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 objective: The HPS-4/TIMI 65/ORION-4 study aims to provide evidence about both the efficacy and safety of inclisiran. It is intended to be conducted at approximately 150 clinical sites in Europe (primarily in the UK) and North America. 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. Consistent with relevant guideline recommendations for people with vascular disease, it is intended that participants be on intensive background LDL-lowering therapy (for example, atorvastatin 40 or 80 mg daily, simvastatin 40 or 80 mg daily, or rosuvastatin 20 or 40 mg daily) at screening. In order to achieve a target LDL cholesterol reduction of at least 1.2 mmol/l [45 mg/dL], it is intended to recruit a study population with a mean LDL cholesterol of at least 2.6 mmol/l [100mg/dL] at baseline.
The primary efficacy outcome is “major adverse cardiovascular events” (MACE), which is the composite of CHD death, myocardial infarction, fatal or non-fatal ischaemic stroke or urgent coronary revascularization (see Section 18.104.22.168). Secondary, tertiary and exploratory outcomes (including assessments of safety) are described in Sections 22.214.171.124 to 126.96.36.199.
Disease area: Cardiovascular
Status: Open to recruitment
CI/PI: Dr Louise Bowman (CI), Dr Manish Saxena (PI)
Sponsor: University of Oxford
Funder: The Medicines Company UK Ltd
Previous trials have shown that lowering bad (LDL) cholesterol with statins reduces the risk of heart attacks and strokes. However, among individuals with a previous history of vascular disease, the risk of a further vascular event remains high, even after several years of statin treatment.
Inclisiran is an investigational drug given by subcutaneous (under the skin) injection which lowers bad (LDL) cholesterol. This study aims to find out whether inclisiran, given every 6 months for about 5 years, safely reduces the risk of heart attacks, strokes or the need for urgent coronary angioplasty or bypass grafts, in people who already have known vascular disease.
People are eligible to join the study if they are aged 55 years or older and have known vascular disease (that is they have had a heart attack, stroke or leg artery bypass or angioplasty, or aortic aneurysm repair).
The study will involve 15,000 participants (12,000 in the UK and 3000 in the US). Half of the participants will receive inclisiran injections and half will receive inactive dummy injections (placebo). Which treatment each participant receives will be decided by randomization (like tossing coin). Neither the participants, nor the study staff will know which treatment they are receiving (but this can be found out if needed). Participants will continue their usual medication prescribed by their GP or other doctors.
ORION-4 study clinics will be set up by NHS and academic institutions and will be run by trained research staff. Participants will attend the study clinic four times in the first nine months and then once every six months. At each clinic visit they will be asked questions about their health, will have a blood sample taken and will be given an injection of inclisiran or placebo.
Sample size and duration
15000 globally, 125 locally for 5 years