An Extension Trial of Inclisiran in Participants With Cardiovascular Disease and High Cholesterol (ORION-3)

• ClinicalTrials.gov Identifier: NCT03060577
• Recruitment Status: Completed
• First Posted: February 23, 2017
• Results First Posted: March 24, 2023
• Last Update Posted: March 24, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: February 17, 2017
• First Posted Date: February 23, 2017
• Results First Submitted Date: November 28, 2022
• Results First Posted Date: March 24, 2023
• Last Update Posted Date: March 24, 2023
• Actual Study Start Date: April 27, 2017
• Actual Primary Completion Date: December 17, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 28, 2023)

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) ]

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.

• Original Primary Outcome Measures (submitted: February 21, 2017): Percentage Change in LDL-C from Day 1 to Day 210 in the Inclisiran Group [ Time Frame: Day 1, Day 210 ]

Current Secondary Outcome Measures (submitted: February 28, 2023)

• Percentage Change in LDL-C From Baseline of the ORION-1 Study (Inclisiran Arm) [ Time Frame: Baseline (ORION-1) and Days 30, 360, 720, 1080 and 1440 (ORION-3) (up to 390, 720, 1080, 1440 and 1800 days total, respectively) ]
  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.
• Absolute Change in LDL-C From Baseline of the ORION-1 Study (Inclisiran Arm) [ Time Frame: 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 (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.
• Percentage Change in PCSK9 Levels From Baseline of the ORION-1 Study (Inclisiran Arm) [ Time Frame: Baseline (ORION-1) and Days 30, 360, 720 and 1440 (ORION-3) (up to 390, 720, 1080 and 1800 days total, respectively) ]
  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.
• Absolute Change in PCSK9 Levels From Baseline of the ORION-1 Study (Inclisiran Arm) [ Time Frame: 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 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.
• Percentage Change in Triglycerides From Baseline of the ORION-1 Study (Inclisiran Arm) [ Time Frame: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively) ]
  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.
• Absolute Change in Triglycerides From Baseline of the ORION-1 Study (Inclisiran Arm) [ Time Frame: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively) ]
  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.
• Percentage Change in Apolipoprotein B From Baseline of the ORION-1 Study (Inclisiran Arm) [ Time Frame: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively) ]
  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.
• Absolute Change in Apolipoprotein B From Baseline of the ORION-1 Study (Inclisiran Arm) [ Time Frame: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively) ]
  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.
• Percentage Change in Lipoprotein-a From Baseline of the ORION-1 Study (Inclisiran Arm) [ Time Frame: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively) ]
  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.
• Absolute Change in Lipoprotein-a From Baseline of the ORION-1 Study (Inclisiran Arm) [ Time Frame: Baseline (ORION-1) and Days 30, 210 and 1440 (ORION-3) (up to 390, 570 and 1800 days total, respectively) ]
  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.
• Number of Participants With ≥50% LDL-C Reduction From Baseline of the ORION-1 Study (Inclisiran Arm) [ Time Frame: Baseline (ORION-1) and Days 30, 360, 720 and 1440 (ORION-3) (up to 390, 720, 1080 and 1800 days total, respectively) ]
  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.
• 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) [ Time Frame: From the start of treatment in ORION-3 to 90 days after end of treatment, assessed up to maximum duration of 4 years ]
  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.

Original Secondary Outcome Measures (submitted: February 21, 2017)

• Percentage Change of Participants in the Inclisiran Group from Day 1 to Day 210 and to Day 1440 (or Final Visit) in LDL-C [ Time Frame: Day 1, Day 210 and Day 1440 (or Final Visit) ]
• Change of Participants in the Inclisiran Group from Day 1 to Day 210 and to Day 1440 (or Final Visit) in LDL-C [ Time Frame: Day 1, Day 210 and Day 1440 (or Final Visit) ]
• Percentage Change of Participants in the Inclisiran Group from Day 1 to Day 210 and to Day 1440 (or Final Visit) in PCSK9 Levels [ Time Frame: Day 1, Day 210 and Day 1440 (or Final Visit) ]
• Change of Participants in the Inclisiran Group from Day 1 to Day 210 and to Day 1440 (or Final Visit) in PCSK9 Levels [ Time Frame: Day 1, Day 210 and Day 1440 (or Final Visit) ]
• 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) [ Time Frame: Day 1, Day 210 and Day 1440 (or Final Visit) ]
• 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) [ Time Frame: Day 1, Day 210 and Day 1440 (or Final Visit) ]
• Proportion of Participants in the Inclisiran Group and the Evolocumab Group Who Attain Global Lipid Modification Targets for Their Level of ASCVD Risk [ Time Frame: Day 210 and Day 1440 (or Final Visit) ]
• 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) [ Time Frame: Day 570 ]
• Proportion of Participants in the Inclisiran Group and the Evolocumab Group with ≥50% LDL-C Reduction [ Time Frame: Day 210 and Day 570 ]
• 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 [ Time Frame: Day 210 and Day 570 ]
• Time to Lipid Lowering Effect in Participants in the Inclisiran Group and the Evolocumab Group [ Time Frame: Day 1 through Day 1440 ]
• Change from Day 1 to Day 360 in LDL-C (Beta Quantification) of Participants in the Evolocumab Group [ Time Frame: Day 1, Day 360 ]
• 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 [ Time Frame: Day 30, Day 360 ]
• Change from Day 450 to Day 720 in Participant-Reported Scores Using the TSQM Questionnaire of Participants in the Inclisiran Group [ Time Frame: Day 450, Day 720 ]
• Participant-Reported Adherence to Self-Injectable Evolocumab [ Time Frame: Day 30 through Day 360 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: An Extension Trial of Inclisiran in Participants With Cardiovascular Disease and High Cholesterol
• 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)
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• 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 Name: ALN-PCSSC
• Drug: Evolocumab
  Evolocumab is a fully human monoclonal antibody that inhibits PCSK9.
  Other Name: REPATHA

Study Arms

• Experimental: Inclisiran-only
  Participants received subcutaneous injections of inclisiran 300 milligrams (mg) on Day 1 and every 180 days thereafter for up to 4 years.
  Intervention: Drug: Inclisiran
• Active Comparator: 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.
  Interventions:

  • Drug: Inclisiran
  • Drug: Evolocumab

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 7, 2022): 382
• Original Estimated Enrollment (submitted: February 21, 2017): 490
• Actual Study Completion Date: December 17, 2021
• Actual Primary Completion Date: December 17, 2021 (Final data collection date for primary outcome measure)

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Germany, Netherlands, United Kingdom, United States

Administrative Information

• NCT Number: NCT03060577
• Other Study ID Numbers: MDCO-PCS-16-01; 2016-003815-37 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: The Medicines Company
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: The Medicines Company
• Collaborators: Not Provided

Investigators

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

• PRS Account: Novartis
• Verification Date: February 2023