Inclisiran for Coronary Artery Disease

(PRECAD Trial)

Overseen By Malick Waqas

Age: 18 - 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Icahn School of Medicine at Mount Sinai

Must not be taking: PCSK9 inhibitors

Disqualifiers: Pregnancy, Active liver disease, Malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 5 years

1600 Participants Needed

Trial Summary

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}

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.

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

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

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

Who Is Running the Clinical Trial?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

Findings from Research

In a study of 15 patients experiencing unexplained coronary artery spasm (CAS) during coronary angiography, increased white blood cell counts and superoxide production were found to be significant predictors of these episodes, indicating a link to intravascular oxidative stress.

The findings suggest that administering antioxidants before coronary angiography could potentially prevent these inexplicable CAS episodes, highlighting a possible therapeutic approach for patients at risk.

NCBI (Pubmed)

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. Leu, HB., Lin, WT., Lin, CP., et al.[2009]

In a study involving 28 patients with coronary artery spasm (CAS), adding macitentan, an endothelin-1 receptor antagonist, did not significantly reduce anginal burden compared to placebo after 28 days of treatment.

The safety profile of macitentan was similar to that of placebo, indicating no additional adverse effects from the treatment.

NCBI (Pubmed)

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. Feenstra, RGT., Jansen, TPJ., Matthijs Boekholdt, S., et al.[2023]

Leukotriene D4 caused significant coronary vasoconstriction and impaired heart function in anesthetized sheep, indicating its strong impact on cardiac health.

The vasoconstriction effect of leukotriene D4 was effectively blocked by the drug FPL 55712, although some impairment in heart function remained, suggesting that leukotriene D4 has multiple mechanisms affecting cardiac performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leukotriene D4: a potent coronary artery vasoconstrictor associated with impaired ventricular contraction. Michelassi, F., Landa, L., Hill, RD., et al.[2019]

Leukotriene C4 significantly contracts atherosclerotic coronary arteries, with a maximum response of about 54.9% compared to a minimal response in non-atherosclerotic arteries, indicating a potential role in coronary heart disease.

The leukotriene receptor antagonist ICI-198,615 effectively reduces the response to leukotriene C4 in atherosclerotic arteries, suggesting that targeting leukotriene receptors could be a therapeutic strategy in managing coronary artery conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of atherosclerosis on the vascular reactivity of isolated human epicardial coronary arteries to leukotriene C4. Allen, SP., Dashwood, MR., Chester, AH., et al.[2014]

A patient experienced persistent exercise-induced ST-segment elevation and angina pectoris even after a successful double-vessel percutaneous transluminal coronary angioplasty (PTCA), indicating ongoing issues despite the procedure.

Reintroducing nifedipine, a calcium channel blocker, effectively eliminated the patient's chest pain and normalized the stress ECG, suggesting that coronary artery spasm at the PTCA site may have contributed to the symptoms and highlighting the importance of drug therapy in managing post-PTCA complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late symptomatic exercise-induced coronary vasospasm after percutaneous transluminal coronary angioplasty. A case report and review. Przybojewski, JZ., Weich, HF.[2014]

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]

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]

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

Leukotriene D4: a potent coronary artery vasoconstrictor associated with impaired ventricular contraction. [2019]

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

Influence of atherosclerosis on the vascular reactivity of isolated human epicardial coronary arteries to leukotriene C4. [2014]

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]