FORMAT-1: Single Bolus Recombinant Nonimmunogenic Staphylokinase (FORtelyzin) Versus Single Bolus Tenecteplase (Metalyse) in STEMI

Sponsor

Supergene, LLC (Industry)

Overall Status

Unknown status

CT.gov ID

NCT02301910

Collaborator

(none)

392

Enrollment

Locations

Arms

Duration (Months)

24.5

Patients Per Site

0.9

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 presenting ST-segment elevation myocardial infarction in comparison to tenecteplase.

Condition or Disease	Intervention/Treatment	Phase
Myocardial Infarction	Drug: Recombinant staphylokinase Drug: Tenecteplase	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.

Risk/benifit for trail participants. Expected benefit is normalisation of blood supply of ischemic myocardium. It will allow to preserve normal heart function and avoid heart failure development. The most frequent advers reactions of Fortelyzin are possibilty of bleeding. It is possible occurence of internal bleeding due to peptic ulcer, erosion of the esophagus, haemorrhoid, veins of esophagus and so on. Thorough collection of patients data and following the drug instruction allows to dicrease risk of bleeding. The benefit of using fibrinolytics for patients with STEMI is supposed to be higher then risk of bleeding. The reperfusion arrhythmias may occur so the careful ECG monitiring is required.

Main goals of the study

to prove an efficacy of the single-bolus intravenous injection of recombinant nonimmunogenic staphylokinase (Fortelyzin) in comparison with single-bolus tenecteplase (Metalyse) in patients with ST-segment elevation myocardial infarction
to prove a safety and to assess possible adverse events in the single-bolus intravenous injection of recombinant nonimmunogenic staphylokinase (Fortelyzin) in comparison with single-bolus tenecteplase (Metalyse) in patients with ST-segment elevation myocardial infarction

Study Design. All eligible patients will be randomized in two equal groups for administration recombinant nonimmunogenic staphylokinase (Fortelyzin) or tenecteplase (Metalyse) by using "envelope method" of randomization. It is an open-lable study. Each of agents will be administered no longer then 12 hours from symptoms onset. Experimental and comparative agent will be administered as prescribed in its instructions.

All randomized patients will receive double anti-platelet therapy and anticoagulant therapy:

Enoxaparin < 75 years:

30 mg intravenous bolus
Subcutaneous injections of 1.0 mg/kg every 12 hours until hospital discharge or for a maximum of 4 days; the first injection should be given within 15 min of the bolus
For the first two subcutaneous injections, a maximum of 100 mg per injection should not be exceeded

≥ 75 years:

No bolus; Subcutaneous injections of 0.75 mg/kg every 12 hours until hospital discharge or for a maximum of 4 days; the first injection should be given immediately.
For the first two subcutaneous injections, a maximum of 75 mg per injection should not be exceeded.

For patients of any age with a creatinine clearance < 30 ml/min, subcutaneous injections of 1.0 mg/kg will be given in intervals of 24 hours.

Clopidogrel < 75 years: - 300 mg per os loading dose

75 mg per os once daily as maintenance dose

≥ 75 years: - No loading dose; 75 mg per os immediately after randomization

75 mg per os once daily (maintenance dose)

Acetylsalicylic acid is expected to be administered routinely to all patients at a dose of 250 mg per os before fibrinolysis and then 75 - 325 mg per os once daily.

Patients who received enoxaparin in the pre-hospital setting should not be administered a different type of heparin prior to catheterisation (and vice versa). If heparin was used in the pre-hospital setting or early in-hospital period, subsequent treatment should not be switched to enoxaparin prior to catheterisation. Prior to catheterisation a dose of 0.3 mg/kg intravenous enoxaparin should be given to patients unless the last subcutaneous dose of enoxaparin was given within the previous 8 hrs.

Catheterisation

If ST-segment resolution is ≥ 50 % in the qualifying lead (that had the maximum initial ST-segment elevation in the baseline ECG) in 90 min, diagnostic coronary angiography (followed by PCI +/- stenting, if indicated) should be performed within 3-24 hours after administration of fibrinolytic agent. This will be considered as planned catheterisation according to protocol
If ST-segment resolution is < 50 % relative to the ST-segment elevation in the qualifying lead at baseline, irrespective of the presence or absence of clinical symptoms, rescue coronary intervention should be performed promptly.
If any of the following indications require coronary intervention (irrespective of previous ST-segment resolution), urgent coronary intervention is indicated at any time:
haemodynamic instability (presence of any of the following requiring inotropic support: sustained hypotension, cardiogenic shock, or congestive heart failure)
refractory ventricular arrhythmias requiring cardioversion or pharmacological treatment
worsening ischaemia
progressive or sustained ST-segment elevation which, in the judgement of the investigator, requires immediate coronary intervention.

Duration of follow-up will be 30 days since randomization

Observation plan There are six visits in clinical trail schedule.

First. In admission to the clinical center but no longer then 12 hour of symptoms onset:

if the patient meet inclusion criteria and does not meet exclusion criteria the patient informed consent will be sign according to the protocol
evaluation of medical history and physical examination
12-lead ECG - confirmation of STEMI
blood analysis (include troponin, CK-MB, INR, APPT, fibrinogen)
urine analisis
correction of therapy (double anti-platelet therapy, enoxaparin)
randomization
intravenous injection of Fortelyzin or Metalyse according to instruction
ECG criteria of reperfusion assessment (90 min)
PCI within 3-24 hours after fibrinolysis

Second (24 hours), Third (72 hours), Fourth (7 days), Fifth (14 days or discharge)

physical examination
12-lead ECG
blood analysis (include troponin, CK-MB, INR, APPT, fibrinogen)
urine analysis
correction of the therapy if nececcary
monitoring of adverse events and bleeding

Sixth (30 day)

monitoring of adverse events and bleeding
assessment of end points

Adverse events (AE). All serious AEs related to study treatment (recombinant nonimmunogenic staphylokinase, tenecteplase, enoxaparin, acetylsalicylic acid, clopidogrel, catheterisation/PCI) will be reported on the serious adverse events (SAE) page as well as on the AE page of the CRF. All SAE neither related to any study treatment nor on the 'list of STEMI related events' will be reported on the SAE page as well as on the AE page of the CRF. All other SAEs not related to any study treatment, but on the 'list of STEMI-related events' will only be recorded on the AE page of the CRF. Only serious AEs (SAEs) and serious/non-serious bleeds will be recorded in the CRF. Non-serious AEs other than bleeds will not be recorded in the CRF.

Detailed instructions - including a flow chart - on the reporting of adverse events will be provided in the Investigator Site File (ISF). During screening/baseline, the patient's condition is assessed; any relevant changes from baseline will be noted subsequently in the source data. Patients and investigators will be required - according to the procedure described above - to report spontaneously any SAEs and bleeds as well as the time of onset, end and intensity of these events. A carefully written record of all SAEs and bleeds will be kept by the investigator in charge of the trial. Records must include data on the time of onset, end time and intensity of the event as well as any treatment or action required for the event and its outcome. All events, including those persisting after trial completion must be followed up until they have resolved or have been sufficiently characterised.

Worsening of pre-existing conditions

Expected fluctuations or expected deterioration of the underlying disease will not be recorded as an AE. Worsening of the disease under study will be recorded as an AE if one of the following criteria is met.
Worsening of disease meets the criteria for an SAE.
Action is taken with investigational drug, i.e. dose is reduced or treatment discontinued or increased.
Treatment is required (concomitant medication is added or changed).
The investigator believes a patient has shown a clear, unexpected deterioration from baseline symptoms.
The same criteria as above apply to recording of AEs resulting from worsening of other pre-existing conditions. Pre-existing conditions are not recorded as AEs if they do not meet the criteria above. Specifically, the following will not be recorded as an AE:
Pre-existing conditions present at baseline, which remain unchanged during the trial.
Expected fluctuations or expected deterioration of a pre-existing condition.

Vital Signs, ECG and Laboratory test results qualifying as AE Changes in safety tests including blood pressure, pulse rate, ECG and laboratory tests will be recorded as AEs, if:

they are not associated with an already reported AE, symptom or diagnosis and
action is taken with the investigational drug, i.e. dose is reduced or treatment discontinued or
treatment is required (concomitant medication is added or changed) An AE is defined as any untoward medical occurrence, including an exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical product. The event does not necessarily have to have a causal relationship with this treatment. All adverse events occurring during the course of the clinical trial (i.e., from signing the informed consent onwards through the observational phase) will be collected, documented and reported to the sponsor by the investigator. A SAE is defined as any AE which results in death, is immediately life-threatening, results in persistent or significant disability / incapacity, requires or prolongs patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for any other reason representing a significant hazard, which is comparable to the aforementioned criteria. All serious adverse events and non-serious bleeds will be fully documented in the appropriate CRFs. For each adverse event, the investigator will provide the onset, end, intensity, treatment required, outcome, seriousness and action taken with the investigational drug. The investigator will determine the relationship of the investigational drug to all AE as defined in the 'Adverse Event Reporting' section of the Investigator Site File. The basis for judging the intensity of the AE as well as the causal relationship between the investigational product and the AE is described below. Intensity of event
Mild: Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate: Enough discomfort to cause interference with usual activity
Severe: Incapacitating or causing inability to work or to perform usual activities

Study Design

Study Type:

Interventional

Anticipated Enrollment :

392 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Multicenter Open Lable Randomized Comparative Study of Efficacy and Safety of Single Bolus Injection of Recombinant Nonimmunogenic Staphylokinase (Fortelyzin) and Tenecteplase (Metalyse) in STEMI Patients

Study Start Date :

Oct 1, 2014

Anticipated Primary Completion Date :

Sep 1, 2016

Anticipated Study Completion Date :

Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Recombinant staphylokinase Lyophilizate for solution making for intravenous injection, 5 mg (745000 ME). 15 mg of drug reconstituted in 15 ml of 0.9% solution of NaCl given as single i.v. bolus over 5 - 10 seconds	Drug: Recombinant staphylokinase 15 mg of drug reconstituted in 15 ml of 0.9% solution of NaCl given as single i.v. bolus over 5 - 10 seconds Other Names: Fortelyzin
Active Comparator: Tenecteplase 50 mg of drug reconstituted in 10 ml sterile water for injection given as single weight-adjusted i.v. bolus over 5 - 10 seconds Weight (kg) Dose (mg) Dose (ml) 55 to <60 30 mg 6 ml 60 to <70 35 mg 7 ml 70 to <80 40 mg 8 ml 80 to <90 45 mg 9 ml 90 50 mg 10 ml	Drug: Tenecteplase 50 mg of drug reconstituted in 10 ml sterile water for injection given as single weight-adjusted i.v. bolus over 5 - 10 seconds Weight (kg) Dose (mg) Dose (ml) 55 to <60 30 mg 6 ml 60 to <70 35 mg 7 ml 70 to <80 40 mg 8 ml Other Names: Metalyse

Arm

Intervention/Treatment

Experimental: Recombinant staphylokinase

Lyophilizate for solution making for intravenous injection, 5 mg (745000 ME). 15 mg of drug reconstituted in 15 ml of 0.9% solution of NaCl given as single i.v. bolus over 5 - 10 seconds

Drug: Recombinant staphylokinase

15 mg of drug reconstituted in 15 ml of 0.9% solution of NaCl given as single i.v. bolus over 5 - 10 seconds

Other Names:

Fortelyzin

Active Comparator: Tenecteplase

50 mg of drug reconstituted in 10 ml sterile water for injection given as single weight-adjusted i.v. bolus over 5 - 10 seconds Weight (kg) Dose (mg) Dose (ml) 55 to <60 30 mg 6 ml 60 to <70 35 mg 7 ml 70 to <80 40 mg 8 ml 80 to <90 45 mg 9 ml 90 50 mg 10 ml

Drug: Tenecteplase

Other Names:

Metalyse

Outcome Measures

Primary Outcome Measures

Reperfusion Criteria of Fibrinolysis [ECG at 90 min. after fibrinolysis, diagnostic coronary angiography]
ST-segment resolution is ≥ 50 % in the qualifying lead (that had the maximum initial ST-segment elevation in the baseline ECG) in 90 min; TIMI 2-3 or TFC 25-40 frames (for TIMI 3) and 41-60 frames (for TIMI 2) by coronary angiography

Secondary Outcome Measures

Cardiovascular Death+Reccurent MI+Stroke+Heart failure [within 30 days after fibrinolysis]
Composite endpoint
All cause death+Reccurent MI+Stroke+Heart failure [within 30 days after fibrinolysis]
Composite endpoint
Cardiovascular death [within 30 days after fibrinolysis]
Death caused by any cardiovascular reason/event
Repeated target vessel revascularization [within 30 days after fibrinolysis]
The need for re-intervention on infarct-related artery within 30 days after fibrinolysis
Development of Heart Failure [within 30 days after fibrinolysis]
In case of at least of the one of the following conditions: Pulmonary oedema/congestion on chest X-ray without suspicion of a non-cardiac cause Rales > 1/3 up from the lung base (Killip class 2 or higher) Pulmonary capillary wedge pressure (PCWP) >25 mmHg Dyspnoea with pO2 < 80 mmHg or O2 sat < 90 % (no supplemental O2) in the absence of known lung disease;
Rehospitalization due to cardiovascular reasons [within 30 days after fibrinolysis]
Overall major and minor bleeding [within 30 days after fibrinolysis]
According to TIMI classification
Severe or life-threatining bleeding [within 30 days after fibrinolysis]
According to GUSTO classification
Overall bleeding [within 30 gays after fibrinolysis]
GUSTO classification
Intracranial haemorrhages [within 30 days after fibrinolysis]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

both gender patients over 18 years
12-lead ECG indicative of an STEMI (ST-segment elevation in acute myocardial infarction, measured at the J point, should be found in two contiguous leads and be ≥0.25 mV in men below the age of 40 years, ≥0.2 mV in men over the age of 40 years, or ≥0.15 mV in women in leads V2-V3 and/or ≥0.1 mV in other leads (in the absence of left ventricular hypertrophy or left bundle branch block
the possibility of fibrinolysis within 12 hour of symptom onset
inability of primary PCI within 60 min of first medical contact (FMC)
informed consent received

Exclusion Criteria:

expected performance of PCI less 60 min from FMC
left bundle branch block or ventricular pacing
cases of sinus bradycardia associated with hypotension, AV block II (Mobitz 2) or AV block III with bradycardia that causes hypotension or heart failure
active bleeding or known bleeding disorders/diathesis
uncontrolled hypertension, defined us single blood pressure measurement ≥180/110 mm Hg prior to randomization
internal bleeding within the past 2 weeks
conditions with increased risk of bleeding (peptic ulceration)
prolonged or traumatic resuscitation within the past 2 weeks
any known history of hemorrhagic stroke, or transitory ischemic attack
ischemic stroke within the past 3 month
puncture of unpressable vessels
cardiogenic shock (Killip class IV)
aortic aneurism
intracranial neoplasm
any head trauma within past 2 weeks
intracranial vessel malformation
recent administration of anticoagulant within the past month
INR >1.3
sensibilisation to staphylokinase
contra-indications to acetylsalicilic acid, clopidogrel, enoxaparin
any conditions with unfavorable prognosis
in case of surgical treatment required within 30 days after randomization
in case of unhallowed medications required
pregnancy, lactation
inability to follow the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Institute of Cardiology	Tomsk	Siberia	Russian Federation	634012
2	St. Iosaf's Belgorod Regional Clinical Hospital	Belgorod		Russian Federation	308007
3	Kemerovo cardiological dispensary	Kemerovo		Russian Federation	650002
4	Research Institute of Complex Problems of Cardiovascular diseases	Kemerovo		Russian Federation	650002
5	City Clinical Hospital #11	Kemerovo		Russian Federation	650014
6	Russian national research medical University named after Pirogov	Moscow		Russian Federation	117997
7	City Clinical Hospital #81	Moscow		Russian Federation	127644
8	The Sklifosovsky Research institute of Emergency	Moscow		Russian Federation	129090
9	Murmansk Regional Clinical Hospital	Murmansk		Russian Federation	183047
10	City Clinical Hospital #5	Nizhniy Novgorod		Russian Federation	603005
11	Regional Clinical Hospital	Ryazan		Russian Federation	390039
12	Samara Regional Clinical Cardiological Dispansery	Samara		Russian Federation	44З070
13	Mariinsk City Hospital	St.-Petersburg		Russian Federation	191014
14	Leningrad Regional Clinical Hospital	St.-Petersburg		Russian Federation	194291
15	Regional Clinical Hospital	Tver		Russian Federation	170036
16	City Clinical Hospital of Emergency #25	Volgograd		Russian Federation	400138