Evaluation of Reduced-Dose Alteplase in Intermediate-High-Risk Acute Pulmonary Embolism: A Randomized Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of reduced dose thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism at day 30. This is clinically relevant as it aims to determine whether a lower dose of thrombolytic treatment can effectively manage acute pulmonary embolism, potentially reducing the risk of adverse effects associated with higher doses.

Secondary objectives include:

• Assessing the **safety** of reduced dose thrombolytic therapy at day 30.
• Evaluating the net clinical benefit of the therapy at day 30.
• Determining the effect on overall mortality at 2 years.
• Assessing the impact on long-term mortality, functional impairment, residual right ventricular dysfunction, and chronic thromboembolic pulmonary hypertension at 2 years.
• Evaluating the effect on the utilization of health care resources at day 30 and day 180.

The clinical trial involves a total of **40 participants** diagnosed with **intermediate-high-risk acute pulmonary embolism**. The study population includes both male and female subjects aged **18 years or older**. Participants were selected based on specific inclusion criteria, such as having an objectively confirmed acute pulmonary embolism with symptoms occurring within two weeks prior to randomization, and an elevated risk of early death or hemodynamic collapse. The trial does not focus on a vulnerable population, and participants are required to have a general health status that allows for the assessment of reduced dose thrombolytic therapy efficacy. Lifestyle considerations such as diet and physical activity are not specified as part of the selection criteria. The trial aims to evaluate the treatment's effectiveness at day 30, with participants needing to provide informed consent and, in France, be insured under a social security system.

The clinical trial is designed to evaluate the efficacy of a reduced dose of thrombolytic therapy in patients with **intermediate-high-risk acute pulmonary embolism**. This is a Phase III, randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. The trial aims to assess the primary outcome, which is a composite of death from any cause, hemodynamic decompensation, or objectively confirmed recurrent pulmonary embolism at day 30. Secondary endpoints include fatal or GUSTO severe or life-threatening bleeding within 30 days, net clinical benefit, and all-cause mortality within 30 days.

The trial will involve the administration of **alteplase** as the active treatment, with a placebo serving as the control. The pharmaceutical form of the active treatment is a solution for injection/infusion, administered via intravenous use. The maximum daily and total dose of alteplase is 50 mg, with a maximum treatment period of one day. Participants will be randomly assigned to receive either the active treatment or placebo, ensuring the study's double-blind nature.

The trial is expected to run from August 4, 2021, to August 4, 2028. Participants will be involved in the study for a duration that includes initial screening, treatment, and follow-up visits. The inclusion visit will involve screening to confirm eligibility based on criteria such as age, confirmed acute pulmonary embolism, and elevated risk of early death or hemodynamic collapse. Follow-up visits will be scheduled to monitor the participants' health status and collect data on the primary and secondary endpoints. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any adverse events.

Participants may be terminated early from the study if they experience severe adverse events, withdraw consent, or if the investigator deems it necessary for their safety. The trial's design ensures rigorous monitoring and data collection to achieve its objectives while maintaining participant safety and scientific integrity.

The clinical trial involves the administration of **ACTILYSE**, a thrombolytic agent, as the experimental medication. **ACTILYSE** is presented in the pharmaceutical form of a powder and solvent for solution, intended for injection and infusion. The active substance in **ACTILYSE** is **alteplase**, a protein-based agent classified under the ATC code B01AD02. The medication is administered via the **intravenous route**. The maximum daily dose and total dose of **ACTILYSE** is 50 mg, with a treatment period limited to one day. The product is manufactured by Boehringer Ingelheim France S.A.S and is authorized for use in France under the marketing authorization number 34009 558 530 1 5.

The study also includes a **placebo** group, which receives a placebo version of **ACTILYSE**. The placebo is labeled as **ACTILYSE 50mg placebo**. The placebo is used to provide a comparator for evaluating the efficacy of the experimental treatment. The placebo does not contain any active substance and is not associated with a specific pharmaceutical form or route of administration. The inclusion of a placebo group is essential for maintaining the integrity of the randomized controlled trial design.

The efficacy of the reduced dose thrombolytic therapy in patients with acute intermediate-high-risk **pulmonary embolism** will be assessed at day 30. The primary efficacy endpoint is a composite outcome that includes death from any cause, hemodynamic decompensation, or objectively confirmed recurrent pulmonary embolism at day 30. Secondary efficacy endpoints include fatal or GUSTO severe or life-threatening bleeding within 30 days, net clinical benefit defined as the composite of the primary efficacy outcome and GUSTO severe or life-threatening bleeding within 30 days, and all-cause mortality within 30 days.