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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called inclisiran to determine if it can reduce plaque buildup in arteries, a condition known as atherosclerosis that can lead to heart problems. The goal is to discover if controlling heart disease risk factors can prevent plaque buildup in individuals without known heart disease. Participants will receive either inclisiran with lifestyle advice or standard medical care to compare results. Those with high cholesterol, plaque buildup in their arteries, or a high risk of heart issues might be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment for heart disease.

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.

Is there any evidence suggesting that inclisiran is likely to be safe for humans?

Research has shown that inclisiran is generally safe for long-term use. Studies have found no new safety issues even after more than six years of treatment, indicating that inclisiran can lower LDL-C (bad cholesterol) without causing serious side effects.

In another study, researchers tested inclisiran on people with high cholesterol and other heart risks. The treatment safely and effectively reduced LDL-C levels. These results provide strong evidence that inclisiran is usually well tolerated. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for coronary artery disease, which often include statins or lifestyle changes, inclisiran offers a unique approach by using RNA interference. It targets PCSK9, a protein that affects LDL cholesterol levels, effectively lowering them with just a few doses per year. This cutting-edge mechanism, combined with its convenient subcutaneous injection delivery, has researchers excited about the potential for sustained and efficient cholesterol management, making it simpler for patients to maintain their heart health over time.

What evidence suggests that inclisiran might be an effective treatment for coronary artery disease?

Studies have shown that inclisiran effectively lowers LDL-C, often called "bad cholesterol." Notably, 81% of patients taking inclisiran reached their cholesterol goals in just 30 days. Lowering LDL-C is crucial because it can reduce the risk of serious heart problems, such as heart attacks and strokes. In this trial, participants in the inclisiran arm will receive the study drug to evaluate its impact on LDL-C levels and heart health. While inclisiran is known for its cholesterol-lowering ability, more research is needed to understand its direct impact on preventing heart disease. However, its significant reduction of LDL-C suggests promise for heart health. ^{1 4 6 7 8}

Who Is on the Research Team?

Valentin Fuster

Principal Investigator

Icahn School of Medicine at Mount Sinai

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11868277/

Current usage of inclisiran for cardiovascular diseases Although the studies showed inclisiran to lower LDL-C effectively, the evidence is still limited with regards to cardiovascular outcomes data.

2. novartis.com novartis.com/news/media-releases/novartis-leqvio-shows-statistically-significant-and-clinically-meaningful-early-ldl-c-goal-achievement-less-muscle-pain

Novartis Leqvio® shows statistically significant and ... Significant benefits were observed as early as 30 days with 81% of patients achieving LDL-C targets1. Results were consistent regardless of age, ...

3. ahajournals.org ahajournals.org/doi/10.1161/circ.150.suppl_1.4139801

Abstract 4139801: Predicted efficacy of Inclisiran compared ... Data quantifying how lowering LDL-C with inclisiran translates into a reduced risk of major adverse cardiovascular events (MACE) and comparison ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03705234

Study Details | NCT03705234 | A Randomized Trial ... The study aims to find out if a new cholesterol-lowering injection (inclisiran) safely lowers the risk of heart attacks and strokes in people who have already ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2666602222000441

Efficacy and safety of inclisiran a newly approved FDA drug PCSK9 inhibition with the monoclonal antibodies evolocumab and alirocumab significantly reduces LDL-C serum levels by approximately 60–65% [12], and these ...

6. novartis.com novartis.com/news/media-releases/novartis-presents-new-long-term-leqvio-inclisiran-data-demonstrating-consistent-efficacy-and-safety-beyond-six-years

Novartis presents new long-term Leqvio® (inclisiran) data ... Novartis presents new long-term Leqvio® (inclisiran) data demonstrating consistent efficacy and safety beyond six years · August 28, 2023 · About ...

7. jacc.org jacc.org/doi/10.1016/j.jacc.2023.10.007

Safety and Tolerability of Inclisiran for Treatment ... Long-term treatment with inclisiran was well tolerated in a diverse population, without new safety signals, supporting the safety of inclisiran in patients ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S2667089525000264

Inclisiran for fast-track lipid-lowering treatment early after ... Inclisiran is safe and effective in lowering LDL-C in patients with familial heterozygous hypercholesterolaemia, patients at high cardiovascular risk and ...