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

NCT ID: NCT03060577

Last Updated: 2023-03-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 382 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-04-27
• Study Completion Date: 2021-12-17

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).

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.

Conditions

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Inclisiran-only

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

Group Type: EXPERIMENTAL

Inclisiran

Intervention Type: 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.

Switching

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.

Group Type: ACTIVE_COMPARATOR

Inclisiran

Intervention Type: 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.

Evolocumab

Intervention Type: DRUG

Evolocumab is a fully human monoclonal antibody that inhibits PCSK9.

Interventions

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.

Intervention Type: DRUG

Evolocumab

Evolocumab is a fully human monoclonal antibody that inhibits PCSK9.

Intervention Type: DRUG

Other Intervention Names

ALN-PCSSC; REPATHA

Eligibility Criteria

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

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

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

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

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

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

11. 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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kausik Ray, MD

Role: PRINCIPAL_INVESTIGATOR

Imperial College London

Locations

Novartis Investigative Site

Jacksonville, Florida, United States

Novartis Investigative Site

Indianapolis, Indiana, United States

Novartis Investigative Site

New York, New York, United States

Novartis Investigative Site

Cincinnati, Ohio, United States

Novartis Investigative Site

Cincinnati, Ohio, United States

Novartis Investigative Site

Greenville, Tennessee, United States

Novartis Investigative Site

Amarillo, Texas, United States

Novartis Investigative Site

Richmond, Virginia, United States

Novartis Investigative Site

Vancouver, British Columbia, Canada

Novartis Investigative Site

Winnipeg, Manitoba, Canada

Novartis Investigative Site

Brampton, Ontario, Canada

Novartis Investigative Site

London, Ontario, Canada

Novartis Investigative Site

Toronto, Ontario, Canada

Novartis Investigative Site

Chicoutimi, Quebec, Canada

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Sherbrooke, Quebec, Canada

Novartis Investigative Site

Québec, , Canada

Novartis Investigative Site

Québec, , Canada

Novartis Investigative Site

St. Johns, , Canada

Novartis Investigative Site

Berlin, , Germany

Novartis Investigative Site

Essen, , Germany

Novartis Investigative Site

Frankfurt, , Germany

Novartis Investigative Site

Heidelberg, , Germany

Novartis Investigative Site

Munich, , Germany

Novartis Investigative Site

Leiden, South Holland, Netherlands

Novartis Investigative Site

Rotterdam, The Netherlands, Netherlands

Novartis Investigative Site

Amsterdam, , Netherlands

Novartis Investigative Site

Deventer, , Netherlands

Novartis Investigative Site

Eindhoven, , Netherlands

Novartis Investigative Site

Goes, , Netherlands

Novartis Investigative Site

Hoogeveen, , Netherlands

Novartis Investigative Site

Hoogezand, , Netherlands

Novartis Investigative Site

Hoorn, , Netherlands

Novartis Investigative Site

The Hague, , Netherlands

Novartis Investigative Site

Utrecht, , Netherlands

Novartis Investigative Site

Utrecht, , Netherlands

Novartis Investigative Site

Venlo, , Netherlands

Novartis Investigative Site

Zwijndrecht, , Netherlands

Novartis Investigative Site

Fowey, Cornwall, United Kingdom

Novartis Investigative Site

Liskeard, Cornwall, United Kingdom

Novartis Investigative Site

Penzance, Cornwall, United Kingdom

Novartis Investigative Site

St Austell, Cornwall, United Kingdom

Novartis Investigative Site

Torpoint, Cornwall, United Kingdom

Novartis Investigative Site

Birmingham, , United Kingdom

Novartis Investigative Site

Edinburgh, , United Kingdom

Novartis Investigative Site

Exeter, , United Kingdom

Novartis Investigative Site

High Wycombe, , United Kingdom

Novartis Investigative Site

London, , United Kingdom

Novartis Investigative Site

Manchester, , United Kingdom

Novartis Investigative Site

Newcastle Upon Tyme, , United Kingdom

Novartis Investigative Site

Plymouth, , United Kingdom

Novartis Investigative Site

Worcester, , United Kingdom

Countries

United States; Canada; Germany; Netherlands; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 36620965 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33990512 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-003815-37

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MDCO-PCS-16-01

Identifier Type: -

Identifier Source: org_study_id