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

NCT03060577 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: MDCO-PCS-16-012016-003815-37
• Study Type: interventional
• Target: 382
• Locations: 5 countries
• Sites: 52

Brief 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).

Conditions

Atherosclerotic Cardiovascular Disease; Symptomatic Atherosclerosis; Type2 Diabetes; Familial Hypercholesterolemia

Outcome Measures

Primary Outcomes (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.

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

Secondary Outcomes (12)

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

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

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

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

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

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

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

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

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

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

Study Arms (2)

Inclisiran-only

EXPERIMENTAL

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

Drug: Inclisiran

Switching

ACTIVE COMPARATOR

Participants 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.

Drug: Inclisiran; Drug: Evolocumab

Interventions

Inclisiran DRUG

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.

Also known as: ALN-PCSSC

Inclisiran-only; Switching

Evolocumab DRUG

Evolocumab is a fully human monoclonal antibody that inhibits PCSK9.

Also known as: REPATHA

Switching

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (52)

Novartis Investigative Site

Jacksonville, Florida, 32216, United States

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Novartis Investigative Site

Indianapolis, Indiana, 46260, United States

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Novartis Investigative Site

New York, New York, 10029, United States

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Novartis Investigative Site

Cincinnati, Ohio, 45229, United States

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Novartis Investigative Site

Cincinnati, Ohio, 45246, United States

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Novartis Investigative Site

Greenville, Tennessee, 37745, United States

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Novartis Investigative Site

Amarillo, Texas, 79106, United States

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Novartis Investigative Site

Richmond, Virginia, 23294, United States

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Novartis Investigative Site

Vancouver, British Columbia, V6Z 1Y6, Canada

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Novartis Investigative Site

Winnipeg, Manitoba, R2H 2A6, Canada

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Novartis Investigative Site

Brampton, Ontario, L6Z 4N5, Canada

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Novartis Investigative Site

London, Ontario, N6A 4G5, Canada

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Novartis Investigative Site

Toronto, Ontario, M5C 2T2, Canada

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Novartis Investigative Site

Chicoutimi, Quebec, G7H 7K9, Canada

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Novartis Investigative Site

Montreal, Quebec, H2W 1R7, Canada

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Novartis Investigative Site

Sherbrooke, Quebec, J1H 5N4, Canada

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Novartis Investigative Site

Québec, G1V 4G5, Canada

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Novartis Investigative Site

Québec, G1V 4W2, Canada

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Novartis Investigative Site

St. Johns, A1B 3V6, Canada

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Novartis Investigative Site

Berlin, 12203, Germany

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Novartis Investigative Site

Essen, 45355, Germany

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Novartis Investigative Site

Frankfurt, 60590, Germany

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Novartis Investigative Site

Heidelberg, 69120, Germany

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Novartis Investigative Site

Munich, 80636, Germany

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Novartis Investigative Site

Leiden, South Holland, 2333 ZA, Netherlands

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Novartis Investigative Site

Rotterdam, The Netherlands, 3021 HC, Netherlands

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Novartis Investigative Site

Amsterdam, 1105 AZ, Netherlands

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Novartis Investigative Site

Deventer, 7416 SE, Netherlands

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Novartis Investigative Site

Eindhoven, 5611NJ, Netherlands

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Novartis Investigative Site

Goes, 4462 RA, Netherlands

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Novartis Investigative Site

Hoogeveen, 7909 AA, Netherlands

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Novartis Investigative Site

Hoogezand, 9603 AE, Netherlands

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Novartis Investigative Site

Hoorn, 1624 NP, Netherlands

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Novartis Investigative Site

The Hague, 2545 CH, Netherlands

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Novartis Investigative Site

Utrecht, 3582 KE, Netherlands

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Novartis Investigative Site

Utrecht, 3584 CX, Netherlands

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Novartis Investigative Site

Venlo, 5912 BL, Netherlands

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Novartis Investigative Site

Zwijndrecht, 3331 LZ, Netherlands

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Novartis Investigative Site

Fowey, Cornwall, PL23 1DT, United Kingdom

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Novartis Investigative Site

Liskeard, Cornwall, PL14 3XA, United Kingdom

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Novartis Investigative Site

Penzance, Cornwall, TR18 AJH, United Kingdom

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Novartis Investigative Site

St Austell, Cornwall, PL26 7RL, United Kingdom

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Novartis Investigative Site

Torpoint, Cornwall, PL11 2TB, United Kingdom

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Novartis Investigative Site

Birmingham, B15 2TH, United Kingdom

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Novartis Investigative Site

Edinburgh, ED16 4SA, United Kingdom

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Novartis Investigative Site

Exeter, EX2 5DW, United Kingdom

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Novartis Investigative Site

High Wycombe, HP16 9QJ, United Kingdom

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Novartis Investigative Site

London, NW3 2QG, United Kingdom

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Novartis Investigative Site

Manchester, M13 9WL, United Kingdom

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Novartis Investigative Site

Newcastle Upon Tyme, NE4 4LP, United Kingdom

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Novartis Investigative Site

Plymouth, PL5 3JB, United Kingdom

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Novartis Investigative Site

Worcester, WR5 1DD, United Kingdom

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Related Publications (2)

• 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.

  PMID: 36620965 DERIVED

• 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.

  PMID: 33990512 DERIVED

MeSH Terms

Conditions

Atherosclerosis; Hyperlipoproteinemia Type II

Interventions

ALN-PCS; evolocumab

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hyperlipoproteinemias; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Study Officials

• Kausik Ray, MD

  Imperial College London

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 17, 2017
• First Posted: February 23, 2017
• Study Start: April 27, 2017
• Primary Completion: December 17, 2021
• Study Completion: December 17, 2021
• Last Updated: March 24, 2023
• Results First Posted: March 24, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will share

Locations

NL (14); GB (14); US (8); CA (11); DE (5)