Single Bolus Recombinant Nonimmunogenic Staphylokinase (Fortelyzin) and Bolus Infusion Alteplase in Patients With AIS

Study Overview
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Brief Summary
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The aim of the study is to determine if single-bolus recombinant nonimmunogenic staphylokinase is effective and save thrombolytic agent in patients with ischemic stroke in comparison to alteplase.

Detailed Description
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Experimental Drug Profile. The active substance of Fortelyzin is Forteplase. It's recombinant protein which contains aminoacid sequence of staphylokinase. 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. Main goals of the study are to prove an efficacy of the single-bolus intravenous injection of recombinant nonimmunogenic staphylokinase (Fortelyzin) in comparison with bolus infusion alteplase(Actilyse) in patients with ischemic stroke. To prove a safety and to assess possible adverse events in the single-bolus intravenous injection of recombinant nonimmunogenic staphylokinase (Fortelyzin) in comparison with bolus infusion alteplase (Actilyse) in patients with ischemic stroke. Study Design. All eligible patients will be randomized in two equal groups for administration recombinant nonimmunogenic staphylokinase (Fortelyzin) or alteplase (Actilyse) by using envelope method of randomization. It is an open-lable study. Each of agents will be administered no longer then 4,5 hours from symptoms onset. Comparative agent will be administered as prescribed in its instructions. All patients will be examination for 90 days

Official Title
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Multicenter Open Label Randomized Comparative Study of Efficacy and Safety of Single Bolus Injection of Recombinant Nonimmunogenic Staphylokinase (Fortelyzin) and Bolus Infusion Alteplase (Actilyse) in Patients With Acute Ischemic Stroke

Conditions
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Ischemic Stroke

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women between the ages of 18 and 80 (Version 1.0) Men and women aged 18 years and older, after 80 years with caution (Version 2.0) Verified diagnosis of ischemic stroke (from 5 to 25 points on the NIHSS scale). (Version 1.0) Verified diagnosis of ischemic stroke (Version 2.0) The time from the onset of the disease is no more than 4.5 hours. Informed consent received Exclusion Criteria: The time of the onset of the first symptoms is more than 4.5 hours from the onset of the disease or the time of the onset of the first symptoms of a stroke is not known (for example, the development of a stroke during sleep - the so-called night stroke). Increased sensitivity to alteplase, gentamicin (residual traces from the production process). Systolic blood pressure above 185 mm Hg. Art. Or diastolic blood pressure above 110 mm Hg. Art. Or the need for / in the administration of drugs to reduce blood pressure to these boundaries. Neuroimaging (CT, MRI) signs of intracranial hemorrhage, brain tumors, arteriovenous malformation, brain abscess, aneurysm of cerebral vessels. Surgery on the brain or spinal cord. Suspicion of subarachnoid hemorrhage. Signs of severe stroke: clinical signs (stroke scale NIH> 25), neuroimaging (according to CT of the brain and / or MRI of the brain in the DWI, the ischemia focuses on the territory of more than 1/3 of the CMA pool). Simultaneous reception of oral anticoagulants, for example, warfarin with INR> 1.3. The use of direct anticoagulants (heparin, heparinoids) in the preceding stroke of 48 h with APTT values above the norm. Prior stroke or severe head injury within 3 months. Significant regression of neurological symptoms during the observation of the patient.(Version 1.0) Light neurological symptoms (NIH <4 points). (Version 1.0) Significant regression of neurological symptoms during the observation of the patient before thrombolisis (Version 2.0) Hemorrhagic stroke or stroke, unspecified in history. Strokes of any genesis in the history of a patient with diabetes mellitus. Gastrointestinal bleeding or bleeding from the genitourinary system in the last 3 weeks. Confirmed exacerbations of gastric ulcer and duodenal ulcer during the last 3 months. Extensive bleeding now or within the previous 6 months. Severe liver disease, including liver failure, cirrhosis, portal hypertension (with varicose veins of the esophagus), active hepatitis. Acute pancreatitis. Bacterial endocarditis, pericarditis. Aneurysms of arteries, malformations of arteries and veins. Suspicion of exfoliating aortic aneurysm. Neoplasms with an increased risk of bleeding. Large operations or severe injuries within the last 14 days, minor surgery or invasive manipulation in the last 10 days. Puncture of uncompensated arteries and veins during the last 7 days. Prolonged or traumatic cardiopulmonary resuscitation (more than 2 min). Pregnancy, obstetrics, 10 days after birth. The number of platelets is less than 100,000 / μL. Blood glucose less than 2.7 mmol / l or more than 22.0 mmol / l. Hemorrhagic diathesis, including renal and hepatic insufficiency. Data on bleeding or acute trauma (fracture) at the time of examination. Seizures in the onset of the disease, if there is no certainty that the seizure is a clinical manifestation of ischemic stroke with a postictal residual deficiency.

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: All eligible patients will be randomized in two equal groups for administration recombinant nonimmunogenic staphylokinase (Fortelyzin) or alteplase (Actilyse) by using envelope method of randomization. It is an open-lable study. Each of agents will be administered no longer then 4,5 hours from symptoms onset. Comparative agent will be administered as prescribed in its instructions. All patients will be examination for 90 days
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Recombinant staphylokinase<br>Lyophilizate for solution making for intravenous injection, 5 mg (745000 ME). 10 mg of drug reconstituted in 10 ml of 0.9% solution of NaCl given as single i.v. bolus over 5 - 10 seconds | Drug: Recombinant staphylokinase<br>* 10 mg of drug reconstituted in 10 ml of 0.9% solution of NaCl given as single i.v. bolus over 5 - 10 seconds<br>* Other names: Fortelyzin;|
| Active Comparator: Actilyse<br>Intravenous alteplase 0.9 mg/kg (10% bolus and 90% as IV infusion over 1 hour, maximum 90 mg) | Drug: Alteplase<br>* Intravenous alteplase 0.9 mg/kg (10% bolus and 90% as IV infusion over 1 hour, maximum 90 mg)<br>* Other names: Actilyse;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Good functional recovery | Good functional recovery on the 90th day (modified Rankin scale, 0-1 point). | within 90 days after fibrinolysis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rankin scale (0-1) + NIHSS (0-1) + Barthel (95-100) | Composite endpoint | within 90 days after fibrinolysis | 
| NIHSS | NIHSS after 24 hours | after 24 hours | 
| NIHSS | NIHSS after 90 days | within 90 days after fibrinolysis | 
| All Cause Death | Death caused by any event | within 90 days after fibrinolysis | 
| Hemorrhagic transformation | Hemorrhagic transformation (all cases). | within 90 days after fibrinolysis | 
| Symptomatic hemorrhagic transformation | Increase in NIHSS index by 4 points or more or death | within 90 days after fibrinolysis | 
| Serious adverse reactions and adverse reactions | Serious adverse reactions and adverse reactions (all cases) | within 90 days after fibrinolysis | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Ischemic Stroke, Fibrinolysis, Fortelyzin