Inclisiran for Cardiovascular Disease

(ORION-4 Trial)

Not currently recruiting at 2 trial locations

Overseen By Marion Mafham

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Oxford

Must not be taking: PCSK9 inhibitors

Disqualifiers: Chronic liver disease, Renal dialysis, Cancer, 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

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

Compensation: Varies

Number of Visits: 3

Duration: 5 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new injection called inclisiran to determine if it can safely lower the risk of heart attacks and strokes in individuals who have experienced these conditions or undergone surgery for blocked arteries. Inclisiran, a cholesterol-lowering medication, is administered every six months to help prevent future cardiovascular issues. Ideal candidates for this trial include those who have had a heart attack, stroke, or surgery for blocked arteries. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking cardiovascular treatment.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are currently or have recently been treated with a monoclonal antibody targeting PCSK9, you may not be eligible to participate.

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

Research has shown that inclisiran is generally safe for long-term use, with studies finding no new safety concerns or unexpected harmful effects. Inclisiran has effectively lowered LDL cholesterol, often referred to as "bad" cholesterol, in various studies.

In one study, inclisiran reduced LDL cholesterol by about 52.6% after six months with two doses. Another large study found that nearly 80% of patients reached their cholesterol goals without major problems. These results suggest that inclisiran is safe for individuals needing to lower their cholesterol levels.

Overall, the evidence supports the safety of inclisiran, as it has been tested in many different people without revealing new risks. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for cardiovascular disease?

Inclisiran is unique because it uses small interfering RNA (siRNA) technology to lower cholesterol levels by targeting the PCSK9 protein, which is different from most current treatments like statins. Statins work by inhibiting an enzyme involved in cholesterol production, while Inclisiran directly reduces the production of the PCSK9 protein, resulting in a longer-lasting effect on cholesterol levels. Researchers are excited about Inclisiran because it only requires injections every six months, offering a convenient and potentially more consistent option for patients compared to daily medications.

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

Research has shown that inclisiran, which participants in this trial may receive, effectively lowers LDL cholesterol, often called "bad" cholesterol. In several studies, patients experienced an average reduction of about 50% in their LDL cholesterol. Specifically, one study found that nearly 80% of patients reached their LDL goals after using inclisiran. Lowering LDL cholesterol is crucial because it reduces the risk of major heart problems like heart attacks and strokes. This makes inclisiran a promising option for people with heart disease. ^{1 2 5 6 7}

Who Is on the Research Team?

Marion Mafham

Principal Investigator

University of Oxford

Louise Bowman

Principal Investigator

University of Oxford

David Preiss

Principal Investigator

University of Oxford

Martin Landray

Principal Investigator

University of Oxford

Are You a Good Fit for This Trial?

This trial is for men over 40 and women over 55 with a history of heart attack, stroke, or procedures for blocked arteries. It's not open to those planning heart surgery soon, with chronic liver disease, on dialysis/transplantation, pregnant/breastfeeding women, or anyone with severe illnesses that could interfere with the study.

Inclusion Criteria

You have been diagnosed with Hypercholesterolemia

Have you at least 4 weeks of been taking statins

Exclusion Criteria

You have been diagnosed with Stroke

I have previously used inclisiran or been in a study for it.

I am scheduled for a heart artery procedure in the next 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive inclisiran or placebo via subcutaneous injection at randomization, 3 months, and then every 6 months

5 years

Injections at randomization, 3 months, and every 6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Inclisiran
• Placebo

Trial Overview ORION-4 is testing whether inclisiran injections can reduce the risk of heart attacks and strokes in people who've already had cardiovascular events. Participants will be randomly assigned to receive either inclisiran or a placebo.

How Is the Trial Designed?

Group I: Inclisiran Experimental Treatment 1 Intervention

Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection at randomization, 3 months and then every 6 months.

Group II: Placebo Placebo Group 1 Intervention

Placebo will be administered as SC injections of saline solution at randomization, 3 months and then every 6 months.

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?

University of Oxford

Lead Sponsor

Trials

1,113

Recruited

21,220,000+

The TIMI Study Group

Collaborator

Trials

22

Recruited

129,000+

Novartis Pharmaceuticals

Industry 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

Tranilast is being tested in a large multicenter study involving 11,500 patients to see if it can effectively reduce the risk of restenosis after coronary revascularization procedures, with a focus on its mechanisms that inhibit smooth muscle cell proliferation and collagen synthesis.

This study is significant as it aims to confirm previous positive results seen in Japanese populations and assess whether tranilast can also lower clinical events like death and myocardial infarction in a Western population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The PRESTO (Prevention of restenosis with tranilast and its outcomes) protocol: a double-blind, placebo-controlled trial. Holmes, D., Fitzgerald, P., Goldberg, S., et al.[2019]

In a study of 84 patients with 89 coronary lesions, pemirolast significantly reduced the rate of restenosis after stent placement, with rates of 15.0% in the pemirolast group compared to 34.1% in the control group.

Pemirolast treatment resulted in a larger lumen cross-sectional area and smaller neointima area, suggesting it may prevent restenosis by inhibiting neointimal hyperplasia, which is the growth of tissue that can block the artery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventive effect of an antiallergic drug, pemirolast potassium, on restenosis after stent placement: quantitative coronary angiography and intravascular ultrasound studies. Ohsawa, H., Noike, H., Kanai, M., et al.[2016]

The NEVO sirolimus-eluting stent (SES) demonstrated significantly less neointimal proliferation compared to the TAXUS Liberté paclitaxel-eluting stent (PES), resulting in better arterial response and less late lumen area loss after 6 months in a study of 100 patients.

The NEVO SES showed a more uniform distribution of neointimal thickness, indicating a more consistent performance, while the TAXUS PES exhibited greater positive vessel remodeling, suggesting different mechanisms of action between the two stent types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravascular ultrasound results from the NEVO ResElution-I trial: a randomized, blinded comparison of sirolimus-eluting NEVO stents with paclitaxel-eluting TAXUS Liberté stents in de novo native coronary artery lesions. Otake, H., Honda, Y., Courtney, BK., et al.[2016]

The XLIMUS sirolimus-eluting stent demonstrated a high delivery success rate of 98% in a study involving 200 patients with complex coronary artery lesions, indicating its effectiveness in challenging cases.

The 1-year rate of major adverse cardiac events (MACE) was 9%, suggesting that the XLIMUS SES is not only deliverable but also safe for patients undergoing percutaneous coronary interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Performance of the XLIMUS Sirolimus-Eluting Coronary Stent in Very Complex Lesions. Briguori, C., Visconti, G., Donahue, M., et al.[2022]

The Inspiron™ sirolimus-eluting stent (SES) demonstrated a significant reduction in the need for repeat revascularization procedures (0.0% vs. 23.5%) compared to the bare metal stent after 4 years, indicating its efficacy in long-term cardiac outcomes.

There were no occurrences of stent thrombosis in the study population, highlighting the safety of the Inspiron™ SES over the 4-year follow-up period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Four-year clinical follow-up of the first-in-man randomized comparison of a novel sirolimus eluting stent with abluminal biodegradable polymer and ultra-thin strut cobalt-chromium alloy: the INSPIRON-I trial. Oliveira, MD., Ribeiro, EE., Campos, CM., et al.[2020]

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. 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) ...

3. 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 ...

4. 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 ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12005059/

Inclisiran in Cardiovascular Health: A Review of ... In the ORION-7 study, inclisiran demonstrated similar lipid-lowering effects across patients with mild, moderate, and severe renal impairment, with drug ...

6. 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 ...

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 ...