Inclisiran for Cardiovascular Disease Prevention

Not currently recruiting at 1226 trial locations

Overseen By Seth J Baum

Age: 18+

Sex: Any

Travel: May Be Covered

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Must be taking: Lipid lowering

Must not be taking: PCSK9 inhibitors

Disqualifiers: ASCVD, Revascularization, Liver disease, others

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

Compensation: Varies

Number of Visits: 1

Duration: Up to 75 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether inclisiran, a cholesterol-lowering drug, can reduce the risk of serious heart problems in individuals at high risk who have not yet experienced a major heart event. Participants will receive either inclisiran or a placebo to compare results. Ideal candidates for the trial have signs of coronary artery disease (narrowed heart arteries) or a high calcium score in their arteries, along with high cholesterol levels managed with stable medication. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking treatment advancements.

Do I have to stop taking my current medications for this trial?

The trial does not specify if you need to stop taking your current medications. However, if you are on lipid-lowering therapy, you must stay on a stable dose for at least 4 weeks before the screening and throughout the study.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on lipid-lowering therapy, you must have been on a stable dose for at least 4 weeks before the screening and be willing to continue it throughout the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study showed that inclisiran lowered LDL cholesterol by 52.6% after two doses, the same amount used in the current trial. Research has shown that inclisiran is generally safe and well-tolerated over time. Most participants in studies reached their cholesterol goals without major issues.

However, some potential long-term side effects require further investigation. Inclisiran has already received approval for other uses, indicating its general safety. Overall, evidence supports its safety for most patients, but staying updated on new research findings is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Inclisiran is unique because it uses a novel mechanism of action to lower cholesterol levels, specifically by targeting PCSK9, a protein that affects LDL receptor breakdown. Unlike traditional statins, which work by inhibiting an enzyme involved in cholesterol production, inclisiran offers a different approach by enhancing the liver's ability to remove LDL cholesterol from the bloodstream. Additionally, inclisiran is administered as a subcutaneous injection just twice a year, offering a convenient alternative to daily pills. Researchers are excited about inclisiran's potential to improve adherence and provide consistent cholesterol control with fewer doses.

What evidence suggests that inclisiran sodium could be an effective treatment for cardiovascular disease prevention?

Research shows that inclisiran sodium, which participants in this trial may receive, can significantly lower LDL cholesterol, often called "bad" cholesterol, a major risk factor for heart problems. Studies have found that inclisiran can reduce LDL levels by about 50%. After 90 days of treatment, 85% of patients reached their recommended cholesterol levels, compared to just 31% of those on standard treatment. In long-term studies, 75% of patients taking inclisiran maintained very low LDL levels, while only 4% of those on a placebo did. This suggests that inclisiran could be promising for reducing the risk of heart attacks, strokes, and other serious heart issues. ^{1 3 4 6 7}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for adults aged 40-80 with high cholesterol and at increased risk of a first major cardiovascular event, but who haven't had one before. They should have an intermediate 10-year heart disease risk score with additional risk factors. Pregnant women, nursing mothers, or those in another study can't participate.

Inclusion Criteria

My heart disease risk for the next 10 years is between 7.5% and 20%, and I have at least two risk factors.

I am between 40 and 80 years old.

You have a higher risk of experiencing a first major cardiovascular event and have not had one before.

Exclusion Criteria

Are you currently participating in another research study?

I have had a major heart or blood vessel event.

You are currently pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive inclisiran sodium 300 mg or placebo administered subcutaneously on Day 1, Day 90, and every 6 months thereafter

Up to 75 months

Visits on Day 1, Day 90, and every 6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Minimum of 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Inclisiran sodium
• Placebo

Trial Overview The trial tests if Inclisiran sodium (a drug given by injection) can prevent serious heart-related events when administered initially, after three months, and then every six months compared to a placebo. The goal is to see if it reduces the occurrence of events like heart attacks or strokes.

How Is the Trial Designed?

Group I: Inclisiran sodium 300mg Experimental Treatment 1 Intervention

Inclisiran sodium 300 mg in 1.5 mL solution for injection (subcutaneous) in pre-filled syringe. Randomized in a 1:1 ratio with matching placebo

Group II: Placebo Placebo Group 1 Intervention

Matching placebo in 1.5ml pre-filled syringe. Randomized in a 1:1 ratio with Inclisiran.

Inclisiran sodium 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?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

In a study of 734 patients with mild-to-moderate essential hypertension, valsartan demonstrated similar effectiveness in reducing diastolic blood pressure compared to lisinopril, with both treatments significantly lowering blood pressure compared to placebo.

Valsartan was associated with a lower incidence of cough (1.1%) compared to lisinopril (8%), suggesting it may be a better tolerated option for patients sensitive to this side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy, tolerability and safety compared to an angiotensin-converting enzyme inhibitor, lisinopril. Black, HR., Graff, A., Shute, D., et al.[2022]

In a study of 281 adults with mild-to-moderate primary hypertension, both lercanidipine and felodipine significantly reduced diastolic blood pressure after 6 weeks of treatment, demonstrating their efficacy in managing hypertension.

Lercanidipine was found to be a safe treatment option, with a similar incidence of adverse events compared to felodipine, indicating that it can be effectively used for blood pressure control without unexpected side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lercanidipine hydrochloride versus felodipine sustained-release for mild-to-moderate hypertension: a multi-center, randomized clinical trial. Wu, Y., Xu, M., Wang, H., et al.[2018]

Inclisiran significantly reduces the risk of myocardial infarction (MI) by 32% in patients with atherosclerotic cardiovascular disease (ASCVD), based on a meta-analysis of three randomized controlled trials involving 3,713 patients.

However, inclisiran does not show a significant effect on reducing the risk of stroke or major cardiovascular events, and while its safety profile is similar to placebo, it is associated with a higher incidence of mild to moderate injection-site reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of inclisiran in stroke or cerebrovascular disease prevention: a systematic review and meta-analysis of randomized controlled trials. Luo, M., Liu, Y., Xu, X., et al.[2023]

In a study involving 7297 patients aged 60 and over, switching from non-selective NSAIDs to celecoxib did not result in a higher rate of cardiovascular events, indicating similar safety profiles for both treatments over a median follow-up of 3 years.

The study found that while gastrointestinal and hematological adverse reactions were more common with non-selective NSAIDs, there was no significant cardiovascular advantage to switching to celecoxib, as the risk of serious events remained low and comparable between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT). MacDonald, TM., Hawkey, CJ., Ford, I., et al.[2022]

Quinaprilat, administered in single and multiple intravenous doses ranging from 0.5 to 10 mg, significantly improved heart function by increasing cardiac index and reducing pressures in the heart and lungs in patients with severe congestive heart failure.

The treatment was well-tolerated with no significant adverse effects, and it effectively lowered levels of angiotensin II and aldosterone while increasing plasma renin activity, demonstrating its mechanism as an ACE inhibitor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemodynamic and hormonal effects of quinaprilat in patients with congestive heart failure. Mitrovic, V., Mudra, H., Bonzel, T., et al.[2014]

The combination of perindopril and lercanidipine significantly lowered blood pressure more effectively than either medication alone in patients with mild essential hypertension, with notable improvements seen as early as 4 weeks into treatment.

Patients receiving the combination therapy experienced fewer adverse events compared to those on monotherapy, indicating a better safety profile for the combination treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety evaluation of perindopril-lercanidipine combined therapy in patients with mild essential hypertension. Yang, Z.[2019]

Celecoxib shows a lower risk of cardiovascular events and all-cause mortality compared to non-selective non-steroidal anti-inflammatory drugs (NSAIDs), with risk ratios of 0.89 and 0.81 respectively, based on a meta-analysis of 21 trials involving rheumatoid arthritis and osteoarthritis patients.

The study suggests that celecoxib is relatively safe for cardiovascular health in these patients, but its safety in individuals taking aspirin or those with existing cardiovascular diseases remains uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of celecoxib in rheumatoid arthritis and osteoarthritis patients: A systematic review and meta-analysis. Cheng, BR., Chen, JQ., Zhang, XW., et al.[2022]

Analysis of registration files for 13 cardiovascular drugs revealed that half of the 146 double-blind phase-III clinical trials utilized active comparator drugs, indicating a robust approach to evaluating drug efficacy against existing treatments.

The study highlighted inconsistencies in trial reporting, such as varying dosing schemes and the use of only placebo or active controls, suggesting a need for standardized reporting to improve the clarity of European Public Assessment Reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative trials in registration files of cardiovascular drugs: comparator drugs and dosing schemes. Wieringa, NF., Vos, R., de Graeff, PA.[2019]

In a 1-year study involving 411 hypertensive patients with left ventricular hypertrophy, indapamide sustained release (SR) 1.5 mg significantly reduced left ventricular mass index (LVMI) by an average of -8.4 g/m2, while enalapril 20 mg showed no significant reduction.

Indapamide SR was more effective than enalapril in reducing LVMI by -6.5 g/m2, and it consistently reduced wall thickness over the treatment period, unlike enalapril, whose effects diminished after 6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regression of left ventricular hypertrophy in hypertensive patients treated with indapamide SR 1.5 mg versus enalapril 20 mg: the LIVE study. Gosse, P., Sheridan, DJ., Zannad, F., et al.[2019]

Between 2011 and 2014, the initiation of diclofenac prescriptions decreased by about 30% among both male and female patients in Germany, indicating a positive response to European risk minimization measures.

Despite the decrease in overall diclofenac use, the proportion of new patients with contraindications (such as heart failure and ischemic heart disease) remained high, suggesting ongoing safety concerns and the need for further research to enhance prescribing practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are prescribers not aware of cardiovascular contraindications for diclofenac? A claims data analysis. Scholle, O., Kollhorst, B., Haug, U.[2020]

In a study involving 123 healthy adults, parecoxib sodium (40 mg twice daily for 7 days) showed a superior gastrointestinal safety profile compared to ketorolac (30 mg four times daily for 5 days), with no subjects developing ulcers or significant erosions.

While 28% of subjects taking ketorolac developed ulcers and 48% had significant erosions, parecoxib sodium's safety was comparable to placebo, indicating it may be a safer alternative for pain management without gastrointestinal risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parecoxib sodium demonstrates gastrointestinal safety comparable to placebo in healthy subjects. Harris, SI., Stoltz, RR., LeComte, D., et al.[2019]

In a study involving 48 healthy volunteers, candesartan cilexetil demonstrated the highest pharmacological potency among angiotensin II receptor antagonists, effectively lowering diastolic blood pressure with a calculated K(i)-dose of 6 mg at 24 hours.

All tested angiotensin II receptor antagonists showed dose-dependent effects on blood pressure, and their K(i)-doses were within the recommended clinical ranges for treating hypertension, indicating their potential efficacy in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacological potency of various AT(1) antagonists assessed by Schild regression technique in man. Belz, GG., Breithaupt-Grögler, K., Butzer, R., et al.[2018]

Sodium Tanshinone II A Sulfonate Injection (STS) significantly improves treatment outcomes for unstable angina pectoris (UAP) when used alongside Western medicine, as shown in a meta-analysis of 17 randomized controlled trials involving 1,372 patients.

While STS enhances effectiveness by improving total effective rates and reducing inflammatory markers, it is associated with a higher occurrence of adverse drug reactions compared to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium Tanshinone II A Sulfonate Injection as Adjuvant Treatment for Unstable Angina Pectoris: A Meta-Analysis of 17 Randomized Controlled Trials. Tan, D., Wu, JR., Zhang, XM., et al.[2022]

VA694, a new NO-releasing COX2 inhibitor, shows promise in reducing cardiovascular risks associated with traditional COX2 inhibitors by releasing nitric oxide, which can improve vascular function.

In a study with young spontaneously hypertensive rats, chronic administration of VA694 slowed the development of hypertension and improved coronary flow, suggesting it may offer both anti-inflammatory and cardiovascular benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The novel anti-inflammatory agent VA694, endowed with both NO-releasing and COX2-selective inhibiting properties, exhibits NO-mediated positive effects on blood pressure, coronary flow and endothelium in an experimental model of hypertension and endothelial dysfunction. Martelli, A., Testai, L., Anzini, M., et al.[2016]

Citations

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

Current usage of inclisiran for cardiovascular diseases Across pivotal trials, including ORION-9, ORION-10, and ORION-11, inclisiran demonstrated LDL-C reductions of approximately 50%, with effects ...

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 ... After 90 days of treatment with Leqvio on top of LLT, 85% of patients achieved their guideline-recommended LDL-C target compared to 31% of those ...

3. leqviohcp.com leqviohcp.com/efficacy/long-term-efficacy

Long-Term Efficacy - LEQVIO® (inclisiran) | HCP 75% of patients receiving LEQVIO achieved an LDL-C <55 mg/dL vs 4% of patients on placebo at month 176. Results were similar in patients with ASCVD in ORION-11.

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1912387

Two Phase 3 Trials of Inclisiran in Patients with Elevated ... In one trial, the LDL cholesterol level was lowered by 52.6% at 180 days after two doses of 284 mg of inclisiran (equivalent to 300 mg of inclisiran sodium) ...

5. ahajournals.org ahajournals.org/doi/10.1161/JAHA.123.032031

Harnessing RNA Interference for Cholesterol Lowering Twice‐yearly maintenance subcutaneous inclisiran (following initial loading doses at Day 1 and Day 90) reduces circulating LDL‐C levels by ≈50% ...

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 ... Nearly 80% (78.4% (95% CI: 76.8, 80.0)) of patients reached their pre-specified LDL-C targets**, and on average, LDL-C levels were reduced by ...

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

Safety and Tolerability of Inclisiran for Treatment ... This analysis indicates that long-term inclisiran is safe and generally well tolerated in a diverse population of patients with dyslipidemia ...