FAQs

ORION-4 is a research study coordinated by the University of Oxford and co-sponsored by The University of Oxford and Novartis Pharmaceutical Corporation. The study aims to find out if a new cholesterol-lowering injection called inclisiran safely reduces 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 unblock their arteries.

This study is testing a medicine called inclisiran which helps to lower bad (LDL) cholesterol in the blood. Doctors hope that giving this injection every 6 months for several years will lower the number of heart attacks and strokes, but they do not know this for certain. Inclisiran is given as an injection into the tissue just under the skin every 6 months, with an extra injection 3 months after starting the treatment. Inclisiran has been approved by the UK Medicines and Healthcare Products Regulatory Agency.

How does inclisiran lower bad cholesterol levels?

Inclisiran blocks the production of a protein called PCSK9¹ in the liver. PCSK9 has an important role in the control of blood cholesterol levels. Higher levels of PCSK9 lead to higher levels of bad (LDL) cholesterol in the blood. This is because of how PCSK9 effects LDL receptors. LDL receptors on the surface of the liver cells remove bad (LDL) cholesterol from the blood stream. PCSK9 attaches to the LDL receptor which causes the liver cell to destroy the LDL receptor instead of reusing it. If PCSK9 levels in the blood are high, there are fewer LDL receptors on the liver cells and more bad (LDL) cholesterol in the blood stream.  

How does inclisiran block the production of PCSK9?

Inclisiran is a small interfering RNA which blocks the production of the protein PCSK9. The instructions for how to make every protein are held in the DNA inside the cell. To make a protein, first, the cell makes a copy of the DNA. The copy of the DNA is called messenger RNA. The messenger RNA is then converted into a sequence of amino acids, the building blocks that make up proteins. Small interfering RNAs prevent the messenger RNA from being converted into the protein.

¹ PCSK9 — proprotein convertase subtilisin/kexin type 9

How have we identified potential participants?

People are invited to join the ORION-4 study if their medical records suggest they have had a heart attack, stroke or an operation or procedure on their arteries. People can take part whether or not they are already taking a statin.

See the Eligibility Criteria section to find out more about who can and can't take part in our study.

The Data Protection section provides more detailed information on how we have identified participants.

Do people invited Have to take part in the study?

No-one has to take part in this study. It is the decision of each person invited. But if people did help, many millions of people from around the world might benefit from this research in years to come.

If a person did join this study, it will not affect any decisions about other medical treatment they might need or be receiving from their own doctors. If a person agrees to take part, we will tell their GP.

Half the people taking part in this study will get the inclisiran injections and half will get the dummy (inactive placebo) injections. Which treatment a person gets will be decided by chance (like tossing a coin). This is called randomisation. Participants, and their doctors, will not know which treatment they are given and the study staff will not know either (although they can find this out if needed).

For ORION-4 to produce the best results, it is important that people stay in the study for about 5 years, if possible. Participants will need to attend the study clinic 3 times in the first 5 months and every 6 months after that. At each visit, a trained researcher (usually a nurse) will ask questions about their health, take a blood sample and give them an injection of either inclisiran or placebo.  

What happens at the First appointment (Screening Visit)?

At the first study visit (called the screening visit), the study nurse will explain the study. Participants will have plenty of time to ask questions. If they want to continue, they will be asked to sign a consent form agreeing to take part.

The nurse will ask about medical history and will take a finger-prick blood sample to measure cholesterol while the participant is in the clinic. If this finger-prick cholesterol level is below a certain level, they will not be able to take part in this study.

If the participant is able to take part in ORION-4, the nurse will then give an injection into the tissue just under the skin of the tummy (abdomen). The research team will then write and inform participants' GPs to let them know that they are planning to join the study.

What happens at the Second appointment (Randomisation visit)?

After about 2 months, participants will have their second appointment (called the randomisation visit) to see if they are willing to commit to the study for about 5 years. If they are happy to continue, the nurse will take a blood sample from a vein in the arm or hand and will give the next injection.

What happens at the Other appointments (Follow-up Visits)?

The next appointment (called the follow-up visit) will be 3 months later. After that, the study nurse will see participants every 6 months for about 5 years. At each follow-up visit, the nurse will ask about any new medical problems since the last appointment, take a blood sample (from a vein in the arm or hand) and will give an injection.

Blood samples will be sent to the laboratory in Oxford for tests and, if participants agree, for long-term storage for future research.

Participants will not need to fast before study visits. Each follow-up appointment will usually take less than half an hour.

This table gives a summary of what will happen at each appointment.

We hope participants will be able to continue getting the injections for the full course of the study. But, if anyone does choose to stop them, it would be helpful if they would allow the study scientists to stay in touch, to see how they get on. Ideally, this means still coming to the study clinic. If this is not possible then it would be very helpful if we could keep in contact by phone.

It helps the study to produce reliable results if we can get complete information about the health of as many participants as possible. However, during the study some participants may decide they no longer wish to, or are no longer able to, stay in contact with the study team.

With participant permission, the study scientists can also get information about people's health from NHS bodies such as NHS England or Health Registries. More information about this is provided in the Data Protection section. 

Participants are free to stop taking part in this study at any time without this having any effect on their future medical care.

About 4 teaspoons of blood will be taken each time. Numbered samples (without a name on) would be stored indefinitely at a secure location in the University of Oxford. Samples may be transferred to other collaborating scientists but would not be sent with any information identifying a participant.

The blood samples participants provide will be used to measure things which we know affect the risk of circulatory problems. This allows us to see whether the effects of inclisiran are different in different groups of people (for example people with higher or lower levels of certain risk factors). The results of blood tests will not be routinely provided to participants or GPs. However, the ORION-4 team may write to GPs about blood results if there is a particular concern.

The study nurse will also ask if participants are happy for these blood samples to be stored long-term to help investigate the effects of inclisiran and the causes of heart disease, strokes and other conditions. However, people can still take part in the study even if they do not give permission for this long-term storage.

Doctors already know about causes of heart attacks and strokes such as high blood pressure and high cholesterol, and are able to treat these with drugs. Scientists also think that other factors might play a part in circulatory problems, but there is limited understanding of how these work. In particular, we have limited knowledge about the effect of genes on risk of heart disease, strokes, diabetes or other important diseases. If we have participant permission to keep blood samples in a very cold freezer, then in the future we might be able to test new scientific discoveries by defrosting and analysing these samples.

Benefits of taking part

Participants will be helping doctors and scientists improve treatment for people who have had heart attacks or strokes, or who may be at risk of having one. If successful, results from this study might help to prevent many thousands of heart attacks, strokes and bypass procedures around the world.

Risks of taking part

Most treatments have side effects, which some people may experience and others may not. If participants do experience any side effects during the study, they will be recorded, so that scientists can learn from these. Participants can stop receiving the study injections any time if they want.

ORION-4 is testing inclisiran, a drug approved for use in the UK. In a previous study including about 350 people treated with inclisiran for 6 months, about 1 in 20 people noticed some redness or soreness where the injection was given, but no other side effects were found. Inclisiran has also been given to over 1500 people in other completed studies and no additional side effects were noted. However, at this stage, scientists cannot rule out the possibility of there being side effects. All drugs have a potential risk of an allergic reaction, which if not treated promptly, could become life-threatening.

Throughout the study, the research team will carefully monitor participants for possible side effects. At every visit, the study nurse will discuss any new information about the drug.

If anyone does experience unexpected symptoms after joining the study they can contact their ORION-4 nurse, or a study doctor on Freephone 0800 585323.

If participants have private medical insurance or require travel insurance, their policy may be affected. They should check this with their insurance provider.

The results will be published in health or scientific journals and be discussed at major conferences. Others will learn from the results, which we hope will show that more lives can be saved by using inclisiran. No individual participant will be identified in any report or publication. We will try our best to inform participants and their GPs of the study results, and any related publicity.

The results will be available on the study website and a description of this clinical trial will be available on the EU Clinical Trials register (EudraCT) and ClinicalTrials.gov.

After the end of the study, inclisiran will not be provided by the ORION-4 team. If the results of ORION-4 show that inclisiran helps to protect against heart attacks and strokes then we hope that it will become widely available for patients.

Participant contribution to the study could be even more valuable if we can continue to get information about health after the final follow-up visit. This way we can learn a lot more about the possible longer-term health effects of this new treatment.

With permission, the study team may like to stay in touch with participants after the final follow-up visit, probably with a simple questionnaire or phone call once or twice a year. Also, the study scientists would like to continue to get information about participants' health, such as details of any admissions to hospital from NHS Digital or other central registries after the end of the scheduled study follow-up period. This may include any health information recorded throughout the participants lifetime. Participants can opt out of this at any time by contacting the study team.

See the Data Protection section for information on how we collect and use participant data.

Participants have all the usual rights of an NHS patient.

The University of Oxford has arrangements in place to provide for harm arising from participation in the study.

In the unlikely event of anyone being harmed by taking part, insurance cover is provided by Novartis Pharmaceutical Company. Any compensation would be paid in accordance with the guidelines of the Association of British Pharmaceutical Industry (ABPI).

If participants have concerns about any aspect of the study they can speak with the ORION-4  team by calling a 24-hour Freephone number: 0800 585323 (UK only). If they remain unhappy and wish to complain formally, they can do this through the NHS Complaints Procedure. They can get details from their hospital.

Cardiovascular disease is a term used to mean the 'furring up' or narrowing of arteries anywhere in the body: in the heart (coronary heart disease), in the brain (cerebrovascular disease) or in the main arteries or legs (peripheral vascular disease).
To find out more, the British Heart Foundation (BHF) website has information and support for those affected by heart and circulatory disease.