Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol (ORION-10)

• ClinicalTrials.gov Identifier: NCT03399370
• Recruitment Status: Completed
• First Posted: January 16, 2018
• Results First Posted: October 5, 2020
• Last Update Posted: October 5, 2020
• Sponsor: The Medicines Company
• Information provided by (Responsible Party): The Medicines Company

Tracking Information

• First Submitted Date: January 3, 2018
• First Posted Date: January 16, 2018
• Results First Submitted Date: July 1, 2020
• Results First Posted Date: October 5, 2020
• Last Update Posted Date: October 5, 2020
• Actual Study Start Date: December 21, 2017
• Actual Primary Completion Date: September 10, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 8, 2020)

• Percentage Change in LDL-C From Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
• Time-adjusted Percentage Change in LDL-C Levels From Baseline After Day 90 and up to Day 540 [ Time Frame: Baseline, Day 90 to Day 540 ]
  Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 540 reported

Original Primary Outcome Measures (submitted: January 8, 2018)

• Percentage Change in LDL-C from Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
• Time-adjusted Percentage Change in LDL-C Levels from Baseline between Day 90 and Day 540 [ Time Frame: Baseline, Day 90, Day 540 ]

Current Secondary Outcome Measures (submitted: September 8, 2020)

• Absolute Change in LDL-C From Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
• Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540 [ Time Frame: Baseline, Day 90 to Day 540 ]
  Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 540 reported
• Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
• Percentage Change in Total Cholesterol From Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
• Percentage Change in Apolipoprotein B (ApoB) From Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
• Percentage Change in Non-HDL-C From Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]

Original Secondary Outcome Measures (submitted: January 8, 2018)

• Absolute Change in LDL-C from Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
• Time-adjusted Absolute Change in LDL-C from Baseline between Day 90 and Day 540 [ Time Frame: Baseline, Day 90, Day 540 ]
• Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) from Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
• Percentage Change in Total Cholesterol from Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
• Percentage Change in Apolipoprotein B (ApoB) from Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]
• Percentage Change in Non-HDL-C from Baseline to Day 510 [ Time Frame: Baseline, Day 510 ]

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

Descriptive Information

• Brief Title: Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol
• Official Title: A Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect of 300 mg of Inclisiran Sodium Given as Subcutaneous Injections in Subjects With Atherosclerotic Cardiovascular Disease (ASCVD) and Elevated Low-Density Lipoprotein Cholesterol (LDL-C)
• Brief Summary: This is a Phase III, placebo-controlled, double-blind, randomized study in participants with ASCVD and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) inclisiran injection(s). The study will be a multicenter study in the United States.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Care Provider); Primary Purpose: Treatment

Condition

• ASCVD
• Elevated Cholesterol

Intervention

• Drug: Inclisiran Sodium
  Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.
• Drug: Placebo
  Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).
  Other Name: Saline Solution

Study Arms

• Experimental: Inclisiran
  Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90, then every 6 months.
  Intervention: Drug: Inclisiran Sodium
• Placebo Comparator: Saline Solution
  Placebo will be administered as a SC injection of saline solution on Day 1, Day 90, then every 6 months.
  Intervention: Drug: Placebo

• Publications *: Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, Bisch JA, Richardson T, Jaros M, Wijngaard PLJ, Kastelein JJP; ORION-10 and ORION-11 Investigators. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-1519. doi: 10.1056/NEJMoa1912387. Epub 2020 Mar 18.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 20, 2018): 1561
• Original Estimated Enrollment (submitted: January 8, 2018): 1500
• Actual Study Completion Date: September 17, 2019
• Actual Primary Completion Date: September 10, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Male or female participants ≥18 years of age.
2. History of ASCVD (coronary heart disease [CHD], cardiovascular disease [CVD], or peripheral arterial disease [PAD]).
3. Serum LDL-C ≥1.8 millimole (mmol)/liter (L) (≥70 mg/dL).
4. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening.
5. Participants on statins should be receiving a maximally tolerated dose.
6. Participants not receiving statins must have documented evidence of intolerance to all doses of at least 2 different statins.
7. Subjects on lipid-lower therapies (such as a statin and/or ezetimibe) should be on a stable dose for ≥30 days before screening with no planned medication or dose change during study participation.

Exclusion Criteria:

1. New York Heart Association (NYHA) class IV heart failure.
2. Uncontrolled cardiac arrhythmia
3. Uncontrolled severe hypertension
4. Active liver disease

5. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least 2 methods of highly effective contraception (failure rate less than 1% per year) (for example, combined oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, or intrauterine device) for the entire duration of the study. Exemptions from this criterion:

   1. Women >2 years postmenopausal (defined as 1 year or longer since last menstrual period) and more than 55 years of age.
   2. Postmenopausal women (as defined above) and less than 55 years of age with a negative pregnancy test within 24 hours of randomization.
   3. 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 (such as condom with spermicide).
7. Treatment with other investigational products or devices within 30 days or 5 half-lives of the screening visit, whichever is longer.
8. Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

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: United States

Administrative Information

• NCT Number: NCT03399370
• Other Study ID Numbers: MDCO-PCS-17-04
• 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: Not Provided
• Current Responsible Party: The Medicines Company
• Original Responsible Party: Same as current
• Current Study Sponsor: The Medicines Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Scott Wright, MD; Mayo Clinic

• PRS Account: The Medicines Company
• Verification Date: September 2020