Reduced-Dose Thrombolytic Therapy for Pulmonary Embolism

(PEITHO-3 Trial)

Recruiting at 114 trial locations

Overseen By Olivier SANCHEZ, MD PhD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Assistance Publique - Hôpitaux de Paris

Must be taking: Low-molecular-weight heparin

Must not be taking: Antiplatelets, Direct oral anticoagulants

Disqualifiers: Hemodynamic instability, Active bleeding, Stroke, 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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 30

Duration: 30 days

800 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment for people with blood clots in their lungs, known as pulmonary embolism. Researchers aim to determine if a lower dose of the clot-busting drug alteplase is safe and effective when combined with blood thinners. Participants will receive either the alteplase treatment or a placebo (a harmless substance with no effect). Suitable candidates for this trial include those who have recently experienced a pulmonary embolism and have symptoms like shortness of breath or low blood pressure. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot take certain blood thinners like direct oral anticoagulants within 12 hours of joining. Also, dual antiplatelet therapy is not allowed, and some other medications may have restrictions.

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

Research has shown that using a lower dose of alteplase to treat pulmonary embolism is safe and effective. Studies have found that this method results in fewer major bleeding incidents compared to the full dose. This finding is significant because bleeding is a serious risk with this medication. Another study found that a reduced dose of alteplase is a safe option for patients at higher risk of pulmonary embolism, making it a promising treatment choice. However, while alteplase can be effective, it still carries a risk of bleeding, which can be severe or life-threatening. Participants should consider these factors when deciding whether to join a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pulmonary embolism?

Researchers are excited about using alteplase for pulmonary embolism because it offers a reduced-dose option compared to the full-dose thrombolytic therapies currently in use. This could potentially lower the risk of bleeding, a significant concern with existing treatments like full-dose alteplase or tenecteplase. While most treatments for pulmonary embolism focus on breaking up clots with higher doses, this approach aims to be just as effective but safer, making it an appealing alternative for patients who might be at higher risk for complications.

What evidence suggests that this treatment might be an effective treatment for pulmonary embolism?

In this trial, participants will receive either a reduced dose of alteplase or a placebo. Research has shown that a lower dose of alteplase can effectively treat pulmonary embolism, a blockage in the lung's arteries. Studies indicate that using half the usual dose of this medication works as well as the full dose while reducing the risk of bleeding. In one study, patients who received the reduced dose experienced similar positive results compared to those on the full dose, but with fewer bleeding incidents. Another study found that administering a low dose of alteplase slowly over time was safe and effective for severe pulmonary embolism cases. Overall, evidence suggests that a reduced dose of alteplase offers a good balance of effectiveness and safety. ^{1 2 6 7 8}

Who Is on the Research Team?

Olivier SANCHEZ, MD

Principal Investigator

Assistance Publique - Hôpitaux de Paris

Stavros Konstantinides, MD

Principal Investigator

University Medical Center Mainz

Are You a Good Fit for This Trial?

This trial is for adults with a recent acute pulmonary embolism, at elevated risk of early death or recurrence. They must have right ventricular dysfunction and raised serum troponin levels. Exclusions include history of brain bleeding, certain drug treatments, recent surgeries or trauma, severe liver disease, uncontrolled hypertension, and women who are pregnant or not using birth control.

Inclusion Criteria

You have a high chance of experiencing severe health problems or a blood clot coming back, based on specific criteria.

Signed informed consent form

You have been diagnosed with a blood clot in your lungs within the past 24 hours before joining the study.

Exclusion Criteria

Current or previous participation in specific clinical studies

I have recently used blood thinners.

I have a brain tumor or cancer that has spread to my brain.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

Treatment

Participants receive either a reduced dose of thrombolytic therapy or placebo, along with parenteral anticoagulation

30 days

Initial visit for randomization and treatment administration

Follow-up

Participants are monitored for safety and effectiveness, including assessment of primary and secondary objectives

6 months

Regular follow-up visits, including assessments at 30 days and 6 months

Long-term follow-up

Assessment of long-term mortality, functional impairment, and other outcomes at 2 years

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Alteplase
• Placebo

Trial Overview The study tests if a reduced dose of Alteplase (thrombolytic therapy) plus low-molecular-weight heparin is effective and safe in patients with intermediate-high-risk acute pulmonary embolism compared to placebo. Participants are randomly assigned to receive either the treatment or placebo.

How Is the Trial Designed?

Group I: Alteplase Experimental Treatment 1 Intervention

Group II: Placebo Placebo Group 1 Intervention

Alteplase is already approved in United States, European Union for the following indications:

Approved in United States as Activase for:

• Acute ischemic stroke
• Acute myocardial infarction
• Pulmonary embolism
• Blocked central venous catheter

Approved in European Union as Actilyse for:

• Acute ischemic stroke
• Acute myocardial infarction
• Pulmonary embolism
• Blocked central venous catheter

Who Is Running the Clinical Trial?

Assistance Publique - Hôpitaux de Paris

Lead Sponsor

Trials

3,369

Recruited

57,400,000+

Boehringer Ingelheim

Industry Sponsor

Trials

2,566

Recruited

16,150,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Instituto de Salud Carlos III

Collaborator

Trials

320

Recruited

648,000+

International Network of VENous Thromboembolism Clinical Research Networks

Collaborator

Trials

1

Recruited

650+

Johannes Gutenberg University Mainz

Collaborator

Trials

214

Recruited

331,000+

Life Sciences Research Partners (D Collen Research Foundation)

Collaborator

Trials

1

Recruited

650+

Published Research Related to This Trial

Thrombolytic therapy (TLT) using actilyse, urokinase medac, and purulase has been evaluated in patients with deep vein thrombosis (DVT) and pulmonary artery thromboembolism (PATE) at a pediatric hospital, highlighting its clinical application.

The study discusses the challenges and considerations in using thrombolysis for treating DVT and PATE, suggesting that while TLT can be beneficial, careful assessment of patient conditions is crucial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Thrombolytic therapy in patients with pulmonary artery thromboembolism and deep vein thrombosis]. Zatevakhin, II., Zolkin, VN., Krivtsov, IuV.[2016]

In a study of 40 patients with high- and intermediate-to-high risk pulmonary artery thromboembolism (PATE), both alteplase and streptokinase showed similar clinical efficacy in treating the condition.

Despite similar efficacy, patients treated with alteplase experienced more severe conditions and relapses, leading to the conclusion that alteplase (Actilyse) is the preferred treatment option for PATE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparative efficacy of various thrombolytic agents in treatment of pulmonary embolism]. Khorev, NG., Beller, AV., Borovikov, ÉV., et al.[2020]

In a study of 1017 patients with acute ischemic stroke, only 23 (2.26%) received alteplase treatment, with a complication rate of 26.09%, primarily due to intracerebral hemorrhage.

Despite the risks, the overall incidence of stroke and the number of patients treated with alteplase have remained stable, indicating consistent use of this therapy in the hospital setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of alteplase in the treatment of acute ischemic stroke. Yayan, J.[2022]

In the GUSTO-III trial involving 15,059 patients, both reteplase (r-PA) and tissue plasminogen activator (t-PA) showed similar mortality rates at 1 year, with 11.06% for t-PA and 11.20% for r-PA, indicating comparable efficacy in treating occluded coronary arteries.

The study revealed a concerning increase in mortality rates from 30 days to 1 year compared to previous trials, suggesting that the current patient population may be at higher risk and emphasizing the need for better secondary prevention strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival outcomes 1 year after reperfusion therapy with either alteplase or reteplase for acute myocardial infarction: results from the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) III Trial. Topol, EJ., Ohman, EM., Armstrong, PW., et al.[2019]

Recombinant tissue plasminogen activator (rt-PA) is the only licensed thrombolytic treatment for acute ischemic stroke in the UK, highlighting its importance in emergency stroke care.

The use of rt-PA can improve long-term clinical outcomes for selected patients when integrated into a comprehensive stroke management service.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thrombolytic therapy for acute ischaemic stroke. Jenkinson, D.[2019]

Low-dose alteplase (tPA) has been shown to be a safe and effective treatment for pulmonary embolism (PE), especially in patients with low body weight and right-ventricular dysfunction, based on a review of clinical trials and case reports.

The risk of major bleeding complications from tPA is dose-dependent, with lower doses being safer for high-risk patients, including the elderly and those with a history of bleeding. More research is needed to establish the best dosing strategies for tPA in treating PE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-Dose Systemic Alteplase (tPA) for the Treatment of Pulmonary Embolism. Brandt, K., McGinn, K., Quedado, J.[2022]

Fibrinolytic agents, like alteplase, have maintained similar efficacy and safety profiles for nearly 20 years, indicating their established role in treatment.

Newer fibrinolytic agents offer longer half-lives, which improve their delivery, yet fibrinolytic therapy remains underutilized, particularly in high-risk patients who could benefit from it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New fibrinolytic agents for MI: as effective as current agents, but easier to administer. Ellis, K., Brener, S.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38165776/

Safety and Efficacy of Reduced-Dose Versus Full ... In a retrospective, PS-weighted observational study, when compared with the full-dose, reduced-dose alteplase results in similar outcomes but fewer hemorrhagic ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6375681/

Half-Dose versus Full-Dose Alteplase for Treatment of ... Recent evidence suggests that half-dose thrombolysis for pulmonary embolism (PE) may provide similar efficacy with reduced bleeding risk compared to full-dose ...

3. academic.oup.com academic.oup.com/eurheartj/article/45/Supplement_1/ehae666.2202/7837116

Efficacy and safety of reduced-dose and slow-infusion ... This single-center study comprised 124 retrospectively evaluated patients (female 58.9 % and mean age 55.4+15.8 years) diagnosed with acute PE ...

4. ceemjournal.org ceemjournal.org/upload/pdf/ceem-23-015.pdf

Reduced-dose systemic fibrinolysis in massive pulmonary ... The present pilot study suggests that an extended infusion of low-dose tPA is safe and effective in treating massive PE. TT was associated ...

5. journal.chestnet.org journal.chestnet.org/article/S0012-3692(10)60061-X/fulltext

Half the Dosage, Similar Efficacy, Less Bleeding - Chest Journal Half the dosage, similar efficacy, less bleeding. The new tissue plasminogen activator regimen for pulmonary embolism?

6. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/1881311

Thrombolysis for Pulmonary Embolism and Risk of All- ... The primary efficacy outcome was all-cause mortality and the primary safety outcome was major bleeding. Secondary efficacy and safety outcomes ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0736467924002373

Mortality Outcomes with Tenecteplase Versus Alteplase in ... This study found TNK to exhibit a similar mortality rate to alteplase in the treatment of PE with hemodynamic instability.

8. activase.com activase.com/safety.html

Important Safety Information | Activase® (Alteplase) Activase can cause significant, sometimes fatal internal or external bleeding, especially at arterial and venous puncture sites.