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ORION-3: An Extension Trial of Inclisiran Compared to Evolocumab in Participants With Cardiovascular Disease and High Cholesterol

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT03060577
Collaborator
(none)
382
Enrollment
52
Locations
2
Arms
56.8
Actual Duration (Months)
7.3
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

ORION-3 is a Phase II, open-label, non-randomized, active comparator extension trial 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).

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

ORION-3 is an open label, long term extension study with two arms: Group 1 (inclisiran only arm) will receive inclisiran only and Group 2 (switching arm) will receive an active comparator (evolocumab) followed by inclisiran.

ORION-3 will be conducted in subjects with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents (eg, diabetes and familial hypercholesterolemia) and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies who have completed study MDCO-PCS-15-01 (ORION-1) [NCT02597127], to evaluate the efficacy, safety, and tolerability of long-term dosing of inclisiran.

Study Design

Study Type:
Interventional
Actual Enrollment :
382 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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)
Actual Study Start Date :
Mar 24, 2017
Actual Primary Completion Date :
Dec 17, 2021
Actual Study Completion Date :
Dec 17, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Inclisiran-only

Participants will receive subcutaneous injections of inclisiran 300 milligrams (mg) on Day 1 and every 180 days thereafter for up to 4 years.

Drug: Inclisiran
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 Names:
  • ALN-PCSSC

    		•
    Active Comparator: Switching

    Participants will receive self-administered subcutaneous injections of evolocumab 140 mg on Day 1 and every 14 days thereafter until Day 336. Then, the participants will receive subcutaneous injections of inclisiran 300 mg on Day 360 and every 180 days thereafter for up to 4 years.

    Drug: Inclisiran
    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 Names:
  • ALN-PCSSC

    • Drug: Evolocumab
    Evolocumab is a fully human monoclonal antibody that inhibits PCSK9.
    Other Names:
  • REPATHA

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percentage Change in LDL-C at Day 210 Compared to Day 1 of the ORION_1 Study (Inclisiran Arm) [Day 1, Day 210]

    Secondary Outcome Measures

    1. Percentage Change of Participants in the Inclisiran Group from Day 1 to Day 210 and to Day 1440 (or Final Visit) in LDL-C [Day 1, Day 210 and Day 1440 (or Final Visit)]

    2. Change of Participants in the Inclisiran Group from Day 1 to Day 210 and to Day 1440 (or Final Visit) in LDL-C [Day 1, Day 210 and Day 1440 (or Final Visit)]

    3. Percentage Change of Participants in the Inclisiran Group from Day 1 to Day 210 and to Day 1440 (or Final Visit) in PCSK9 Levels [Day 1, Day 210 and Day 1440 (or Final Visit)]

    4. Change of Participants in the Inclisiran Group from Day 1 to Day 210 and to Day 1440 (or Final Visit) in PCSK9 Levels [Day 1, Day 210 and Day 1440 (or Final Visit)]

    5. Percentage Change of Participants in the Inclisiran Group from Day 1 to Day 210 and to Day 1440 (or Final Visit) in Total Cholesterol, Triglycerides, HDL-C, non-HDL-C, VLDL-C, Apo-A1, Apo-B, and Lp(a) [Day 1, Day 210 and Day 1440 (or Final Visit)]

    6. Change of Participants in the Inclisiran Group from Day 1 to Day 210 and to Day 1440 (or Final Visit) in Total Cholesterol, Triglycerides, HDL-C, non-HDL-C, VLDL-C, Apo-A1, Apo-B, and Lp(a) [Day 1, Day 210 and Day 1440 (or Final Visit)]

    7. Proportion of Participants in the Inclisiran Group and the Evolocumab Group Who Attain Global Lipid Modification Targets for Their Level of ASCVD Risk [Day 210 and Day 1440 (or Final Visit)]

    8. Proportion of Participants in the Evolocumab Group Who Attain Global Lipid Modification Targets for Their Level of ASCVD Risk at Day 570 (210 Days After Starting Inclisiran) [Day 570]

    9. Proportion of Participants in the Inclisiran Group and the Evolocumab Group with ≥50% LDL-C Reduction [Day 210 and Day 570]

    10. Number of Participants in the Inclisiran Group and the Evolocumab Group Reaching on Treatment LDL-C Levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL [Day 210 and Day 570]

    11. Time to Lipid Lowering Effect in Participants in the Inclisiran Group and the Evolocumab Group [Day 1 through Day 1440]

    12. Change from Day 1 to Day 360 in LDL-C (Beta Quantification) of Participants in the Evolocumab Group [Day 1, Day 360]

    13. Change from Day 30 to Day 360 in Participant-Reported Scores Using the Treatment Satisfaction Questionnaire for Medication (TSQM) Questionnaire of Participants in the Inclisiran Group and the Evolocumab Group [Day 30, Day 360]

    14. Change from Day 450 to Day 720 in Participant-Reported Scores Using the TSQM Questionnaire of Participants in the Inclisiran Group [Day 450, Day 720]

    15. Participant-Reported Adherence to Self-Injectable Evolocumab [Day 30 through Day 360]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Completion of Study MDCO-PCS-15-01 and no contraindication to receiving inclisiran or evolocumab.

    2. 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.

    3. Willing to self-inject.

    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 participant at significant risk (according to investigator's [or delegate's] judgment).

    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. 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).

    4. 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.

    5. 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

    • 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

    1. Males who are unwilling to use an acceptable method of birth control during the entire study period (that is, condom with spermicide).

    2. Treatment with investigational medicinal products other than inclisiran or devices within 30 days or five half˗lives, whichever is longer.

    3. Planned use of investigational medicinal products other than inclisiran or devices during the course of the study.

    4. Participants with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients

    5. Previous or current treatment (within 90 days of study entry) with monoclonal antibodies directed towards PCSK9.

    6. 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).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Jacksonville Center for Clinical Research Jacksonville Florida United States 32216
    2 Midwest Institute For Clinical Research Indianapolis Indiana United States 46260
    3 Mount Sinai Icahn School of Medicine New York New York United States 10029
    4 Metabolic And Atherosclerosis Research Center Cincinnati Ohio United States 45227
    5 Sterling Research Group Cincinnati Ohio United States 45246
    6 Wellmont CVA Heart Institute Greeneville Tennessee United States 37745
    7 Amarillo Heart Clinical Research Institute, Inc. Amarillo Texas United States 79106
    8 National Clinical Research, Inc. Richmond Virginia United States 23294
    9 St. Paul's Hospital Vancouver British Columbia Canada V6Z 1Y6
    10 St. Boniface Hospital Winnipeg Manitoba Canada R2H 2A6
    11 Eastern Regional Health Authority, Patient Research Centre Saint John's Newfoundland and Labrador Canada A1B 3V6
    12 Brampton Research Associates Brampton Ontario Canada L6Z 4N5
    13 Lawson Health Research Institute London Ontario Canada N6A 5A5
    14 St. Michael's Hospital Toronto Ontario Canada M5C 2T2
    15 ECOGENE-21 Clinical Trials Center Chicoutimi Quebec Canada G7H 7K9
    16 Institut de Recherches Cliniques de Montreal Montreal Quebec Canada H2W 1R7
    17 Centre intégré universitaire de santé et de services sociaux de l'Estrie - Centre hospitalier universitaire de Sherbrooke (CIUSSS de l'Estrie - CHUS) Sherbrooke Quebec Canada J1H 5N4
    18 Université Laval Quebec Quebec Canada G1V 4G5
    19 Clinique des maladies lipidique Quebec Quebec Canada G1V 4W2
    20 Medical University Berlin Berlin Germany 12203
    21 Medical Center Essen Essen Germany 45355
    22 University Hospital Frankfurt Frankfurt Germany 60590
    23 Medical University Hospital Heidelberg, Internal Medicine III Heidelberg Germany 69120
    24 Technical University Munich, German Heart Center Munich Germany 80636
    25 Amsterdam Medical Center Amsterdam Netherlands 1105 AZ
    26 Haga Hospital Den Haag Netherlands 2545 CH
    27 Deventer Ziekenhuis Deventer Netherlands 7416 SE
    28 Andromed Eindoven Eindhoven Netherlands 5611 NV
    29 Admiraal de Ruyter Hospital, Cardiology Goes Netherlands 4462 RA
    30 Bethesda Diabetes Research Center Hoogeveen Netherlands 7909 AA
    31 Medisch Centrum Gorecht Hoogezand Netherlands 9603 AE
    32 VOC Hoorn Hoorn Netherlands 1624 NP
    33 Leids Universitair Medisch Centrum (LUMC) Leiden Netherlands 2333 ZA
    34 Andromed Rotterdam Rotterdam Netherlands 3039 BD
    35 Diakonesseshuis, Vascular Policlinic Utrecht Netherlands 3582 KE
    36 UMC Utrecht Utrecht Netherlands 3584 CX
    37 VieCurie Venlo, Cardiology Venlo Netherlands 5912 BL
    38 Albert Schweitzer Hospital, Cardiology Zwijndrecht Netherlands 3331 LZ
    39 Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust Birmingham United Kingdom B15 2TH
    40 Edinburgh Royal Infirmary Edinburgh United Kingdom EH16 4SA
    41 The Royal Devon and Exeter NHS Trust Exeter United Kingdom EX2 5DW
    42 Fowey River Practice Fowey United Kingdom PL23 1DT
    43 Buckinghamshire NHS Trust High Wycombe United Kingdom HP11 2TT
    44 Oak Tree Surgery Liskeard United Kingdom PL14 3XA
    45 Royal Free Hospital London United Kingdom NW3 2QG
    46 Central Manchester University Hospital NHS Foundation Trust Manchester United Kingdom M13 9WL
    47 The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital Newcastle upon Tyne United Kingdom NE1 4LP
    48 The Alverton Practice Penzance United Kingdom TR18 4JH
    49 Knowle House Surgery Plymouth United Kingdom PL5 3JB
    50 Brannel Surgery Saint Austell United Kingdom PL26 7RL
    51 Rame Medical Ltd (Rame Research) Torpoint United Kingdom PL11 2TB
    52 Worcestershire Acute NHS Trust Worcester United Kingdom WR5 1DD

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Principal Investigator: Kausik Ray, MD, Imperial College London

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT03060577
    Other Study ID Numbers:
    • MDCO-PCS-16-01
    First Posted:
    Feb 23, 2017
    Last Update Posted:
    Feb 8, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Cardiovascular Diseases
    Atherosclerosis
    Hyperlipoproteinemia Type II
    Hypercholesterolemia
    Evolocumab

    Study Results

    No Results Posted as of Feb 8, 2022