Massive Pulmonary Embolism: Trial of Non-immunogenic Recombinant Staphylokinase VS Alteplase FORPE

Study Overview
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Brief Summary
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Objective: to evaluate the efficacy and safety of the Recombinant Non-immunogenic Staphylokinase with its single bolus administration in comparison with the bolus-infusion administration of the Alteplase in patients with massive pulmonary embolism

Detailed Description
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The main goal of treating massive PE is to save the lives of patients by restoring pulmonary perfusion, preventing the development of chronic postembolic pulmonary hypertension and recurrent PE. According to data of clinical trials, with timely initiation of therapy for massive pulmonary embolism, mortality can be significantly reduced. Recombinant protein which contains aminoacid sequence of staphylokinase - Fortelizin® (the active substance is Forteplase). It is single chain molecula, consists of 138 aminoacids, weight 15.5 kDa. When staphylokinase is added to human plasma containing a fibrin clot, it preferentially reacts with plasmin at the clot surface, forming a plasmin-staphylokinase complex. This complex activates plasminogen trapped in the thrombus. The plasmin-staphylokinase complex and plasmin bound to fibrin are protected from inhibition by alpha2-antiplasmin. Once liberated from the clot (or generated in plasma), however, they are rapidly inhibited by alpha2-antiplasmin. This selectivity of action confines the process of plasminogen activation to the thrombus, preventing excessive plasmin generation, alpha2-antiplasmin depletion, and fibrinogen degradation in plasma. In rabbits anti forteplase antibodies are not produced. It was achieved by replacement of amino acids in immunogenic epitop of molecule staphylokinase. Blood fibrinogen decrease after i.v. injection of Fortelyzin less 10% within first 24 hours. Angiographic data suggests that restoration of coronary blood flow appears in up to 80% of patients with STEMI after i.v. injection of Fortelyzin. The main objectives of the study: to assess the efficacy, safety and possible adverse events of the drug Recombinant Non-immunogenic Staphylokinase with its single bolus administration in comparison with the bolus-infusion administration of the drug Alteplase® in patients with massive pulmonary embolism. Study Design. Multicenter, open-label, randomized, comparative clinical study of non-inferiority study of efficacy and safety in parallel groups. At clinical centers, patients will be equally randomly distributed by the envelope method into two groups of 155 patients each (310 people in total, including 10% of those who may have dropped out)to receive Recombinant Non-immunogenic Staphylokinase or Alteplase®. The drugs will be administered after the signed informed consent. Recombinant Non-immunogenic Staphylokinase will be administered intravenously at a dose of 15 mg as a single bolus for 10-15 seconds. Alteplase® will be administered in accordance with the instructions for use. Patients will be monitored for 30 days from the moment of randomization: in the intensive care unit up to 7 days, after it in the hospital until discharge - an average of 14 days and an outpatient visits on the 30th day. The recruitment of patients for the study will be competitive.

Official Title
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Multicenter, Open Label, Randomized Comparative Trial of the Efficacy and Safety of a Single Bolus Recombinant Non-immunogenic Staphylokinase and Bolus-infusion of Alteplase in Patients With Massive Pulmonary Embolism (FORPE)

Conditions
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Massive Pulmonary Embolism

Intervention / Treatment
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* Drug: Recombinant nonimmunogenic staphylokinase
* Drug: Alteplase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18 and over Verified diagnosis of massive PE (using MSCT with PA contrast) Signs of overload / dysfunction of the right ventricle (at least one) in combination with persistent arterial hypotension or shock Patient consent to use reliable contraceptive methods throughout the study and for 3 weeks after: women who have a negative pregnancy test and use the following contraceptives: intrauterine devices, oral contraceptives, contraceptive patch, prolonged injectable contraceptives, double barrier method of contraception. Women who are not fertile can also take part in the study (documented conditions: hysterectomy, tubal ligation, infertility, menopause for more than 1 year); men using barrier contraception. The study may also involve men who are not fertile (documented conditions: vasectomy, infertility) Availability of signed and dated informed consent of the patient to participate in the study. Exclusion Criteria: • Increased risk of bleeding: Extensive bleeding at present or within the previous 6 months, hemorrhagic diathesis; Intracranial (including subarachnoid) hemorrhage at present or in history, suspected hemorrhagic stroke; A history of hemorrhagic stroke or stroke of unknown etiology; Ischemic stroke or transient ischemic attack within the last 6 months, except for the current acute ischemic stroke within 4.5 hours; A history of diseases of the central nervous system (including neoplasms, aneurysms, surgery on the brain or spinal cord); Major surgery or major trauma within the previous 3 months, recent traumatic brain injury; Long-term or traumatic cardiopulmonary resuscitation (> 2 min), delivery within the previous 10 days, recent puncture of an uncompressible blood vessel (eg, subclavian or jugular vein); Severe liver disease, including liver failure, cirrhosis, portal hypertension (including esophageal varices) and active hepatitis; Confirmed gastric or duodenal ulcer within the last three months; Neoplasm with an increased risk of bleeding; Concurrent administration of oral anticoagulants, for example, warfarin with an INR> 1.3; Arterial aneurysms, developmental defects of arteries / veins; Severe uncontrolled arterial hypertension; Acute pancreatitis; Bacterial endocarditis, pericarditis; suspicion of aortic dissecting aneurysm; any other conditions, in the opinion of the doctor, associated with a high risk of bleeding. Lactation, pregnancy Known hypersensitivity to Alteplase, Fortelizin.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: At clinical centers, patients will be equally randomly distributed by the envelope method into two groups to receive Fortelizin® or Alteplase®. The drugs will be administered after the signed informed consent. Fortelizin® will be administered intravenously at a dose of 15 mg as a single bolus for 10-15 seconds. Alteplase® will be administered in accordance with the instructions for use. All patients will be examination for 30 days.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Recombinant nonimmunogenic staphylokinase<br>lyophilisate for preparation of a solution for intravenous administration, 5 mg (745,000 IU) complete with a solvent. 15 mg (2,235,000 IU) - 3 vials, intravenously as a quick single bolus injection for 10-15 seconds, regardless of body weight. | Drug: Recombinant nonimmunogenic staphylokinase<br>* 15 mg of drug reconstituted in 10 ml of 0.9% solution of NaCl given as single i.v. bolus over 10-15 seconds<br>* Other names: Fortelyzin;|
| Experimental: Alteplase<br>Alteplase® is administered in accordance with the instructions for use for pulmonary embolism( 10 mg bolus and 90 mg as IV infusion over 2 hours, maximum 100 mg). In patients weighing less than 65 kg, the total dose should not exceed 1.5 mg / kg. | Drug: Alteplase<br>* Alteplase® is administered in accordance with the instructions for use for pulmonary embolism ( 10 mg bolus and 90 mg as IV infusion over 2 hours, maximum 100 mg). In patients weighing less than 65 kg, the total dose should not exceed 1.5 mg / kg.<br>* Other names: Actillyze;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death from all causes | The efficacy is evaluated in terms of the number of deaths from all causes | within 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systolic pulmonary artery pressure measures (V1, V2, V4, V5) | The efficacy is evaluated in terms of systolic pulmonary artery pressure values | days 1, 2, 7, 14 | 
| Hemodynamic collapse | The efficacy is evaluated in terms of the number of hemodynamic collapse | within 7 days | 
| Recurrent PE | The efficacy is evaluated in terms of the number of recurrent PE | within 7 days | 
| Death from PE | The efficacy is evaluated in terms of the number of deaths from PE | within 30 days | 
| Death from all causes | The efficacy is evaluated in terms of the number of deaths from all causes | within 30 days | 
| Hemodynamic collapse within 7 days + recurrent PE within 7 days + death from PE within 30 days | The efficacy is evaluated in terms of the number of hemodynamic collapse + recurrent PE + deaths from PE | within 30 days | 
| Safety endpoint - ischemic and hemorrhagic stroke | The safety is evaluated in terms of the number of ischemic and hemorrhagic stroke | within 7 days | 
| Safety endpoint - BARC type 3 and 5 bleeding | The safety is evaluated in terms of the number of BARC type 3 and 5 bleeding | within 30 days | 
| Safety endpoint - Number and severity of serious adverse events (SAEs) and AEs in organs and systems | The safety is evaluated in terms of the number and severity of SAEs and AEs in organs and systems | within 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Massive pulmonary embolism, Fibrinolysis, Recombinant Non-immunogenic Staphylokinase