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

Primary Purpose

Massive Pulmonary Embolism

Status
Completed
Phase
Phase 3
Locations
Russian Federation
Study Type
Interventional
Intervention
Recombinant nonimmunogenic staphylokinase
Alteplase
Sponsored by
Supergene, LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Massive Pulmonary Embolism focused on measuring Massive pulmonary embolism, Fibrinolysis, Recombinant Non-immunogenic Staphylokinase

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • V.F. Dolgopolov Vyselki Central District Hospital
  • Sergiyev Posad Regional Clinical Hospital
  • Belgorod Regional Clinical Hospital of St. Joseph
  • Kuzbass Cardiology center
  • Krasnoyarsk Regional Clinical Hospital
  • Kursk Regional Clinical Hospital
  • D.D. Pletnev City Clinical Hospital
  • I.V. Davydovskii City Clinical Hospital
  • S.S. Yudin City Clinical Hospital
  • V.V. Vinogradov City Clinical Hospital
  • V.V. Veresaev City Clinical Hospital
  • N.V. Sklifosovsky Research Institute for Emergency Medicine
  • S.P. Botkin City Clinical Hospital
  • Murmansk Regional Clinical Hospital
  • N.N. Burdenko Penza Regional Clinical hospital
  • G.A. Zakharyin Clinical hospital №6
  • Saint Petersburg "Mariinskaya" City Hospital
  • Holy Martyr Elizabeth Saint Petersburg City Hospital
  • V.P. Polyakov Samara Regional Clinical Cardiology Dispensary
  • Saratov Regional Clinical Cardiology Dispensary
  • Tver Regional Clinical Hospital
  • City Clinical hospital №4
  • City Clinical Hospital of Emergency №25

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Recombinant nonimmunogenic staphylokinase

Alteplase

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Death from all causes
The efficacy is evaluated in terms of the number of deaths from all causes

Secondary Outcome Measures

Systolic pulmonary artery pressure measures (V1, V2, V4, V5)
The efficacy is evaluated in terms of systolic pulmonary artery pressure values
Hemodynamic collapse
The efficacy is evaluated in terms of the number of hemodynamic collapse
Recurrent PE
The efficacy is evaluated in terms of the number of recurrent PE
Death from PE
The efficacy is evaluated in terms of the number of deaths from PE
Death from all causes
The efficacy is evaluated in terms of the number of deaths from all causes
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
Safety endpoint - ischemic and hemorrhagic stroke
The safety is evaluated in terms of the number of ischemic and hemorrhagic stroke
Safety endpoint - BARC type 3 and 5 bleeding
The safety is evaluated in terms of the number of BARC type 3 and 5 bleeding
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

Full Information

First Posted
December 18, 2020
Last Updated
August 2, 2023
Sponsor
Supergene, LLC
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1. Study Identification

Unique Protocol Identification Number
NCT04688320
Brief Title
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

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Completed
Study Start Date
December 15, 2020 (Actual)
Primary Completion Date
July 27, 2023 (Actual)
Study Completion Date
July 27, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Supergene, LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Massive Pulmonary Embolism
Keywords
Massive pulmonary embolism, Fibrinolysis, Recombinant Non-immunogenic Staphylokinase

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
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)
Masking Description
All eligible patients will be randomized in two equal groups for administration recombinant nonimmunogenic staphylokinase (Fortelyzin) or alteplase (Actilize) by using "envelope method" of randomization.
Allocation
Randomized
Enrollment
310 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Recombinant nonimmunogenic staphylokinase
Arm Type
Experimental
Arm Description
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.
Arm Title
Alteplase
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Recombinant nonimmunogenic staphylokinase
Other Intervention Name(s)
Fortelyzin
Intervention Description
15 mg of drug reconstituted in 10 ml of 0.9% solution of NaCl given as single i.v. bolus over 10-15 seconds
Intervention Type
Drug
Intervention Name(s)
Alteplase
Other Intervention Name(s)
Actillyze
Intervention Description
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.
Primary Outcome Measure Information:
Title
Death from all causes
Description
The efficacy is evaluated in terms of the number of deaths from all causes
Time Frame
within 7 days
Secondary Outcome Measure Information:
Title
Systolic pulmonary artery pressure measures (V1, V2, V4, V5)
Description
The efficacy is evaluated in terms of systolic pulmonary artery pressure values
Time Frame
days 1, 2, 7, 14
Title
Hemodynamic collapse
Description
The efficacy is evaluated in terms of the number of hemodynamic collapse
Time Frame
within 7 days
Title
Recurrent PE
Description
The efficacy is evaluated in terms of the number of recurrent PE
Time Frame
within 7 days
Title
Death from PE
Description
The efficacy is evaluated in terms of the number of deaths from PE
Time Frame
within 30 days
Title
Death from all causes
Description
The efficacy is evaluated in terms of the number of deaths from all causes
Time Frame
within 30 days
Title
Hemodynamic collapse within 7 days + recurrent PE within 7 days + death from PE within 30 days
Description
The efficacy is evaluated in terms of the number of hemodynamic collapse + recurrent PE + deaths from PE
Time Frame
within 30 days
Title
Safety endpoint - ischemic and hemorrhagic stroke
Description
The safety is evaluated in terms of the number of ischemic and hemorrhagic stroke
Time Frame
within 7 days
Title
Safety endpoint - BARC type 3 and 5 bleeding
Description
The safety is evaluated in terms of the number of BARC type 3 and 5 bleeding
Time Frame
within 30 days
Title
Safety endpoint - Number and severity of serious adverse events (SAEs) and AEs in organs and systems
Description
The safety is evaluated in terms of the number and severity of SAEs and AEs in organs and systems
Time Frame
within 30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alexander I Kirienko, MD, PhD
Organizational Affiliation
Pirogov Russian National Research Medical University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sergey S Markin, MD, PhD
Organizational Affiliation
Supergene, LLC
Official's Role
Study Director
Facility Information:
Facility Name
V.F. Dolgopolov Vyselki Central District Hospital
City
Vyselki
State/Province
Krasnodar Region
ZIP/Postal Code
353100
Country
Russian Federation
Facility Name
Sergiyev Posad Regional Clinical Hospital
City
Sergiyev Posad
State/Province
Moscow Region
ZIP/Postal Code
141301
Country
Russian Federation
Facility Name
Belgorod Regional Clinical Hospital of St. Joseph
City
Belgorod
ZIP/Postal Code
308007
Country
Russian Federation
Facility Name
Kuzbass Cardiology center
City
Kemerovo
ZIP/Postal Code
650002
Country
Russian Federation
Facility Name
Krasnoyarsk Regional Clinical Hospital
City
Krasnoyarsk
ZIP/Postal Code
660022
Country
Russian Federation
Facility Name
Kursk Regional Clinical Hospital
City
Kursk
ZIP/Postal Code
305007
Country
Russian Federation
Facility Name
D.D. Pletnev City Clinical Hospital
City
Moscow
ZIP/Postal Code
105077
Country
Russian Federation
Facility Name
I.V. Davydovskii City Clinical Hospital
City
Moscow
ZIP/Postal Code
109240
Country
Russian Federation
Facility Name
S.S. Yudin City Clinical Hospital
City
Moscow
ZIP/Postal Code
115446
Country
Russian Federation
Facility Name
V.V. Vinogradov City Clinical Hospital
City
Moscow
ZIP/Postal Code
117292
Country
Russian Federation
Facility Name
V.V. Veresaev City Clinical Hospital
City
Moscow
ZIP/Postal Code
127644
Country
Russian Federation
Facility Name
N.V. Sklifosovsky Research Institute for Emergency Medicine
City
Moscow
ZIP/Postal Code
129090
Country
Russian Federation
Facility Name
S.P. Botkin City Clinical Hospital
City
Moscow
Country
Russian Federation
Facility Name
Murmansk Regional Clinical Hospital
City
Murmansk
ZIP/Postal Code
183047
Country
Russian Federation
Facility Name
N.N. Burdenko Penza Regional Clinical hospital
City
Penza
ZIP/Postal Code
440026
Country
Russian Federation
Facility Name
G.A. Zakharyin Clinical hospital №6
City
Penza
ZIP/Postal Code
440071
Country
Russian Federation
Facility Name
Saint Petersburg "Mariinskaya" City Hospital
City
Saint Petersburg
ZIP/Postal Code
191014
Country
Russian Federation
Facility Name
Holy Martyr Elizabeth Saint Petersburg City Hospital
City
Saint Petersburg
ZIP/Postal Code
195257
Country
Russian Federation
Facility Name
V.P. Polyakov Samara Regional Clinical Cardiology Dispensary
City
Samara
ZIP/Postal Code
443070
Country
Russian Federation
Facility Name
Saratov Regional Clinical Cardiology Dispensary
City
Saratov
ZIP/Postal Code
410039
Country
Russian Federation
Facility Name
Tver Regional Clinical Hospital
City
Tver
ZIP/Postal Code
170036
Country
Russian Federation
Facility Name
City Clinical hospital №4
City
Vladimir
ZIP/Postal Code
600009
Country
Russian Federation
Facility Name
City Clinical Hospital of Emergency №25
City
Volgograd
ZIP/Postal Code
400138
Country
Russian Federation

12. IPD Sharing Statement

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

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