Clinical trial NCT04688320: Massive Pulmonary Embolism: Trial of Non-immunogenic Recombinant Staphylokinase VS Alteplase FORPE
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Massive Pulmonary Embolism
Keywords: Massive pulmonary embolism
Fibrinolysis
Recombinant Non-immunogenic Staphylokinase
Lead sponsor: Supergene, LLC
Sponsor class: INDUSTRY
First posted: 2020-12-29
Enrollment: 310
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Death From All Causes
timeFrame: within 7 days
Secondary outcomes:
measure: Systolic Pulmonary Artery Pressure Measures (V1, V2, V4, V5)
timeFrame: baseline and day 1, 7, 14 after randomisation
measure: Haemodynamic Collapse
timeFrame: within 7 days
measure: Recurrent Pulmonary Embolism (PE)
timeFrame: within 7 days
measure: Death From PE
timeFrame: within 30 days
measure: Death From All Causes
timeFrame: within 30 days
measure: Haemodynamic Collapse Within 7 Days + Recurrent PE Within 7 Days + Death From All Causes Within 30 Days
timeFrame: within 30 days
measure: Safety Endpoint - Haemorrhagic Stroke
timeFrame: within 7 days
measure: Safety Endpoint - BARC Type 3+5 Bleeding
timeFrame: within 30 days
measure: Safety Endpoint - Number and Severity of Serious Adverse Events (SAEs)
timeFrame: within 30 days
Other outcomes:
Locations:
city: Vyselki
country: Russian Federation
facility: V.F. Dolgopolov Vyselki Central District Hospital
state: Krasnodar Region
city: Sergiyev Posad
country: Russian Federation
facility: Sergiyev Posad Regional Clinical Hospital
state: Moscow Region
city: Belgorod
country: Russian Federation
facility: Belgorod Regional Clinical Hospital of St. Joseph
city: Kemerovo
country: Russian Federation
facility: Kuzbass Cardiology center
city: Krasnoyarsk
country: Russian Federation
facility: Krasnoyarsk Regional Clinical Hospital
city: Kursk
country: Russian Federation
facility: Kursk Regional Clinical Hospital
city: Moscow
country: Russian Federation
facility: D.D. Pletnev City Clinical Hospital
city: Moscow
country: Russian Federation
facility: I.V. Davydovskii City Clinical Hospital
city: Moscow
country: Russian Federation
facility: S.S. Yudin City Clinical Hospital
city: Moscow
country: Russian Federation
facility: V.V. Vinogradov City Clinical Hospital
city: Moscow
country: Russian Federation
facility: V.V. Veresaev City Clinical Hospital
city: Moscow
country: Russian Federation
facility: N.V. Sklifosovsky Research Institute for Emergency Medicine
city: Moscow
country: Russian Federation
facility: S.P. Botkin City Clinical Hospital
city: Murmansk
country: Russian Federation
facility: Murmansk Regional Clinical Hospital
city: Penza
country: Russian Federation
facility: N.N. Burdenko Penza Regional Clinical hospital
city: Penza
country: Russian Federation
facility: G.A. Zakharyin Clinical hospital №6
city: Saint Petersburg
country: Russian Federation
facility: Saint Petersburg "Mariinskaya" City Hospital
city: Saint Petersburg
country: Russian Federation
facility: Holy Martyr Elizabeth Saint Petersburg City Hospital
city: Samara
country: Russian Federation
facility: V.P. Polyakov Samara Regional Clinical Cardiology Dispensary
city: Saratov
country: Russian Federation
facility: Saratov Regional Clinical Cardiology Dispensary
city: Tver
country: Russian Federation
facility: Tver Regional Clinical Hospital
city: Vladimir
country: Russian Federation
facility: City Clinical hospital №4
city: Volgograd
country: Russian Federation
facility: City Clinical Hospital of Emergency №25
Study officials:
affiliation: Pirogov Russian National Research Medical University
name: Alexander I Kirienko, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Supergene, LLC
name: Sergey S Markin, MD, PhD
role: STUDY_DIRECTOR
References: