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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03705234
Recruitment Status : Recruiting
First Posted : October 15, 2018
Last Update Posted : September 16, 2022
Sponsor:
Collaborators:
The TIMI Study Group
Novartis Pharmaceuticals
Information provided by (Responsible Party):
University of Oxford

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Atherosclerotic Cardiovascular Disease Drug: Inclisiran Drug: Placebo Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: 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
Actual Study Start Date : October 30, 2018
Estimated Primary Completion Date : July 2026
Estimated Study Completion Date : December 2049

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Atherosclerosis

Arms and Interventions
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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 Name: Saline solution


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Number of participants with MACE among those recorded to be taking high-intensity statin at baseline [ Time Frame: Median follow-up of 5-years ]
  2. Number of participants with a composite of CHD death or myocardial infarction [ Time Frame: Median follow-up of 5-years ]
  3. Number of participants with cardiovascular death [ Time Frame: Median follow-up of 5-years ]

Eligibility Criteria
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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03705234


Contacts
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Contact: Louise Bowman +44 (0)1865 743743 orion4@ndph.ox.ac.uk
Contact: Marion Mafham +44 (0)1865 743743 orion4@ndph.ox.ac.uk

Locations
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United States, Massachusetts
TIMI Study Group Recruiting
Boston, Massachusetts, United States, 02115
Contact: David Morrow, MD, MPH    617-278-0145    TIMI@partners.org   
Contact: Michelle O'Donoghue, MD, MPH    617-278-0145    TIMI@partners.org   
United Kingdom
CTSU, University of Oxford Recruiting
Oxford, Oxfordshire, United Kingdom, OX3 7LF
Contact: Louise Bowman         
Sponsors and Collaborators
University of Oxford
The TIMI Study Group
Novartis Pharmaceuticals
Investigators
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Principal Investigator: Louise Bowman University of Oxford
Principal Investigator: Marion Mafham University of Oxford
Principal Investigator: David Preiss University of Oxford
Principal Investigator: Martin Landray University of Oxford
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT03705234    
Other Study ID Numbers: CTSU_MDCO_PCS-17-01
First Posted: October 15, 2018    Key Record Dates
Last Update Posted: September 16, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: After the main study results have been announced and published
Access Criteria: See URL
URL: https://www.ndph.ox.ac.uk/data-access

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Oxford:
Inclisiran
PCSK9
Cardiovascular
LDL Cholesterol
 Cholesterol
Lipid
RNA interference
Additional relevant MeSH terms:
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Cardiovascular Diseases
Atherosclerosis
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases