II, open-label, multicenter, non-randomized, active comparator long term extension study. Total study duration was 4 years from first participant enrolled to the last subject completed. The study consisted of three study periods:

Screening Period: Participants completing study MDCO-PCS-15-01 (ORION-1) were screened for all inclusion and exclusion criteria of study ORION-3.

Treatment Period: Participants fulfilling all eligibility criteria of ORION-3 were enrolled. Participants who received inclisiran in ORION-1 received inclisiran sodium throughout this study up to 4 years (Group 1; Inclisiran-only arm), and participants who received placebo in ORION-1 received evolocumab as open-label comparator up to Day 336, and then transitioned to inclisiran on Day 360 and every 180 days thereafter for up to 4 years (Group 2; Switching arm).

Safety follow up: Participants were followed up for safety during 4 weeks after the last dose of study treatment. Including the Screening Period, the total study duration for a participant was up to 4 years.

Being tested
Inclisiran, Evolocumab
Medical subject headings
Atherosclerosis, Hyperlipoproteinemia Type II

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • InclisiranDrug

    Also called ALN-PCSSC

    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.

  • EvolocumabDrug

    Also called REPATHA

    Evolocumab is a fully human monoclonal antibody that inhibits PCSK9.

Study groups in NCT03060577
Study groupRoleWhat they receive
Inclisiran-onlyExperimentalParticipants received subcutaneous injections of inclisiran 300 milligrams (mg) on Day 1 and every 180 days thereafter for up to 4 years.
Receives: Drug: Inclisiran
SwitchingActive comparatorParticipants received self-administered subcutaneous injections of evolocumab 140 mg on Day 1 and every 14 days thereafter until Day 336. Then, participants received subcutaneous injections of inclisiran 300 mg on Day 360 and every 180 days thereafter for up to 4 years.
Receives: Drug: Inclisiran; Drug: Evolocumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage Change in LDL-C From Baseline of the ORION-1 Study to Day 210 in ORION-3 (Inclisiran Arm)

    Percent Change in LDL-C (beta-quantification) from baseline of the ORION-1 Study to Day 210 in ORION-3. A negative percentage score represents a reduction in LDL-C. Change is relative to ORION-1 Baseline, which is defined as the last available record prior to first study drug administration in ORION-1.

    Measured: Baseline (ORION-1) and Day 210 (ORION-3) (up to 570 days total)

Secondary outcomes (12)

  1. Percentage Change in LDL-C From Baseline of the ORION-1 Study (Inclisiran Arm)

    Percent Change in LDL-C (beta-quantification) from baseline of the ORION-1 Study overtime in ORION-3. A negative percentage score represents a reduction in LDL-C. Changes are relative to ORION-1 Baseline, which is defined as the last available record prior to first study drug administration in ORION-1.

    Measured: Baseline (ORION-1) and Days 30, 360, 720, 1080 and 1440 (ORION-3) (up to 390, 720, 1080, 1440 and 1800 days total, respectively)

  2. Absolute Change in LDL-C From Baseline of the ORION-1 Study (Inclisiran Arm)

    Absolute Change in LDL-C (beta-quantification) from baseline of the ORION-1 Study overtime in ORION-3. A negative score represents a reduction in LDL-C. Changes are relative to ORION-1 Baseline, which is defined as the last available record prior to first study drug administration in ORION-1.

    Measured: Baseline (ORION-1) and Days 30, 360, 720, 1080 and 1440 (ORION-3) (up to 390, 720, 1080, 1440 and 1800 days total, respectively)

  3. Percentage Change in PCSK9 Levels From Baseline of the ORION-1 Study (Inclisiran Arm)

    Percent Change in PCSK9 from baseline of the ORION-1 Study overtime in ORION-3. A negative percentage score represents a reduction in PCSK9. Changes are relative to ORION-1 Baseline, which is defined as the last available record prior to first study drug administration in ORION-1.

    Measured: Baseline (ORION-1) and Days 30, 360, 720 and 1440 (ORION-3) (up to 390, 720, 1080 and 1800 days total, respectively)

  4. Absolute Change in PCSK9 Levels From Baseline of the ORION-1 Study (Inclisiran Arm)

    Absolute Change in PCSK9 from baseline of the ORION-1 Study overtime in ORION-3. A negative score represents a reduction in PCSK9. Changes are relative to ORION-1 Baseline, which is defined as the last available record prior to first study drug administration in ORION-1.

    Measured: Baseline (ORION-1) and Days 30, 360, 720 and 1440 (ORION-3) (up to 390, 720, 1080 and 1800 days total, respectively)

  5. Percentage Change in Triglycerides From Baseline of the ORION-1 Study (Inclisiran Arm)

    Percent Change in Triglycerides from baseline of the ORION-1 Study overtime in ORION-3. A negative percentage score represents a reduction in Triglycerides. Changes are relative to ORION-1 Baseline, which is defined as the last available record prior to first study drug administration in ORION-1.

    Measured: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively)

  6. Absolute Change in Triglycerides From Baseline of the ORION-1 Study (Inclisiran Arm)

    Absolute Change in Triglycerides from baseline of the ORION-1 Study overtime in ORION-3. A negative score represents a reduction in Triglycerides. Changes are relative to ORION-1 Baseline, which is defined as the last available record prior to first study drug administration in ORION-1.

    Measured: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively)

  7. Percentage Change in Apolipoprotein B From Baseline of the ORION-1 Study (Inclisiran Arm)

    Percent Change in Apolipoprotein B from baseline of the ORION-1 Study overtime in ORION-3. A negative percentage score represents a reduction in Apolipoprotein B. Changes are relative to ORION-1 Baseline, which is defined as the last available record prior to first study drug administration in ORION-1.

    Measured: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively)

  8. Absolute Change in Apolipoprotein B From Baseline of the ORION-1 Study (Inclisiran Arm)

    Absolute Change in Apolipoprotein B from baseline of the ORION-1 Study overtime in ORION-3. A negative score represents a reduction in Apolipoprotein B. Changes are relative to ORION-1 Baseline, which is defined as the last available record prior to first study drug administration in ORION-1.

    Measured: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively)

  9. Percentage Change in Lipoprotein-a From Baseline of the ORION-1 Study (Inclisiran Arm)

    Percent Change in Lipoprotein-a from baseline of the ORION-1 Study overtime in ORION-3. A negative percentage score represents a reduction in Lipoprotein-a. Changes are relative to ORION-1 Baseline, which is defined as the last available record prior to first study drug administration in ORION-1.

    Measured: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively)

  10. Absolute Change in Lipoprotein-a From Baseline of the ORION-1 Study (Inclisiran Arm)

    Absolute Change in Lipoprotein-a from baseline of the ORION-1 Study overtime in ORION-3. A negative score represents a reduction in Lipoprotein-a. Changes are relative to ORION-1 Baseline, which is defined as the last available record prior to first study drug administration in ORION-1.

    Measured: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively)

  11. Number of Participants With ≥50% LDL-C Reduction From Baseline of the ORION-1 Study (Inclisiran Arm)

    Number of Participants with ≥50% LDL-C (beta-quantification) Reduction from baseline of the ORION-1 Study overtime in ORION-3. Changes are relative to ORION-1 Baseline, which is defined as the last available record prior to first study drug administration in ORION-1.

    Measured: Baseline (ORION-1) and Days 30, 360, 720 and 1440 (ORION-3) (up to 390, 720, 1080 and 1800 days total, respectively)

  12. Number of Participants Reaching on Treatment LDL-C Levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL (Inclisiran Arm)

    Individual responsiveness to inclisiran is defined as the number of Participants Reaching on Treatment LDL-C Levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL at any time point.

    Measured: From the start of treatment in ORION-3 to 90 days after end of treatment, assessed up to maximum duration of 4 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Feb 2017
  2. Study start27 Apr 2017
  3. Primary completion17 Dec 2021
  4. Study completion17 Dec 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
382 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03060577
Sponsor's protocol ID
MDCO-PCS-16-01
Other IDs
2016-003815-37, 2016
Acronym
ORION-3
Status last verified
Feb 2023
First submitted
17 Feb 2017
Last updated
24 Mar 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: 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

Publications

  • Ray KK, Troquay RPT, Visseren FLJ, Leiter LA, Scott Wright R, Vikarunnessa S, Talloczy Z, Zang X, Maheux P, Lesogor A, Landmesser U. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. Lancet Diabetes Endocrinol. 2023 Feb;11(2):109-119. doi: 10.1016/S2213-8587(22)00353-9. Epub 2023 Jan 5.

    PubMed 36620965

  • Warden BA, Duell PB. Inclisiran: A Novel Agent for Lowering Apolipoprotein B-containing Lipoproteins. J Cardiovasc Pharmacol. 2021 Aug 1;78(2):e157-e174. doi: 10.1097/FJC.0000000000001053.

    PubMed 33990512

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Inclisiran and Evolocumab in people with Atherosclerotic Cardiovascular Disease and Symptomatic Atherosclerosis, run by Novartis Pharmaceuticals at 52 sites in 5 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 52 sites in Netherlands, United Kingdom, Canada, United States, Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 Mar 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage Change in LDL-C From Baseline of the ORION-1 Study to Day 210 in ORION-3 (Inclisiran Arm) (time frame: Baseline (ORION-1) and Day 210 (ORION-3) (up to 570 days total)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03060577, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Mar 2023.

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