NCT06494501

The Prevent Coronary Artery Disease Trial

• Status: Recruiting
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 1,600 (estimated)
• Sponsor: Icahn School of Medicine at Mount Sinai · Academic / Other
• Sex: All
• Age: 30 Years – 50 Years
• Healthy volunteers: Not accepted

Summary

Despite increasing evidence that exposure to cardiovascular risk factors (CVRF) at an early age increases the prevalence of subclinical atherosclerosis and is associated with a greater risk of cardiovascular events later in life, there is a lack of randomized trial evidence to support primary prevention strategies in adults aged 30-50 years. The researchers have designed a randomized controlled trial to evaluate whether strict control of CVRF in young adults without known cardiovascular disease, will reduce the progression of total atherosclerosis burden, a surrogate endpoint for symptomatic cardiovascular disease, compared with usual care. The researchers propose a randomized controlled trial enrolling 1,600 healthy young adults who meet the inclusion criteria and who do not meet any exclusion criteria. Eligible study participants will be randomized, in a 1:1 ratio, to either the intervention group (active treatment strategy) or to the control group (guideline-directed medical therapy). Randomization will be stratified by the presence or absence of atherosclerotic plaque in vascular ultrasound.

Detailed description

Atherosclerotic cardiovascular disease (ASCVD) is the most common cause of death in the world and contributes importantly to the majority of the world's deaths. Substantial data suggest that maintaining optimal population serum low density lipoprotein cholesterol (LDL-C), starting early in life, has the potential to lower the risk of incident ASCVD. However, this strategy of early initiation of LDL-C lowering therapies would represent a major paradigm shift from current guideline-based practice. Widespread acceptance and implementation of this approach in the medical community necessary to gain a population benefit will require a randomized clinical trial demonstrating benefit. Thus, the researchers will begin a trial, PRECAD, that evaluates LDL-C lowering in the early adult years through measurements of subclinical atherosclerosis. The significance of subclinical atherosclerosis has been established in population-based studies. In a cohort of \>4,000 subjects between 40-54 years, the Progression of Early Atherosclerosis (PESA) study showed that 63% of the asymptomatic participants presented subclinical atherosclerosis, and that it progresses with time. Subclinical atherosclerosis was associated with cardiovascular events along 10 years of follow-up in the CAFES-CAVE study. Similar findings were reported from the BioImage study in the HRP cohort have shown that presence of plaque, even in asymptomatic phases, improved risk reclassification and was independently associated with adverse cardiovascular events in long-term follow-up. Hence, demonstrating prevention of atherosclerosis progression is strongly suggestive of future clinical benefit. LDL-C, even at levels currently considered normal, is independently associated with the presence and extent of early systemic atherosclerosis in the absence of major cardiovascular risk factors. These findings support more effective LDL-C lowering for primary prevention. Research from multiple observational cohort studies has shown that risk of cardiovascular disease increases with increased exposure to elevated LDL-C, independent of other risk factors, in a concentration-dependent fashion. In the CARDIA study, which enrolled adults aged 18- 30 years with a median 16-year follow-up, incident cardiovascular disease risk increased as accumulation of exposure to LDL-C increased. Further, LDL-C level predicts progression of subclinical atherosclerosis measured by the PESA score, and subclinical atherosclerosis progression predicts CHD. For the composite event of all-cause death, nonfatal myocardial infarction, or nonfatal stroke, the updated event outcomes have the following distribution across PESA score categories: no disease (n=1,536), number of events = 10 (0.65%); focal (n=875), number of events = 8 (0.91%); intermediate (n=1,112), number of events = 13 (1.17%); generalized (n=547), number events = 13 (2.38%). These preliminary results, although unpublished, provide a rationale that higher PESA score portends a higher clinical event rate. Under a different imaging score of atherosclerosis burden, a similar association between atherosclerosis burden and clinical event rate has also been observed in the preliminary (unpublished) data of the BioImage Study. The connection between the atherosclerosis burden and incident CHD offers a surrogate endpoint for CHD that will progress sooner, permitting a much shorter trial that will convincingly assess the primary prevention benefit of maintaining low LDL-C beginning early in adult life. Strict diet and aggressive lifestyle changes are associated with LDL-C reduction, but adherence is generally poor. In the last year, the World Health Organization has included new strategies such as the polypill in its list of essential medicines, in response to the limitation that lack of adherence places on the management of patients, particularly in the setting of prevention. Particularly difficult is to guarantee adherence in young populations due to the absence of risk awareness. Thus, new strategies should be implemented to guarantee adherence in these population subgroups. Inclisiran is a small interfering RNA administered twice-yearly (after the initial and 3-month doses) by a health care professional via subcutaneous injection that decreases production of proprotein convertase subtilisin-lexin type 9 (PCSK9) in the liver to low LDL-C levels. This treatment has been shown as a safe, effective, and well tolerated in a diverse population, and could represent a great opportunity to increase adherence in the setting of primary prevention. A population requiring special attention are patients with familial hypercholesterolemia (FH). LDL-C is 2 times higher in patients with heterozygous FH, and 4-5 times higher in patients with homozygous familial hypercholesterolemia compared to the general population. Based on the high baseline LDL-C levels in FH patients, lowering of LDL-C may not be achieved with statins alone. Inclisiran has also been shown effective in adults with FH who are treated with maximally tolerated statin therapy with or without ezetimibe. The hypothesis is that compared to usual care, maintaining LDL-C below 55 mg/dL, beginning in the early adult years (30-50 years), in addition to a strict control of other risk factors, will reduce progression of total atherosclerosis burden.

Conditions

• Atherosclerotic Cardiovascular Disease

Interventions

Type	Name	Description
DRUG	Inclisiran	Subjects will be administered a single subcutaneous injection of 284 mg inclisiran for injection at predefined time points.

Timeline

• Start date: 2024-09-12
• Primary completion: 2032-06-30
• Completion: 2032-06-30
• First posted: 2024-07-10
• Last updated: 2025-04-29

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study