Reduced-Dose Thrombolytic Therapy for Pulmonary Embolism

(PEITHO-3 Trial)

Recruiting at 96 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

650 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a smaller dose of a clot-busting drug combined with a blood thinner in patients with serious lung clots. The goal is to see if this approach is effective and safer than higher doses, reducing the risk of severe bleeding.

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.

What data supports the effectiveness of the drug alteplase for treating pulmonary embolism?

A study comparing alteplase with another drug, streptokinase, found that alteplase is a preferred choice for treating pulmonary embolism, despite similar overall effectiveness. Additionally, alteplase is already used effectively for other conditions like stroke and heart attacks, suggesting its potential benefit for pulmonary embolism. ^{1 2 3 4 5}

Is reduced-dose thrombolytic therapy with alteplase generally safe for humans?

Alteplase, also known as rt-PA, has been used for many years to treat conditions like stroke and heart attacks. It is considered safe, but like all medications, it can have side effects. ^{1 2 3 5 6}

How is the drug alteplase unique in treating pulmonary embolism?

Alteplase is unique for treating pulmonary embolism because it is used in a reduced-dose form, which may offer similar benefits with potentially fewer side effects compared to standard doses. It is a thrombolytic (clot-busting) drug that helps dissolve blood clots, and its use in low doses for pulmonary embolism is being evaluated for effectiveness and safety. ^{1 2 3 4 7}

Research Team

Olivier SANCHEZ, MD

Principal Investigator

Assistance Publique - Hôpitaux de Paris

Stavros Konstantinides, MD

Principal Investigator

University Medical Center Mainz

Eligibility Criteria

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.

I am 18 years old or older.

Signed informed consent form

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

References

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

Thrombolytic therapy for acute ischaemic stroke. [2019]

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

[Comparative efficacy of various thrombolytic agents in treatment of pulmonary embolism]. [2020]

3. United States 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. [2019]

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

Low-Dose Systemic Alteplase (tPA) for the Treatment of Pulmonary Embolism. [2022]

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

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

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

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

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

[Thrombolytic therapy in patients with pulmonary artery thromboembolism and deep vein thrombosis]. [2016]