Evaluation of Catheter-Directed Thrombolysis with Alteplase in Intermediate-High Risk Acute Pulmonary Embolism Patients

The primary objective of this multicentre, randomized trial is to investigate the clinical outcomes in patients with **intermediate-high risk acute pulmonary embolism** treated with catheter-directed thrombolysis (CDT) compared to standard anticoagulation therapy. The clinical relevance of this study lies in its potential to improve patient outcomes by evaluating a combined endpoint, which includes any death, pulmonary embolism (PE) recurrence, and cardiorespiratory decompensation.

Secondary objectives include:

• Investigating the efficacy of CDT compared to standard anticoagulation.
• Assessing adverse events, including major and minor bleeding complications.
• Evaluating the duration of intensive care unit and hospital length of stay.
• Analyzing hospitalization costs to determine cost-effectiveness.
• Assessing patients' functional status, performance, and quality of life.
• Evaluating the incidence of chronic thromboembolic pulmonary hypertension (CTEPH).

The clinical trial focuses on patients diagnosed with **intermediate-high risk acute pulmonary embolism**. The study population includes both male and female participants, aged between 18 and 80 years. Participants are required to have a computed tomography angiography (CTA)-verified proximal pulmonary embolism with symptom onset less than 14 days prior to enrollment. Additionally, they must present with intermediate-high risk pulmonary embolism, characterized by a simplified Pulmonary Embolism Severity Index (sPESI) score of 1 or higher, right ventricular dysfunction, and elevated biomarkers such as high-sensitivity troponin or NT-proBNP levels. The trial does not include vulnerable populations. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. Participants must provide signed informed consent to be included in the study.

The clinical trial is designed as a **randomized**, controlled study to evaluate the efficacy of catheter-directed thrombolysis in patients with **intermediate-high risk acute pulmonary embolism**. The trial employs a **double-blind** methodology to ensure unbiased results, with participants randomly assigned to either the treatment group receiving **alteplase** or a control group receiving standard anticoagulation therapy. The primary objective is to assess clinical outcomes, including all-cause mortality, recurrence of pulmonary embolism, and cardiorespiratory decompensation within seven days of randomization. Secondary endpoints include individual components of the primary endpoint, therapy failure, stroke incidence, and various measures of functional status and quality of life over a period extending up to 24 months.

The trial is expected to run until December 31, 2026, with recruitment having commenced on October 19, 2022. Participants will be involved in the study for a maximum of 24 months, with the possibility of early termination if they experience significant adverse events or fail to comply with the study protocol. The sequence of study visits begins with an inclusion visit, where eligibility is confirmed based on criteria such as age, computed tomography angiography-verified proximal pulmonary embolism, and specific risk factors. Follow-up visits are scheduled at various intervals, including 7 days, 30 days, 12 months, and 24 months, to monitor primary and secondary endpoints. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.

The clinical trial involves the administration of **ACTILYSE**, a pharmaceutical product containing the active substance **alteplase**. ACTILYSE is formulated as a **solution for injection/infusion** and is provided as a powder and solvent for reconstitution. The medication is administered via **infusion**. The maximum daily dose is 20 mg, with a total maximum dose of 20 mg over a treatment period of one day. The product is manufactured by Boehringer Ingelheim International GmbH and is not a pediatric formulation. The active substance, alteplase, is a protein of non-human origin, classified under the ATC code B01AD02.

In this trial, ACTILYSE is used as part of a catheter-directed thrombolysis (CDT) strategy for patients with intermediate-high risk acute pulmonary embolism. The study aims to compare the clinical outcomes of patients treated with CDT using ACTILYSE against those receiving standard anticoagulation therapy. The trial does not involve any orphan drug designation or pediatric formulations. Compliance with the dosing schedule is monitored to ensure adherence to the protocol.

Efficacy in the clinical trial titled "A Multicentre, Randomized Trial of Catheter-directed thrombolysis in intermediate-high risk acute pulmonary embolism (PRAGUE-26)" will be assessed using a combination of primary and secondary endpoints. The primary endpoints include all-cause mortality, **pulmonary embolism (PE)** recurrence, and cardiorespiratory decompensation or collapse, all measured within 7 days of randomization. Secondary endpoints encompass a range of clinical outcomes, such as the individual components of the primary endpoint assessed at 7 days, 30 days, and 12 months, as well as first-line therapy failure during hospitalization.

Additional secondary endpoints include ischemic or hemorrhagic stroke within 7 and 30 days, serious adverse events within 12 months, and various measures of hospitalization duration and cost-effectiveness within 30 days. Bleeding complications will be evaluated using the GUSTO and ISTH classifications within 30 days, and all bleeding complications will be scored by the Bleeding Academic Research Consortium (BARC) classification at 30 days and 12 months. Changes in echocardiographic parameters such as the RV-to-LV diameter ratio and systolic pulmonary artery pressure will be measured at multiple time points, including 24 hours post-randomization, 30 days, 12 months, and 24 months.

Functional status will be assessed using the World Health Organization (WHO) functional class at discharge, 30 days, 12 months, and 24 months, and the 6-Minute Walk Test (6MWT) at 12 and 24 months. Quality of life will be evaluated using the EQ-5D scale at 30 days, 12 months, and 24 months. The diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) will be assessed within 24 months. These efficacy parameters will be collected and analyzed according to the specified time frames to determine the clinical outcomes of catheter-directed thrombolysis compared to standard anticoagulation therapy in patients with intermediate-high risk acute pulmonary embolism.