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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 : November 29, 2019
Sponsor:
Collaborators:
The Medicines Company
The TIMI Study Group
Information provided by (Responsible Party):
University of Oxford

Tracking Information
First Submitted Date  ICMJE October 10, 2018
First Posted Date  ICMJE October 15, 2018
Last Update Posted Date November 29, 2019
Actual Study Start Date  ICMJE October 30, 2018
Estimated Primary Completion Date December 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 21, 2019)
Number of participants with a major adverse cardiovascular event [ Time Frame: Median follow-up of 5-years ]
Defined as time to first occurrence of:
  • Coronary heart disease (CHD) death;
  • Myocardial infarction;
  • Fatal or non-fatal ischemic stroke; or
  • Urgent coronary revascularization procedure.
Original Primary Outcome Measures  ICMJE
 (submitted: October 10, 2018)
Major adverse cardiovascular event [ Time Frame: Median follow-up of 5-years ]
Defined as time to first occurrence of:
  • Coronary heart disease (CHD) death;
  • Myocardial infarction;
  • Fatal or non-fatal ischemic stroke; or
  • Urgent coronary revascularization procedure.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 21, 2019)
  • Number of participants with a composite of CHD death or myocardial infarction [ Time Frame: Median follow-up of 5-years ]
  • Number of participants with cardiovascular death [ Time Frame: Median follow-up of 5-years ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 10, 2018)
  • A composite of CHD death or myocardial infarction [ Time Frame: Median follow-up of 5-years ]
  • Cardiovascular death [ Time Frame: Median follow-up of 5-years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease
Official Title  ICMJE 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
Brief Summary ORION-4 is a research study coordinated by the University of Oxford and co-sponsored by The University of Oxford and The Medicines Company. 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.
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 55 years or older 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Atherosclerotic Cardiovascular Disease
Intervention  ICMJE
  • Drug: Inclisiran
    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  ICMJE
  • Experimental: Inclisiran
    Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection at randomization, 3 months and then every 6 months.
    Intervention: Drug: Inclisiran
  • Placebo Comparator: Placebo
    Placebo will be administered as SC injections of saline solution at randomization, 3 months and then every 6 months.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 10, 2018)
15000
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2049
Estimated Primary Completion Date December 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 55 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Louise Bowman +44 (0)1865 743743 orion4@ndph.ox.ac.uk
Contact: Marion Mafham +44 (0)1865 743743 orion4@ndph.ox.ac.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03705234
Other Study ID Numbers  ICMJE CTSU_MDCO_PCS-17-01
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  ICMJE
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
Supporting Materials: 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
Responsible Party University of Oxford
Study Sponsor  ICMJE University of Oxford
Collaborators  ICMJE
  • The Medicines Company
  • The TIMI Study Group
Investigators  ICMJE
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
PRS Account University of Oxford
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP