Anti-Coagulant + Anti-Platelet Therapy for Stroke Prevention

(CAPTIVA Trial)

Recruiting at 103 trial locations

Overseen By Dixon Yang

Age: 18+

Sex: Any

Travel: May Be Covered

Trial Phase: Phase 3

Sponsor: University of Florida

Must not be taking: Thrombolytics, Antithrombotics, CYP3A4 inhibitors

Disqualifiers: Intracranial tumor, Cardiac embolism, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

1683 Participants Needed

Trial Summary

What is the purpose of this trial?

The primary goal of the trial is to determine if the experimental arms (rivaroxaban or ticagrelor or both) are superior to the clopidogrel arm for lowering the 1-year rate of ischemic stroke, intracerebral hemorrhage, or vascular death.

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

The trial does not specify if you need to stop your current medications, but it does mention that you cannot take any antithrombotic medication other than aspirin, unless it's for specific conditions like DVT prevention. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Ticagrelor (Brilinta) for stroke prevention?

Ticagrelor, when used with aspirin, has been shown to reduce the rate of death from vascular causes, heart attacks, or strokes in patients with acute coronary syndromes, although its effectiveness specifically for stroke prevention in patients with a history of stroke is limited. ^{1 2 3 4 5}

Is the combination of anti-coagulant and anti-platelet therapy generally safe for humans?

Ticagrelor, an anti-platelet drug, has been shown to be safe in clinical trials for acute coronary syndrome, with similar safety profiles for both its generic and branded versions. However, it carries a warning for bleeding risks, which is common for drugs that prevent blood clots. ^{1 2 4 6 7}

How is the drug combination of Clopidogrel, Rivaroxaban, and Ticagrelor unique for stroke prevention?

This drug combination is unique because it combines both antiplatelet and anticoagulant therapies, which can significantly reduce the risk of recurrent strokes compared to using aspirin alone, although it may increase the risk of bleeding. This approach targets multiple pathways involved in blood clot formation, offering a more comprehensive prevention strategy for patients with atherosclerotic diseases. ^{8 9 10 11 12}

Research Team

Brian L. Hoh, MD, MBA

Principal Investigator

University of Florida

Marc I. Chimowitz, MBChB

Principal Investigator

Medical University of South Carolina

Eligibility Criteria

Adults aged 30-80 with recent symptoms or signs of a stroke due to 70-99% blockage in a major brain artery, who can swallow pills and have certain heart or blood vessel conditions. Excluded are those with previous stent treatments for the lesion, bleeding disorders, severe liver issues, uncontrolled high blood pressure, substance abuse, certain heart conditions that could cause clots, planned major surgeries within 90 days after joining the trial, severe neurological deficits preventing independence, life expectancy under one year due to other illnesses.

Inclusion Criteria

I have been treating my diabetes with insulin for 15 years or more.

I have a narrowed artery due to plaque buildup confirmed by imaging tests.

Index infarct is attributed to 70-99% stenosis (or flow gap on MRA) of a major intracranial artery (carotid artery, MCA stem (M1), vertebral artery, or basilar artery) documented by CTA, MRA, or catheter angiography

Exclusion Criteria

Pregnancy or of childbearing potential and unwilling to use contraception for the duration of this study, or currently breastfeeding

I haven't had major surgery in the last 30 days and don't plan any in the next 90 days.

I have a heart condition that could cause blood clots.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either ticagrelor, rivaroxaban, or clopidogrel in combination with aspirin to prevent stroke and vascular death

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, focusing on ischemic stroke, intracerebral hemorrhage, or vascular death

4 weeks

Treatment Details

Interventions

• Clopidogrel
• Rivaroxaban
• Ticagrelor

Trial Overview The study is testing if adding rivaroxaban or ticagrelor (or both) to aspirin is better than just clopidogrel plus aspirin at reducing the risk of another stroke or death from vascular causes within a year. Participants will be randomly assigned to one of these treatment combinations.

Participant Groups

Group I: Experimental Arm: Ticagrelor and Aspirin Experimental Treatment 2 Interventions

Ticagrelor (180mg loading dose, then 90mg twice daily) and aspirin (81mg daily)

Group II: Experimental Arm: Rivaroxaban and Aspirin Experimental Treatment 2 Interventions

Rivaroxaban (2.5mg twice daily) and aspirin (81mg daily)

Group III: Standard of Care Arm: Clopidogrel and Aspirin Active Control 2 Interventions

Clopidogrel (600mg loading dose, then 75mg once daily) and aspirin (81mg daily)

Clopidogrel is already approved in European Union, United States, Canada, Japan, China for the following indications:

Approved in European Union as Plavix for:

• Prevention of atherothrombotic events in patients with myocardial infarction, stroke, or peripheral arterial disease
• Acute coronary syndrome

Approved in United States as Plavix for:

• Reduction of myocardial infarction and stroke in patients with acute coronary syndrome
• Reduction of myocardial infarction and stroke in patients with recent myocardial infarction, recent stroke, or established peripheral arterial disease

Approved in Canada as Plavix for:

• Prevention of atherothrombotic events in patients with myocardial infarction, stroke, or peripheral arterial disease
• Acute coronary syndrome

Approved in Japan as Plavix for:

• Prevention of recurrence of ischemic cerebrovascular disorder
• Prevention of recurrence of myocardial infarction

Approved in China as Plavix for:

• Prevention of atherothrombotic events in patients with myocardial infarction, stroke, or peripheral arterial disease
• Acute coronary syndrome

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

University of Cincinnati

Collaborator

Trials

442

Recruited

639,000+

Medical University of South Carolina

Collaborator

Trials

994

Recruited

7,408,000+

Janssen Scientific Affairs, LLC

Industry Sponsor

Trials

165

Recruited

579,000+

Ricardo Attar

Janssen Scientific Affairs, LLC

Chief Executive Officer since 2008

PhD in Molecular Biology, University of Buenos Aires

Dr. Anastasia G. Daifotis

Janssen Scientific Affairs, LLC

Chief Medical Officer since 2023

MD

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

Ticagrelor is a new type of P2Y(12) antagonist that works differently from traditional antiplatelet medications like clopidogrel and prasugrel, providing a potentially more effective option for treating acute coronary syndromes.

Clinical trials have shown that ticagrelor, when used with aspirin, has a favorable safety profile and can overcome some limitations associated with clopidogrel, making it a valuable addition to antiplatelet therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ticagrelor: a P2Y12 antagonist for use in acute coronary syndromes. Wijeyeratne, YD., Joshi, R., Heptinstall, S.[2022]

Ticagrelor (Brilinta) has been approved by the FDA as an oral antiplatelet medication to be used with low-dose aspirin for reducing thrombotic cardiovascular events in patients with acute coronary syndrome (ACS).

Ticagrelor will compete with existing medications like clopidogrel (Plavix) and prasugrel (Effient), especially as clopidogrel is expected to become available as a generic option soon.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ticagrelor (Brilinta)--better than clopidogrel (Plavix)? [2018]

Ticagrelor, a potent oral platelet inhibitor, significantly reduces the risk of death, myocardial infarction, or stroke in patients with acute coronary syndromes compared to clopidogrel, as shown in the PLATO study.

While ticagrelor does not increase the overall rate of major bleeding compared to clopidogrel, it is associated with a higher incidence of non-procedure-related bleeding, indicating a need for careful monitoring in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Medication of the month. Ticagrelor (Brilique): potent oral antagonist of platelet activity]. Lancellotti, P.[2018]

Ticagrelor is an effective antiplatelet medication used in patients with acute coronary syndrome, helping to reduce the risk of heart attacks and other cardiovascular events.

Clinical studies have shown that ticagrelor provides a greater reduction in major adverse cardiovascular events compared to traditional treatments like clopidogrel, making it a preferred choice in acute settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ticagrelor (brilinta), an antiplatelet drug for acute coronary syndrome. Fuller, R., Chavez, B.[2021]

Aspirin and clopidogrel are established antiplatelet agents that are effective and safe for patients with a history of stroke or transient ischemic attack, highlighting their importance in managing cerebrovascular atherothrombosis.

Novel antiplatelet agents like prasugrel, ticagrelor, and vorapaxar show limited efficacy in preventing cerebrovascular events and may pose risks for patients with a history of stroke, indicating the need for careful consideration in their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy versus safety: the dilemma of using novel platelet inhibitors for the treatment of patients with ischemic stroke and coronary artery disease. Iannopollo, G., Camporotondo, R., De Ferrari, GM., et al.[2021]

In a study involving 29 healthy volunteers, the generic drug Ticaloguard® was found to have similar therapeutic effects and safety profiles compared to the brand-name drug Brilique® in terms of platelet aggregation, indicating that it can be used interchangeably in treating acute coronary syndrome.

The study emphasizes the importance of testing the therapeutic equivalence of generic drugs, especially for critical medications, rather than relying solely on bioequivalence, to ensure patient safety and effective treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Testing P2Y12 platelet inhibitors generics beyond bioequivalence: a parallel single-blinded randomized trial. Zarif, B., Soliman, L., Sabry, NA., et al.[2022]

Ticagrelor (Brilinta™) was approved by the FDA for treating acute coronary syndromes based on the PLATO trial, which involved 18,624 patients and compared its efficacy to clopidogrel over 6-12 months.

Despite its approval, there were significant concerns from FDA reviewers regarding its efficacy and safety, particularly related to bleeding risks and the potential reduction in effectiveness when used with high doses of aspirin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ticagrelor FDA approval issues revisited. Serebruany, VL.[2018]

Antiplatelet treatment is essential for preventing atherothrombotic strokes, but traditional drugs like aspirin and thienopyridines have limitations, including increased bleeding risk and variable patient response.

Newer antiplatelet agents, such as ticagrelor and prasugrel, do not significantly improve stroke prevention compared to aspirin or clopidogrel and also carry a higher risk of bleeding, highlighting the need for new drug targets in antiplatelet therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stroke prevention: from available antiplatelet drugs to novel molecular targets. Di Minno, MN., Momi, S., Di Minno, A., et al.[2019]

Dual antiplatelet therapy, consisting of aspirin and clopidogrel, is essential for preventing ischemic events in patients with coronary atherosclerotic disease, especially during acute coronary syndromes and after stent placement.

While triple antithrombotic therapy (dual antiplatelet therapy plus warfarin) can effectively prevent thromboembolism and stent thrombosis, it significantly increases the risk of bleeding, highlighting the need for careful management and expertise in balancing these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining antiplatelet and anticoagulant therapies. Holmes, DR., Kereiakes, DJ., Kleiman, NS., et al.[2022]

The COMPASS study showed that combining rivaroxaban with acetylsalicylic acid (ASA) significantly reduces the risk of stroke, cardiovascular death, and myocardial infarction by 24% compared to ASA alone, highlighting the efficacy of dual-pathway thrombosis inhibition in patients with atherosclerotic diseases.

Patients receiving the combination therapy experienced a 67% reduction in the risk of recurrent stroke, with an annual incidence of only 1.1% compared to 3.4% in those on ASA alone, indicating a strong safety profile and effectiveness in preventing recurrent noncardioembolic ischemic strokes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current opportunities for secondary prevention of atherothrombotic stroke]. Maksimova, MY.[2021]

The combination of antiplatelet and anticoagulant drugs in patients with acute coronary syndromes poses significant challenges due to a lack of strong clinical evidence and guidelines, especially as many patients also require double antiplatelet therapy.

The ATLAS-ACS 2 TIMI 51 study showed promising results for the use of rivaroxaban in combination with double antiplatelet therapy, suggesting potential benefits for patients with acute coronary syndromes, although the overall evidence remains limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Anticoagulants and dual antiplatelet therapy combined, a challenge to our intelligence]. Morais, J.[2015]

Aspirin remains the first-line antiplatelet drug for long-term prevention of recurrent heart issues after a myocardial infarction, while dual antiplatelet therapy has been shown to improve outcomes in acute coronary syndromes despite a higher risk of bleeding.

The article reviews the best combinations of aspirin with P2Y12 inhibitors (like clopidogrel, prasugrel, or ticagrelor) and discusses new antithrombotic agents that may enhance treatment effectiveness in high-risk patients, particularly those with both atrial fibrillation and acute coronary syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiplatelet and antithrombotic treatment for secondary prevention in ischaemic heart disease. Lettino, M., Leonardi, S., De Maria, E., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Ticagrelor: a P2Y12 antagonist for use in acute coronary syndromes. [2022]

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

Ticagrelor (Brilinta)--better than clopidogrel (Plavix)? [2018]

3. Belgium pubmed.ncbi.nlm.nih.gov

[Medication of the month. Ticagrelor (Brilique): potent oral antagonist of platelet activity]. [2018]

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

Ticagrelor (brilinta), an antiplatelet drug for acute coronary syndrome. [2021]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Efficacy versus safety: the dilemma of using novel platelet inhibitors for the treatment of patients with ischemic stroke and coronary artery disease. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Testing P2Y12 platelet inhibitors generics beyond bioequivalence: a parallel single-blinded randomized trial. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Ticagrelor FDA approval issues revisited. [2018]

8. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Stroke prevention: from available antiplatelet drugs to novel molecular targets. [2019]

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

Combining antiplatelet and anticoagulant therapies. [2022]

10. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Current opportunities for secondary prevention of atherothrombotic stroke]. [2021]

11. Portugal pubmed.ncbi.nlm.nih.gov

[Anticoagulants and dual antiplatelet therapy combined, a challenge to our intelligence]. [2015]

12. England pubmed.ncbi.nlm.nih.gov

Antiplatelet and antithrombotic treatment for secondary prevention in ischaemic heart disease. [2018]