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

Sponsor

Supergene, LLC (Industry)

Overall Status

Completed

CT.gov ID

NCT03151993

Collaborator

(none)

336

Enrollment

Locations

Arms

27.1

Actual Duration (Months)

18.7

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Ischemic Stroke	Drug: Recombinant staphylokinase Drug: Alteplase	Phase 3

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

Study Design

Study Type:

Interventional

Actual Enrollment :

336 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

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 daysAll 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)

Masking Description:

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Mar 18, 2017

Actual Primary Completion Date :

Mar 23, 2019

Actual Study Completion Date :

Jun 20, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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	Drug: 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 Other Names: Fortelyzin
Active Comparator: Actilyse Intravenous alteplase 0.9 mg/kg (10% bolus and 90% as IV infusion over 1 hour, maximum 90 mg)	Drug: Alteplase Intravenous alteplase 0.9 mg/kg (10% bolus and 90% as IV infusion over 1 hour, maximum 90 mg) Other Names: Actilyse

Arm

Intervention/Treatment

Experimental: 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

Drug: 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

Other Names:

Fortelyzin

Active Comparator: Actilyse

Intravenous alteplase 0.9 mg/kg (10% bolus and 90% as IV infusion over 1 hour, maximum 90 mg)

Drug: Alteplase

Intravenous alteplase 0.9 mg/kg (10% bolus and 90% as IV infusion over 1 hour, maximum 90 mg)

Other Names:

Actilyse

Outcome Measures

Primary Outcome Measures

Good functional recovery [within 90 days after fibrinolysis]
Good functional recovery on the 90th day (modified Rankin scale, 0-1 point).

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Regional Clinical Hospital	Barnaul	Russian Federation	656024
2	St.Iosaf's Belgorod Regional Clinical Hospital	Belgorod	Russian Federation	308007
3	Regional Clinical Hospital №3	Chelyabinsk	Russian Federation	454021
4	Regional Clinical Hospital №1	Ekaterinburg	Russian Federation	620014
5	Regional Clinical Hospital	Irkutsk	Russian Federation	664079
6	Regional Clinical Hospital	Kaluga	Russian Federation	248007
7	Ochapowski Regional Hospital №1	Krasnodar	Russian Federation	350086
8	Regional Clinical Hospital	Kursk	Russian Federation	305007
9	Regional Clinical Hospital	Nizhny Novgorod	Russian Federation	603126
10	Regional Clinical Hospital	Orenburg	Russian Federation	460018
11	City Clinical Hospital №11	Ryazan'	Russian Federation	390000
12	Regional Clinical Hospital	Ryazan	Russian Federation	390039
13	Regional Clinical Hospital	Samara	Russian Federation	443095
14	Regional Clinical Hospital	Sankt-peterburg	Russian Federation	194291
15	Regional Clinical Hospital	Tver	Russian Federation	170036
16	Regional Clinical Hospital	Ulyanovsk	Russian Federation	432017
17	City Clinical Hospital of Emergency №25	Volgograd	Russian Federation	400138
18	Regional Clinical Hospital №1	Voronezh	Russian Federation	394066

Sponsors and Collaborators

Supergene, LLC

Investigators

Principal Investigator: Evgenii I Gusev, MD, PhD, Pirogov Russian National Research Medical University
Study Director: Sergey S Markin, MD, PhD, Supergene, LLC