Single Bolus Recombinant Nonimmunogenic Staphylokinase (F... | NCT03151993

Status Module

Description Module

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

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Recombinant staphylokinase	Experimental	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
Actilyse	Active Comparator	Intravenous alteplase 0.9 mg/kg (10% bolus and 90% as IV infusion over 1 hour, maximum 90 mg)	Drug: Alteplase

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Recombinant staphylokinase	Drug	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

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	within 90 days after fibrinolysis

Secondary Outcomes

Measure	Description	Time Frame
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.

Eligibility Module

Eligibility Criteria

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.

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

Facility	Status	City	State	ZIP	Country	Contacts
Regional Clinical Hospital		Barnaul		656024	Russia
St.Iosaf's Belgorod Regional Clinical Hospital

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
20598969	Background	Armstrong PW, Gershlick A, Goldstein P, Wilcox R, Danays T, Bluhmki E, Van de Werf F; STREAM Steering Committee. The Strategic Reperfusion Early After Myocardial Infarction (STREAM) study. Am Heart J. 2010 Jul;160(1):30-35.e1. doi: 10.1016/j.ahj.2010.04.007.
10220625	Background	Van de Werf F, Cannon CP, Luyten A, Houbracken K, McCabe CH, Berioli S, Bluhmki E, Sarelin H, Wang-Clow F, Fox NL, Braunwald E. Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: the ASSENT-1 trial. The ASSENT-1 Investigators. Am Heart J. 1999 May;137(5):786-91. doi: 10.1016/s0002-8703(99)70400-x.

Label	URL
Efficacy Guidelines. The work carried out by ICH under the Efficacy heading is concerned with the design, conduct, safety and reporting of clinical trials.	View source

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Jul 15, 2016

Arm/Group Information

ID	Title	Description
BG000	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
BG001	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)
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Categorical

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
	OG00084 OG00168

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Welch's t-test		<0.01		Odds Ratio (OR)	9.5			2-Sided	95	-1.7	20.7					Non-Inferiority	The non-inferiority hypothesis would be declared if the lower limit of the 95% CI for an mRS score of 0-1 on day 90 did not cross the margin of noninferiority of 16%. The non-inferiority hypothesis was tested using Welch's t-test for the primary outcome only.

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.

Posted

Number

patients

within 90 days after fibrinolysis

ID	Title	Description
OG000	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
OG001	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)

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.

Posted

Median

Inter-Quartile Range

score

after 24 hours

ID	Title	Description
OG000	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
OG001	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)

Units	Counts
Participants	OG000

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.

Posted

Median

Inter-Quartile Range

score

within 90 days after fibrinolysis

ID	Title	Description
OG000	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
OG001	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)

Units	Counts
Participants	OG000

Secondary

All Cause Death

Death caused by any event

Posted

Number

patients

within 90 days after fibrinolysis

ID	Title	Description
OG000	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
OG001	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)

Units	Counts
Participants	OG000

Secondary

Intracranial Haemorrhage

The number of intracranial hemorrhage (events)

Posted

Number

events

within 90 days after fibrinolysis

ID	Title	Description
OG000	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
OG001	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)

Units	Counts
Participants	OG000

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.

Posted

Number

events

within 90 days after fibrinolysis

ID	Title	Description
OG000	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
OG001	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)

Units	Counts

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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	17	168	22	168	7	168
EG001	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)	24	168	38	168	8	168

Serious Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Cerebral oedema	Nervous system disorders	Systematic Assessment	EG0007 events7 affected168 at risk EG00114 events14 affected168 at risk
Symptomatic intracranial haemorrhage	Nervous system disorders	Systematic Assessment	EG0005 events5 affected168 at risk EG00113 events13 affected168 at risk
Surgery	Nervous system disorders	Systematic Assessment	EG0005 events5 affected168 at risk EG0013 events3 affected168 at risk
Neurosurgery	Nervous system disorders	Systematic Assessment	EG0002 events2 affected168 at risk EG0011 events1 affected168 at risk
Acute myocardial infarction	Cardiac disorders	Systematic Assessment	EG0001 events1 affected168 at risk EG0011 events1 affected168 at risk
Pulmonary thromboembolism	Blood and lymphatic system disorders	Systematic Assessment	EG0001 events1 affected168 at risk EG0013 events3 affected168 at risk
New acute ischaemic stroke	Nervous system disorders	Systematic Assessment	EG0001 events1 affected168 at risk EG0010 events0 affected168 at risk
Gastric ulcer	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected168 at risk EG0012 events2 affected168 at risk
Takotsubo cardiomyopathy	Cardiac disorders	Systematic Assessment	EG0000 events0 affected168 at risk EG0011 events1 affected168 at risk

ID	Term
D020521	Stroke
D002561	Cerebrovascular Disorders
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D014652	Vascular Diseases
D002318	Cardiovascular Diseases

ID	Term
D012697	Serine Endopeptidases
D010450	Endopeptidases
D010447	Peptide Hydrolases
D006867	Hydrolases
D004798	Enzymes
D045762	Enzymes and Coenzymes
D057057	Serine Proteases
D010960	Plasminogen Activators
D001779	Blood Coagulation Factors
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D001685	Biological Factors