Ischemic Stroke
Conditions
Keywords
Acute Ischemic Stroke, Fibrinolysis, Fortelyzin
Brief summary
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
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
Interventions
10 mg of drug reconstituted in 10 ml of 0.9% solution of NaCl given as single i.v. bolus over 5 - 10 seconds
DRUGAlteplase
Intravenous alteplase 0.9 mg/kg (10% bolus and 90% as IV infusion over 1 hour, maximum 90 mg)
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 (Actilyse) by using envelope method of randomization.
Intervention 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
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Good Functional Recovery | within 90 days after fibrinolysis | The number of patients with Modified Rankin Scale (mRS) scores 0-1 on day 90 after drug administration, where 0 - No symptoms, 1 - No significant disability. All scale is 0 - No symptoms, 1 - No significant disability, 2 - Slight disability, 3 - Moderate disability, 4 - Moderately severe disability, 5 - Severe disability, 6 - Dead. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Median of NIHSS After 24 Hours | after 24 hours | The median of The National Institutes of Health Stroke Scale (NIHSS) at 24 h after drug administration, where: 0 - No stroke symptoms, 1-4 - Minor stroke, 5-15 - Moderate stroke, 16-20 - Moderate to severe stroke, 21-42 - Severe stroke. |
| The Median of NIHSS After 90 Days | within 90 days after fibrinolysis | The median of The National Institutes of Health Stroke Scale (NIHSS) after 90 days of drug administration, where: 0 - No stroke symptoms, 1-4 - Minor stroke, 5-15 - Moderate stroke, 16-20 - Moderate to severe stroke, 21-42 - Severe stroke. |
| The Number of Patients With Modified Rankin Scale (0-1) + NIHSS (0-1) + Barthel (95-100) | within 90 days after fibrinolysis | Composite endpoint, included the number of patients reached Modified Rankin scale 0-1 score, NIHSS 0-1 score and Barthel index 95-100. Modified Rankin scale: 0 - No symptoms, 1 - No significant disability, 2 - Slight disability, 3 - Moderate disability, 4 - Moderately severe disability, 5 - Severe disability, 6 - Dead. The National Institutes of Health Stroke Scale (NIHSS): 0 - No stroke symptoms, 1-4 - Minor stroke, 5-15 - Moderate stroke, 16-20 - Moderate to severe stroke, 21-42 - Severe stroke. Barthel index: 80-100 - Independent, 60-79 - Minimally dependent, 40-59 - Partially dependent, 20-39 - Very dependent, \<20 - Totally dependent. |
| Intracranial Haemorrhage | within 90 days after fibrinolysis | The number of intracranial hemorrhage (events) |
| Symptomatic Intracranial Haemorrhage | within 90 days after fibrinolysis | The number of symptomatic intracranial haemorrhage according to ECASS III definition (events). The ECASS III definition of symptomatic intracranial haemorrhage was any haemorrhage with neurologic deterioration, as indicated by an NIHSS score that was higher by 4 points or more than the value at baseline or the lowest value in the first 7 days, or any haemorrhage leading to death. In addition, the haemorrhage must have been identified as the predominant cause of the neurologic deterioration. |
| All Cause Death | within 90 days after fibrinolysis | Death caused by any event |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Recombinant Staphylokinase 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
Recombinant staphylokinase: 10 mg of drug reconstituted in 10 ml of 0.9% solution of NaCl given as single i.v. bolus over 5 - 10 seconds | 168 |
| Actilyse Intravenous alteplase 0.9 mg/kg (10% bolus and 90% as IV infusion over 1 hour, maximum 90 mg)
Alteplase: Intravenous alteplase 0.9 mg/kg (10% bolus and 90% as IV infusion over 1 hour, maximum 90 mg) | 168 |
| Total | 336 |
Baseline characteristics
| Characteristic | Recombinant Staphylokinase | Actilyse | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 84 Participants | 88 Participants | 172 Participants |
| Age, Categorical Between 18 and 65 years | 84 Participants | 80 Participants | 164 Participants |
| Age, Continuous | 64.4 years STANDARD_DEVIATION 9.6 | 64.6 years STANDARD_DEVIATION 10.6 | 64.5 years STANDARD_DEVIATION 10.1 |
| Baseline mRS score | 4 score | 4 score | 4 score |
| Baseline NIHSS score | 11 score | 11 score | 11 score |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Russia | 168 Participants | 168 Participants | 336 Participants |
| Sex: Female, Male Female | 106 Participants | 112 Participants | 218 Participants |
| Sex: Female, Male Male | 62 Participants | 56 Participants | 118 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 17 / 168 | 24 / 168 |
| other Total, other adverse events | 7 / 168 | 8 / 168 |
| serious Total, serious adverse events | 22 / 168 | 38 / 168 |
Outcome results
Primary
Good Functional Recovery
The number of patients with Modified Rankin Scale (mRS) scores 0-1 on day 90 after drug administration, where 0 - No symptoms, 1 - No significant disability. All scale is 0 - No symptoms, 1 - No significant disability, 2 - Slight disability, 3 - Moderate disability, 4 - Moderately severe disability, 5 - Severe disability, 6 - Dead.
Time frame: within 90 days after fibrinolysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Staphylokinase | Good Functional Recovery | 84 patients |
| Actilyse | Good Functional Recovery | 68 patients |
p-value: <0.0195% CI: [-1.7, 20.7]Welch's t-test
Secondary
All Cause Death
Death caused by any event
Time frame: within 90 days after fibrinolysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Staphylokinase | All Cause Death | 17 patients |
| Actilyse | All Cause Death | 24 patients |
Secondary
Intracranial Haemorrhage
The number of intracranial hemorrhage (events)
Time frame: within 90 days after fibrinolysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Staphylokinase | Intracranial Haemorrhage | 31 events |
| Actilyse | Intracranial Haemorrhage | 28 events |
Secondary
Symptomatic Intracranial Haemorrhage
The number of symptomatic intracranial haemorrhage according to ECASS III definition (events). The ECASS III definition of symptomatic intracranial haemorrhage was any haemorrhage with neurologic deterioration, as indicated by an NIHSS score that was higher by 4 points or more than the value at baseline or the lowest value in the first 7 days, or any haemorrhage leading to death. In addition, the haemorrhage must have been identified as the predominant cause of the neurologic deterioration.
Time frame: within 90 days after fibrinolysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Staphylokinase | Symptomatic Intracranial Haemorrhage | 5 events |
| Actilyse | Symptomatic Intracranial Haemorrhage | 13 events |
Secondary
The Median of NIHSS After 24 Hours
The median of The National Institutes of Health Stroke Scale (NIHSS) at 24 h after drug administration, where: 0 - No stroke symptoms, 1-4 - Minor stroke, 5-15 - Moderate stroke, 16-20 - Moderate to severe stroke, 21-42 - Severe stroke.
Time frame: after 24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recombinant Staphylokinase | The Median of NIHSS After 24 Hours | 6 score |
| Actilyse | The Median of NIHSS After 24 Hours | 6 score |
Secondary
The Median of NIHSS After 90 Days
The median of The National Institutes of Health Stroke Scale (NIHSS) after 90 days of drug administration, where: 0 - No stroke symptoms, 1-4 - Minor stroke, 5-15 - Moderate stroke, 16-20 - Moderate to severe stroke, 21-42 - Severe stroke.
Time frame: within 90 days after fibrinolysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recombinant Staphylokinase | The Median of NIHSS After 90 Days | 2 score |
| Actilyse | The Median of NIHSS After 90 Days | 2 score |
Secondary
The Number of Patients With Modified Rankin Scale (0-1) + NIHSS (0-1) + Barthel (95-100)
Composite endpoint, included the number of patients reached Modified Rankin scale 0-1 score, NIHSS 0-1 score and Barthel index 95-100. Modified Rankin scale: 0 - No symptoms, 1 - No significant disability, 2 - Slight disability, 3 - Moderate disability, 4 - Moderately severe disability, 5 - Severe disability, 6 - Dead. The National Institutes of Health Stroke Scale (NIHSS): 0 - No stroke symptoms, 1-4 - Minor stroke, 5-15 - Moderate stroke, 16-20 - Moderate to severe stroke, 21-42 - Severe stroke. Barthel index: 80-100 - Independent, 60-79 - Minimally dependent, 40-59 - Partially dependent, 20-39 - Very dependent, \<20 - Totally dependent.
Time frame: within 90 days after fibrinolysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Staphylokinase | The Number of Patients With Modified Rankin Scale (0-1) + NIHSS (0-1) + Barthel (95-100) | 59 patients |
| Actilyse | The Number of Patients With Modified Rankin Scale (0-1) + NIHSS (0-1) + Barthel (95-100) | 52 patients |