Massive Pulmonary Embolism
Conditions
Keywords
Massive pulmonary embolism, Fibrinolysis, Recombinant Non-immunogenic Staphylokinase
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.
Interventions
15 mg of drug reconstituted in 10 ml of 0.9% solution of NaCl given as single i.v. bolus over 10-15 seconds
DRUGAlteplase
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.
Sponsors
Supergene, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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.
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Death From All Causes | within 7 days | The efficacy is evaluated in terms of the number of deaths from all causes |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Haemodynamic Collapse | within 7 days | The efficacy is evaluated in terms of the number of haemodynamic collapse |
| Recurrent Pulmonary Embolism (PE) | within 7 days | The efficacy is evaluated in terms of the number of recurrent PE |
| Death From PE | within 30 days | The efficacy is evaluated in terms of the number of deaths from PE |
| Death From All Causes | within 30 days | The efficacy is evaluated in terms of the number of deaths from all causes |
| Systolic Pulmonary Artery Pressure Measures (V1, V2, V4, V5) | baseline and day 1, 7, 14 after randomisation | The efficacy is evaluated in terms of systolic pulmonary artery pressure values |
| Safety Endpoint - Haemorrhagic Stroke | within 7 days | The safety is evaluated in terms of the number of haemorrhagic stroke within 7 days of randomisation |
| Safety Endpoint - BARC Type 3+5 Bleeding | within 30 days | The safety is evaluated in terms of the number of BARC type 3+5 bleeding. Type 3a: overt bleeding plus a hemoglobin drop of 3 to 5 g/dL; any transfusion with overt bleeding. Type 3b: overt bleeding plus a hemoglobin drop of 5 g/dL; cardiac tamponade; bleeding requiring surgical intervention for control; bleeding requiring intravenous vasoactive agents. Type 3c: intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal); subcategories confirmed by autopsy or imaging, or lumbar puncture; intraocular bleed compromising vision. Type 5a: probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious. Type 5b: definite fatal bleeding; overt bleeding or autopsy, or imaging confirmation. |
| Safety Endpoint - Number and Severity of Serious Adverse Events (SAEs) | within 30 days | The safety is evaluated in terms of the number and severity of serious adverse events (SAEs) |
| Haemodynamic Collapse Within 7 Days + Recurrent PE Within 7 Days + Death From All Causes Within 30 Days | within 30 days | The efficacy is evaluated in terms of the number of haemodynamic collapse + recurrent PE + deaths from all causes |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Recombinant Nonimmunogenic Staphylokinase 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.
Recombinant nonimmunogenic staphylokinase: 15 mg of drug reconstituted in 10 ml of 0.9% solution of NaCl given as single i.v. bolus over 10-15 seconds | 155 |
| Alteplase 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.
Alteplase: 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. | 155 |
| Total | 310 |
Baseline characteristics
| Characteristic | Total | Recombinant Nonimmunogenic Staphylokinase | Alteplase |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 141 Participants | 80 Participants | 61 Participants |
| Age, Categorical Between 18 and 65 years | 169 Participants | 75 Participants | 94 Participants |
| Age, Continuous | 63 years STANDARD_DEVIATION 13 | 64 years STANDARD_DEVIATION 13 | 62 years STANDARD_DEVIATION 13 |
| Baseline diastolic blood pressure | 60 mm Hg | 60 mm Hg | 60 mm Hg |
| Baseline heart rate | 110 beats per min | 110 beats per min | 110 beats per min |
| Baseline respiratory rate | 24 breaths per min | 24 breaths per min | 24 breaths per min |
| Baseline SpO2 | 89 % | 89 % | 89 % |
| Baseline systolic blood pressure | 90 mm Hg | 90 mm Hg | 90 mm Hg |
| Body mass index, kg/m^2 | 32 kg/m^2 STANDARD_DEVIATION 6 | 32 kg/m^2 STANDARD_DEVIATION 6 | 31 kg/m^2 STANDARD_DEVIATION 6 |
| Onset to treatment time | 22 h | 27 h | 17.1 h |
| PESI class V patients | 185 Participants | 103 Participants | 82 Participants |
| Pulmonary Embolism Severity Index (PESI) score | 132 score | 135 score | 128 score |
| Qanadli index | 66.2 % of pulmonary artery obstruction STANDARD_DEVIATION 19.8 | 65.8 % of pulmonary artery obstruction STANDARD_DEVIATION 19.8 | 67.8 % of pulmonary artery obstruction STANDARD_DEVIATION 19.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 310 Participants | 155 Participants | 155 Participants |
| Region of Enrollment Russia | 310 participants | 155 participants | 155 participants |
| Right ventricle end-diastolic diameter | 50 mm | 50 mm | 50 mm |
| Right ventricular/lLeft ventricular end-diastolic diameter | 1.40 ratio | 1.39 ratio | 1.40 ratio |
| Sex: Female, Male Female | 158 Participants | 84 Participants | 74 Participants |
| Sex: Female, Male Male | 152 Participants | 71 Participants | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 145 | 4 / 146 |
| other Total, other adverse events | 72 / 155 | 86 / 155 |
| serious Total, serious adverse events | 9 / 145 | 17 / 146 |
Outcome results
Primary
Death From All Causes
The efficacy is evaluated in terms of the number of deaths from all causes
Time frame: within 7 days
Population: in the per-protocol population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Recombinant Nonimmunogenic Staphylokinase | Death From All Causes | 3 Participants |
| Alteplase | Death From All Causes | 4 Participants |
p-value: <0.0595% CI: [0.11, 4.52]Welch's t-test
Secondary
Death From All Causes
The efficacy is evaluated in terms of the number of deaths from all causes
Time frame: within 30 days
Population: The efficacy is evaluated in terms of the number of deaths from all causes in the per-protocol population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Recombinant Nonimmunogenic Staphylokinase | Death From All Causes | 6 Participants |
| Alteplase | Death From All Causes | 4 Participants |
Secondary
Death From PE
The efficacy is evaluated in terms of the number of deaths from PE
Time frame: within 30 days
Population: The efficacy is evaluated in terms of the number of deaths from PE in the per-protocol population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Recombinant Nonimmunogenic Staphylokinase | Death From PE | 4 Participants |
| Alteplase | Death From PE | 2 Participants |
Secondary
Haemodynamic Collapse
The efficacy is evaluated in terms of the number of haemodynamic collapse
Time frame: within 7 days
Population: The efficacy is evaluated in terms of the number of haemodynamic collapse in the per-protocol population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Nonimmunogenic Staphylokinase | Haemodynamic Collapse | 1 events |
| Alteplase | Haemodynamic Collapse | 3 events |
Secondary
Haemodynamic Collapse Within 7 Days + Recurrent PE Within 7 Days + Death From All Causes Within 30 Days
The efficacy is evaluated in terms of the number of haemodynamic collapse + recurrent PE + deaths from all causes
Time frame: within 30 days
Population: The efficacy is evaluated in terms of the number of haemodynamic collapse + recurrent PE + deaths from all causes within 30 days in the per-protocol population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Nonimmunogenic Staphylokinase | Haemodynamic Collapse Within 7 Days + Recurrent PE Within 7 Days + Death From All Causes Within 30 Days | 8 events |
| Alteplase | Haemodynamic Collapse Within 7 Days + Recurrent PE Within 7 Days + Death From All Causes Within 30 Days | 9 events |
Secondary
Recurrent Pulmonary Embolism (PE)
The efficacy is evaluated in terms of the number of recurrent PE
Time frame: within 7 days
Population: The efficacy is evaluated in terms of the number of recurrent PE in the per-protocol population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Nonimmunogenic Staphylokinase | Recurrent Pulmonary Embolism (PE) | 1 events |
| Alteplase | Recurrent Pulmonary Embolism (PE) | 2 events |
Secondary
Safety Endpoint - BARC Type 3+5 Bleeding
The safety is evaluated in terms of the number of BARC type 3+5 bleeding. Type 3a: overt bleeding plus a hemoglobin drop of 3 to 5 g/dL; any transfusion with overt bleeding. Type 3b: overt bleeding plus a hemoglobin drop of 5 g/dL; cardiac tamponade; bleeding requiring surgical intervention for control; bleeding requiring intravenous vasoactive agents. Type 3c: intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal); subcategories confirmed by autopsy or imaging, or lumbar puncture; intraocular bleed compromising vision. Type 5a: probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious. Type 5b: definite fatal bleeding; overt bleeding or autopsy, or imaging confirmation.
Time frame: within 30 days
Population: The safety is evaluated in terms of the number of BARC type 3+5 bleeding within 30 days in the per-protocol population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Nonimmunogenic Staphylokinase | Safety Endpoint - BARC Type 3+5 Bleeding | 0 events |
| Alteplase | Safety Endpoint - BARC Type 3+5 Bleeding | 5 events |
Secondary
Safety Endpoint - Haemorrhagic Stroke
The safety is evaluated in terms of the number of haemorrhagic stroke within 7 days of randomisation
Time frame: within 7 days
Population: The safety is evaluated in terms of the number of haemorrhagic stroke within 7 days of randomisation in the per-protocol population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Nonimmunogenic Staphylokinase | Safety Endpoint - Haemorrhagic Stroke | 0 events |
| Alteplase | Safety Endpoint - Haemorrhagic Stroke | 3 events |
Secondary
Safety Endpoint - Number and Severity of Serious Adverse Events (SAEs)
The safety is evaluated in terms of the number and severity of serious adverse events (SAEs)
Time frame: within 30 days
Population: The safety is evaluated in terms of the number and severity of serious adverse events (SAEs) in the per-protocol population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Nonimmunogenic Staphylokinase | Safety Endpoint - Number and Severity of Serious Adverse Events (SAEs) | 9 events |
| Alteplase | Safety Endpoint - Number and Severity of Serious Adverse Events (SAEs) | 17 events |
Secondary
Systolic Pulmonary Artery Pressure Measures (V1, V2, V4, V5)
The efficacy is evaluated in terms of systolic pulmonary artery pressure values
Time frame: baseline and day 1, 7, 14 after randomisation
Population: The efficacy is evaluated in terms of decreasing of pulmonary artery systolic pressure (PASP) values on baseline and day 1, 7, 14 after randomisation in the per-protocol population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Recombinant Nonimmunogenic Staphylokinase | Systolic Pulmonary Artery Pressure Measures (V1, V2, V4, V5) | PASP on day 7 | 36 mm Hg |
| Recombinant Nonimmunogenic Staphylokinase | Systolic Pulmonary Artery Pressure Measures (V1, V2, V4, V5) | PASP on baseline | 59 mm Hg |
| Recombinant Nonimmunogenic Staphylokinase | Systolic Pulmonary Artery Pressure Measures (V1, V2, V4, V5) | PASP on day 14 | 35 mm Hg |
| Recombinant Nonimmunogenic Staphylokinase | Systolic Pulmonary Artery Pressure Measures (V1, V2, V4, V5) | PASP on day 1 | 44 mm Hg |
| Alteplase | Systolic Pulmonary Artery Pressure Measures (V1, V2, V4, V5) | PASP on day 14 | 35 mm Hg |
| Alteplase | Systolic Pulmonary Artery Pressure Measures (V1, V2, V4, V5) | PASP on day 7 | 35 mm Hg |
| Alteplase | Systolic Pulmonary Artery Pressure Measures (V1, V2, V4, V5) | PASP on day 1 | 42 mm Hg |
| Alteplase | Systolic Pulmonary Artery Pressure Measures (V1, V2, V4, V5) | PASP on baseline | 58 mm Hg |