Atherosclerotic Cardiovascular DiseasePhase 3ORION-4NCT03705234
A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease
A Phase 3 study testing Inclisiran in people with Atherosclerotic Cardiovascular Disease, run by University of Oxford at 2 sites in 2 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 40 years and older
- Conditions the study is for
- Atherosclerotic Cardiovascular Disease
- What is being tested?
- Inclisiran
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 16,124 participants
- Where
- 2 sitesin 2 countries
- Study dates
- 30 Oct 2018to Dec 2049
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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;
Show all 12Show fewer
- 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.
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
United Kingdom1 site
CTSU, University of Oxford
Oxford, Oxfordshire, OX3 7LF
About this study
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
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.
Read the 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.
- Conditions
- Atherosclerotic Cardiovascular Disease
- Being tested
- Inclisiran, Placebo
- Keywords
- Inclisiran, PCSK9, Cardiovascular, LDL Cholesterol, Cholesterol, Lipid, RNA interference
- Medical subject headings
- Atherosclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
InclisiranDrug
Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.
PlaceboDrug
Also called Saline solution
Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).
| Study group | Role | What they receive |
|---|---|---|
| Inclisiran | Experimental | Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection at randomization, 3 months and then every 6 months. Receives: Drug: Inclisiran |
| Placebo | Placebo comparator | Placebo will be administered as SC injections of saline solution at randomization, 3 months and then every 6 months. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Median follow-up of 5-years
Secondary outcomes (3)
Number of participants with MACE among those recorded to be taking high-intensity statin at baseline
Measured: Median follow-up of 5-years
Number of participants with a composite of CHD death or myocardial infarction
Measured: Median follow-up of 5-years
Number of participants with cardiovascular death
Measured: Median follow-up of 5-years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Oct 2018
- Study start30 Oct 2018
- Primary completionOct 2026 (estimated)
- Study completionDec 2049 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Atherosclerotic Cardiovascular DiseaseStudies of the same condition, open and under way.
- More trials run by University of OxfordThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 16,124 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Collaborators
- The TIMI Study Group, Novartis Pharmaceuticals
- Responsible party
- Sponsor
- Investigators
- Louise Bowman, Principal investigator, University of OxfordMarion Mafham, Principal investigator, University of OxfordDavid Preiss, Principal investigator, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03705234
- Sponsor's protocol ID
- CTSU_MDCO_PCS-17-01
- Other IDs
- ISRCTN88876914
- Acronym
- ORION-4
- Status last verified
- Apr 2026
- First submitted
- 10 Oct 2018
- Last updated
- 1 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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
Publications
Mafham MM, Zayed MG, Collins R, Sabatine MS, Armitage J, Brittain D, da Costa BR, Chen F, Goonasekera MA, Hill M, Hopewell JC, Landray MJ, Lay MD, Lesogor A, Maggioni AP, Morrow DA, Nunn M, O'Donoghue ML, Ray KK, Rizkala A, Schwartz GG, Stevens W, Wallendszus K, Wright RS, Wijesurendra R, Wincott E, Preiss D, Bowman L; ORION-4 Collaborative Group. 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: Trial design, recruitment, and baseline characteristics. Am Heart J. 2026 Aug 7;303:107546. doi: 10.1016/j.ahj.2026.107546. Online ahead of print.
PubMed 42567431Warden BA, Duell PB. Inclisiran: A Novel Agent for Lowering Apolipoprotein B-containing Lipoproteins. J Cardiovasc Pharmacol. 2021 Aug 1;78(2):e157-e174. doi: 10.1097/FJC.0000000000001053.
PubMed 33990512
Study at a glance
From the registry record, last updated by the sponsor on 1 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03705234
- Acronym / sponsor ID
- ORION-4 / CTSU_MDCO_PCS-17-01
- Conditions
- Atherosclerotic Cardiovascular Disease
- Keywords
- Inclisiran, PCSK9, Cardiovascular, LDL Cholesterol, Cholesterol, Lipid, RNA interference
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 16,124 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Collaborators
- The TIMI Study Group, Novartis Pharmaceuticals
- Study start
- 30 Oct 2018 (actual)
- Primary completion
- Oct 2026 (estimated)
- Study completion
- Dec 2049 (estimated)
- First posted
- 15 Oct 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Inclisiran | Experimental | Drug: InclisiranInclisiran sodium 300 milligrams (mg) will be administered as a SC injection at randomization, 3 months and then every 6 months. |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo will be administered as SC injections of saline solution at randomization, 3 months and then every 6 months. |
Who may qualify
- Ages
- 40 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (12 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| InclisiranInclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis. | Drug | Inclisiran |
| PlaceboAlso: Saline solutionPlacebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection). | Drug | Placebo |
Primary outcome
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.
3 secondary outcomes
Number of participants with MACE among those recorded to be taking high-intensity statin at baseline
Time frame: 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
Number of participants with cardiovascular death
Time frame: Median follow-up of 5-years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 May 2026.
- Derived from this study: PubMed 42567431Mafham MM, Zayed MG, Collins R, Sabatine MS, Armitage J, Brittain D, da Costa BR, Chen F, Goonasekera MA, Hill M, Hopewell JC, Landray MJ, Lay MD, Lesogor A, Maggioni AP, Morrow DA, Nunn M, O'Donoghue ML, Ray KK, Rizkala A, Schwartz GG, Stevens W, Wallendszus K, Wright RS, Wijesurendra R, Wincott E, Preiss D, Bowman L; ORION-4 Collaborative Group. 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: Trial design, recruitment, and baseline characteristics. Am Heart J. 2026 Aug 7;303:107546. doi: 10.1016/j.ahj.2026.107546. Online ahead of print.
- Derived from this study: PubMed 33990512Warden BA, Duell PB. Inclisiran: A Novel Agent for Lowering Apolipoprotein B-containing Lipoproteins. J Cardiovasc Pharmacol. 2021 Aug 1;78(2):e157-e174. doi: 10.1097/FJC.0000000000001053.
- Study websiteLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. 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
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Louise Bowman principal investigator
University of Oxford
Marion Mafham principal investigator
University of Oxford
David Preiss principal investigator
University of Oxford
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Inclisiran in people with Atherosclerotic Cardiovascular Disease, run by University of Oxford at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 1 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of participants with a major adverse cardiovascular event (MACE) (time frame: Median follow-up of 5-years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03705234, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 May 2026.