A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Atherosclerotic Cardiovascular Disease

Intervention / Treatment
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* Drug: Inclisiran
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inclisiran, PCSK9, Cardiovascular, LDL Cholesterol, Cholesterol, Lipid, RNA interference