A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease (ORION-4)

October 31, 2023 updated by: University of Oxford

HPS-4/TIMI 65/ORION-4: A Double-blind Randomized Placebo-controlled Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Atherosclerotic Cardiovascular Disease

ORION-4 is a research study coordinated by the University of Oxford and co-sponsored by The University of Oxford and Novartis (Protocol: CTSU_MDCO-PCS-17-01 (CKJX839B12301)). The study aims to find out if a new cholesterol-lowering injection (inclisiran) safely lowers the risk of heart attacks and strokes in people who have already had one of these conditions, or who have had an operation or procedure to treat blocked arteries.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

The ORION-4 study aims to provide evidence about both the efficacy and safety of inclisiran. Inclisiran is a PCKS9 synthesis inhibitor which has been found to reduce LDL-cholesterol by about 50-60%. ORION-4 will investigate the effects of inclisiran on major adverse cardiovascular events.

The study is intended to be conducted at approximately 180 clinical sites in the UK and the USA. Approximately 15,000 participants aged 40 years or older for men, and 55 years or older for women, with pre-existing atherosclerotic cardiovascular disease will be randomized between inclisiran sodium 300 mg and matching placebo (given by subcutaneous injection on the day of randomization, at 3 months and then every 6-months) in a 1:1 ratio for a planned median duration of about 5 years.

Study Type

Interventional

Enrollment (Actual)

16124

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United Kingdom
    • Oxfordshire
      • Oxford, Oxfordshire, United Kingdom, OX3 7LF
        • CTSU, University of Oxford
  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • TIMI Study Group

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

38 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria

History or evidence of at least one of the following:

  • Prior MI; or
  • Prior ischemic stroke; or
  • Peripheral artery disease as evident by prior lower extremity artery revascularization or aortic aneurysm repair.

Minimum age is 40 years for men and 55 years for women

Exclusion Criteria

None of the following must be satisfied (based on self-reported medical history):

  • Acute coronary syndrome or stroke less than 4 weeks before the Screening visit or during the Run-in period;
  • Coronary revascularization procedure planned within the next 6 months;
  • Known chronic liver disease;
  • Current or planned renal dialysis or transplantation;
  • Previous exposure to inclisiran or participation in a randomized trial of inclisiran;
  • Previous (within about 3 months), current or planned treatment with a monoclonal antibody targeting PCSK9, or with a drug known to be contra-indicated with inclisiran (none currently known);
  • Known to be poorly compliant with clinic visits or prescribed medication;
  • Medical history that might limit the individual's ability to take trial treatments for the duration of the study (e.g. severe respiratory disease; cancer or evidence of spread within approximately the last 5 years, other than non-melanoma skin cancer; or history of alcohol or substance misuse) or may put the individual at significant risk in the opinion of the investigator (or their authorised deputy) if he/she were to participate in the trial;
  • Women of child-bearing potential, current pregnancy, or lactation;
  • Current participation in a clinical trial with an unlicensed drug or device; or
  • Staff personnel directly involved with the study and any family member of the investigational study staff.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Inclisiran
Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection at randomization, 3 months and then every 6 months.
Drug: Inclisiran
Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.
Placebo Comparator: Placebo
Placebo will be administered as SC injections of saline solution at randomization, 3 months and then every 6 months.
Drug: Placebo
Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).
Other Names:
  • Saline solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants with a major adverse cardiovascular event (MACE)
Time Frame: Median follow-up of 5-years

Defined as time to first occurrence - during the scheduled treatment period - of:

  • Coronary heart disease (CHD) death;
  • Myocardial infarction;
  • Fatal or non-fatal ischemic stroke; or
  • Urgent coronary revascularization procedure.
Median follow-up of 5-years

Secondary Outcome Measures

Outcome Measure
Time Frame
Number of participants with MACE among those recorded to be taking high-intensity statin at baseline
Time Frame: Median follow-up of 5-years
Median follow-up of 5-years
Number of participants with a composite of CHD death or myocardial infarction
Time Frame: Median follow-up of 5-years
Median follow-up of 5-years
Number of participants with cardiovascular death
Time Frame: Median follow-up of 5-years
Median follow-up of 5-years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Oxford

Collaborators

Novartis Pharmaceuticals
The TIMI Study Group

Investigators

  • Principal Investigator: Louise Bowman, University of Oxford
  • Principal Investigator: Martin Landray, University of Oxford
  • Principal Investigator: Marion Mafham, University of Oxford
  • Principal Investigator: David Preiss, University of Oxford

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 30, 2018

Primary Completion (Estimated)

July 1, 2026

Study Completion (Estimated)

December 1, 2049

Study Registration Dates

First Submitted

October 10, 2018

First Submitted That Met QC Criteria

October 10, 2018

First Posted (Actual)

October 15, 2018

Study Record Updates

Last Update Posted (Actual)

November 2, 2023

Last Update Submitted That Met QC Criteria

October 31, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CTSU_MDCO_PCS-17-01

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Proposals for substudies must be approved by the Steering Committee. Procedure for accessing the data for this study are available on https://www.ndph.ox.ac.uk/data-access

IPD Sharing Time Frame

After the main study results have been announced and published

IPD Sharing Access Criteria

See URL

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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