Inclisiran for Coronary Artery Disease

(PRECAD Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Valentin Fuster

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Icahn School of Medicine at Mount Sinai

Must not be taking: PCSK9 inhibitors

Disqualifiers: Pregnancy, Active liver disease, Malignancy, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are currently using monoclonal antibodies directed towards PCSK9, you must stop at least 90 days before screening.

What makes the drug Inclisiran unique for treating coronary artery disease?

Inclisiran is unique because it works by using RNA interference to lower LDL cholesterol (bad cholesterol) levels, which is different from traditional drugs that often target cholesterol production or absorption. It is administered as an injection only twice a year, offering a convenient dosing schedule compared to daily medications. ^{1 2 3 4 5}

Research Team

Valentin Fuster

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

This trial is for healthy young adults aged 30-50 without known cardiovascular disease. It aims to see if strict control of heart risk factors can slow down the buildup of plaque in arteries, which could lead to heart problems later on.

Inclusion Criteria

Presence of subclinical atherosclerosis as assessed by 3DVUS or by the presence of coronary artery calcium (defined as coronary artery calcium score ≥25), independent of risk calculators, and/or high lifetime risk (≥30%) using the ASCVD calculator, and/or intermediate 10-year risk (≥7.5%) using the ASCVD calculator in the presence of 2 risk enhancers

I am between 30 and 50 years old.

I have never had heart, brain, or blood vessel diseases.

Exclusion Criteria

I have a serious illness besides heart disease that may shorten my life to under 5 years.

Planned use of other investigational products or devices during the course of the study

History of hypersensitivity to the study treatment or its excipients or to other siRNA drugs

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive inclisiran or guideline-directed medical therapy for LDL-C control

5 years

Every 2 months for intervention group, every 6 months for control group

Follow-up

Participants are monitored for changes in atherosclerotic plaque burden and cardiovascular disease incidence

5 years

Regular follow-up visits as per treatment group schedule

Treatment Details

Interventions

• Inclisiran (Anti-metabolites)

Trial Overview The study tests Inclisiran, a medication that may help manage cholesterol levels. Participants will be randomly assigned to either receive Inclisiran or usual care based on current medical guidelines.

Participant Groups

Group I: Inclisiran Experimental Treatment 1 Intervention

Participants in this arm will receive the study drug (inclisiran, for 5 years). Specific measures will be implemented to achieve the following goals: LDL-C \<55 mg/dl; blood pressure \<130/80 mmHg; and HbA1c \<6.5%. Diet and lifestyle recommendations will be recommended to all patients as a first step. Follow-up will occur every 2 months until goals are achieved. If the goal is not achieved, the subsequent recommendation will be implemented. Pharmacologic treatment may be implemented as early as the first visit at the discretion of the physician. * Product Name: inclisiran * Active ingredient: inclisiran sodium * Dosage Form: Solution for Injection * Unit Dose Inclisiran sodium 300 mg/1.5 mL vial (equivalent to 284 mg inclisiran) * Route of Administration: SC use * Physical Description: Clear, colorless to pale yellow solution essentially free of particulates

Group II: Control Group Active Control 1 Intervention

Participants in this group will receive guideline directed medical treatment, according to American Heart Association/American College of Cardiology guidelines. These recommendations will be provided to the primary care physicians to be followed, according to standards of care. Follow-up visits will occur every 6 months, although patients might be seen more often according to their provider´s criteria.

Inclisiran is already approved in European Union, United States, China for the following indications:

🇪🇺 Approved in European Union as Leqvio for:

• Primary hypercholesterolemia (heterozygous familial and non-familial)
• Mixed dyslipidemia

🇺🇸 Approved in United States as Leqvio for:

• Heterozygous familial hypercholesterolemia (HeFH)
• Clinical atherosclerotic cardiovascular disease (ASCVD)
• Primary hypercholesterolemia

🇨🇳 Approved in China as Leqvio for:

• Primary hypercholesterolemia (heterozygous familial and non-familial)
• Mixed dyslipidemia

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Mount Sinai Fuster Heart Hospital New York, NY

Who Is Running the Clinical Trial?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Patients Recruited

579,000+

References

1. United States pubmed.ncbi.nlm.nih.gov

Predictors of inexplicable coronary artery spasm during coronary angiography in patients with stable angina--the role of intravascular oxidative stress. [2009] This study was conducted to investigate the potential role of intravascular oxidative stress in inexplicable episodes of coronary artery spasm (CAS) during coronary angiography (CAG).

2. Ireland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of the endothelin-1 receptor antagonist macitentan in epicardial and microvascular vasospasm; a proof-of-concept study. [2023] Treatment of patients diagnosed with angina due to epicardial or microvascular coronary artery spasm (CAS) is challenging because patients often remain symptomatic despite conventional pharmacological therapy. In this prospective, randomized, double-blind, placebo-controlled, sequential cross-over proof-of-concept study, we compared the efficacy and safety of macitentan, a potent inhibitor of the endothelin-1 receptor, to placebo in symptomatic patients with CAS despite background pharmacological treatment.

3. United States pubmed.ncbi.nlm.nih.gov

Leukotriene D4: a potent coronary artery vasoconstrictor associated with impaired ventricular contraction. [2019] Leukotriene D4 (2 c 10(-9) mole), injected into the left circumflex coronary artery of anesthetized sheep, produced profound coronary vasoconstriction and impaired regional ventricular wall motion. This cardiac effect was neither inhibited by prior treatment of the sheep with a cyclooxygenase inhibitor nor associated with thromboxane B2 release into the coronary sinus. Intravenous FPL 55712 completely abolished the coronary vasoconstriction of leukotriene D4, but a significant reduction of regional wall shortening persisted.

4. Italy pubmed.ncbi.nlm.nih.gov

Influence of atherosclerosis on the vascular reactivity of isolated human epicardial coronary arteries to leukotriene C4. [2014] Leukotrienes, lipid mediators derived from arachidonic acid by the 5-lipoxygenase pathway, have been implicated in a variety of myocardial ischemic events including myocardial infarction and coronary spasm. We have examined the comparative effects of leukotriene C4 in isolated human non-atherosclerotic and atherosclerotic coronary arteries to gain an insight into the role of leukotrienes in coronary heart disease. Human coronary arteries, obtained from recipient hearts at the time of cardiac transplantation, were cut into rings and examined in an isolated organ bath. In atherosclerotic arteries leukotriene C4 (1nM-100nM) produced a maximal contractile response of 54.9 +/- 7.98% KCI (n = 7) and the mean EC50 value was 11.1nM (95% confidence interval: 9.4-13.0). The leukotriene receptor antagonist ICI-198,615 (3 x 10(-8)M) produced an approximate 50-fold rightward shift of the leukotriene C4 dose-response curve (n = 5). In contrast, non-atherosclerotic arteries were either non-responsive (n = 5) or only weakly responsive (n = 2) to leukotriene C4 (1nM-100nM), producing an average maximum response of 3.65 +/- 3.05% KCI (n = 7; p

5. South Africa pubmed.ncbi.nlm.nih.gov

Late symptomatic exercise-induced coronary vasospasm after percutaneous transluminal coronary angioplasty. A case report and review. [2014] A patient who underwent a successful double-vessel percutaneous transluminal coronary angioplasty (PTCA) had suffered from exercise-induced ST-segment elevation associated with angina pectoris (AP). This ECG pattern was present both before and 12 months after PTCA while nifedipine (Adalat; Bayer-Miles) therapy was electively discontinued. Reintroduction of calcium blockade with this drug eliminated the chest pain and resulted in normalization of the stress ECG. Cardiac catheterization at 6 and 12 months after PTCA demonstrated continuing angiographic improvement of the coronary stenoses of the left anterior descending and left circumflex (LCx) coronary arteries previously subjected to PTCA. It is believed that coronary artery spasm at the PTCA site on the LCx coronary artery was responsible for the AP and exercise-induced ST-segment elevation. Likely pathogenetic mechanisms of coronary vasospasm during and after the performance of PTCA, as well as the interrelationship with re-stenosis and the clinical implications of drug therapy, are discussed.