Efficacy and Safety of a Half-dose Bolus of r-SAK Prior to Primary PCI in ST-elevation Myocardial Infarction

Study Overview
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Brief Summary
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As an effective treatment for acute ST-segment elevation myocardial infarction (STEMI), early reperfusion may reduce the infarct size and improve the prognosis of patients. However, it remains uncertain whether adjunctive thrombolytic therapy administered immediately prior to primary percutaneous coronary intervention (PCI) improves outcomes in patients undergoing the procedure within 120 minutes. In this investigator-initiated, prospective, multi-center, randomized, double-blind, placebo-controlled trial, subjects meeting the inclusion/exclusion criteria should be randomly assigned 1:1 to the trial group (r-SAK) or the control group (placebo). The risk of major adverse cardiovascular events within 90 days will be observed.

Detailed Description
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Acute myocardial infarction (AMI) is a serious and critical disease that causes acute coronary artery stenosis, spasm or occlusion due to the rupture or erosion of coronary artery plaque, resulting in myocardial ischemia and necrosis. Myocardial ischemia and necrosis can cause myocardial cell loss, ventricular remodeling and local inflammatory reaction, leading to decreased cardiac output or increased intracardiac pressure, and eventually progress to heart failure (HF), which seriously affects the prognosis of patients. The FAST-MI study found that 37.5% of AMI patients were complicated with HF, and the 1-year mortality of these patients was significantly increased. Early reperfusion treatment as an effective means of AMI treatment can promote myocardial reperfusion, save dying myocardium and reduce infarct area, which is of great significance to improve the clinical prognosis of patients. At this stage, many primary hospitals do not have the conditions for emergency percutaneous coronary intervention (PCI). Transferring patients to PCI hospitals takes a lot of time, delaying the best time for early reperfusion treatment. In addition, the thrombus burden in the coronary artery increases with the prolongation of ischemia time. Stent implantation in the coronary artery with excessive thrombus burden is prone to slow blood flow or no reflow, resulting in the occurrence of major adverse cardiovascular events (MACE). In view of the above problems, guidelines suggest that if the estimated transit time is more than 120 minutes, thrombolytic therapy should be performed before transport; If the estimated transfer time is less than 120 minutes, it can be directly transferred to the PCI hospital. However, it remains uncertain whether adjunctive thrombolytic therapy administered immediately prior to primary PCI improves outcomes in patients undergoing the procedure within 120 minutes (facilitated PCI). Multiple previous studies comparing facilitated PCI with primary PCI found facilitated PCI to be inferior in terms of clinical outcomes, while other studies based on reduced-dose thrombolysis confirmed the superiority of facilitated PCI in better patency of infarct-related artery (IRA). Recombinant staphylokinase (r-SAK), as the third-generation thrombolytic agent, may serve as the potential thrombolytic drug to contemporary facilitated PCI by virtue of its high fibrinolytic activity and fibrin selectivity. Staphylokinase (SAK) is produced by Staphylococcus aureus and it is a protein containing 136 amino acid residues. Its ability for dissolving blood clots was first discovered in 1948. Studies have shown that SAK is not directly convert plasminogen (PLG) into plasminogen (PLi), but first combines with PLG in a 1:1 ratio to form a complex. The complex can lead to the exposure of PLG active site, from single chain to double chain PLi, resulting to form an active SAK-PLI complex, which subsequently activates PLG molecules. Then PLG transforms into PLi and further dissolve the thrombus. R-SAK was developed in 1990 by Shanghai Institute of Plant and Biological Physiology. It is a gene recombinant drug prepared by molecular cloning of SAK gene in Escherichia coli. Its biological characteristics are very similar to natural SAK, and r-SAK is a highly fibrin-specific fibrinolysis agent. R-SAK is considered to be one of the most promising thrombolytic drugs due to its high thrombolysis activity (especially in platelet-rich arterial thrombosis), inactivation of system fibrinolysis, and few side effects. Clinical studies have shown that the efficacy of r-SAK in the treatment of AMI is better than urokinase, comparable to RT-PA, and it does not increase serious bleeding complications such as intracranial hemorrhage. In terms of pharmacokinetics, r-SAK has a fast distribution and a long action time in human body. Half-lives of distribution term is 13.30±2.06min and elimination term is 67.94±21.39min when intravenous injection 10 mg r-SAK in 30min. A single bolus of r-SAK as early as possible during the first medical contact (such as prehospital care or primary hospitals or medical centers with conditional PCI) can maximize the time window for reperfusion therapy. Achieving early reperfusion by means of facilitated PCI is consistent with the core of STEMI treatment, but the efficacy and safety of facilitated PCI are still controversial. OPTIMA-6, designed as shorter symptom onset to treatment time, a half-dose thrombolytic agent, and upstream use of the potent antiplatelet agent, will therefore evaluate the efficacy and safety of a half-dose bolus of r-SAK vs. placebo prior to primary PCI to inform clinical practice of contemporary facilitated PCI in patients with STEMI.

Official Title
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Efficacy and Safety of a Half-dose Bolus of r-SAK Prior to Primary PCI in ST-elevation Myocardial Infarction: a Multicenter Randomized Double-blind Placebo-controlled Trial (OPTIMA-6)

Conditions
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ST Elevation Myocardial Infarction

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-75 years, weight ≥45 kg Diagnosed as STEMI (meeting the following two conditions simultaneously) Ischemic chest pain lasts ≥ 30 minutes ECG indicates that ST-segment elevation of two or more contiguous precordial leads ≥ 0.1 mV, or ST-segment elevation of two or more contiguous precordial leads ≥ 0.2 mV Time from onset of persistent chest pain to randomization ≤12 hours Primary PCI expected to be performed ≥30 minutes, and ≤120 minutes Exclusion Criteria: Cardiogenic shock Active bleeding or known at high risk of bleeding (including grade Ⅲ or Ⅳ retinopathy or retinal gastrointestinal or urinary tract hemorrhage within the past 1 month) Ischemic stroke or TIA in the past 6 months History of hemorrhagic stroke Known intracranial aneurysm Severe trauma, surgery or head injury within 1 month Suspected aortic dissection or infective endocarditis Puncture with difficult hemostasis by compression within 1 month (e.g., visceral biopsy, compartment puncture) Currently taking anticoagulants Poorly controlled hypertension ( ≥180/110 mmHg) Severe hepatic or renal impairment indicated by the consultation or previous history (glutamic-pyruvic transaminase or glutamic oxalacetic transaminase >3 times upper limit of normal value; eGFR <15 ml/min/1.73m^2, calculated based on CKD-EPI) Known allergy to r-SAK Pregnancy, lactation, or planning for pregnancy History of chronic total occlusion, myocardial infarction or CABG Having taken antiplatelet drugs other than aspirin and ticagrelor, such as clopidogrel, prasugrel or cilostazol after the symptom onset Patients with other conditions that made them unsuitable to be recruited at the discretion of the investigators

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: r-SAK group<br>intravenous injection of single-bolus 5 mg r-SAK in 3 min | Drug: Recombinant staphylokinase<br>* Intravenous injection of r-SAK is administered within 10 minutes after diagnosis of acute ST-segment elevation myocardial infarction<br>|
| Placebo Comparator: placebo group<br>intravenous injection of placebo in 3 min | Drug: Placebo<br>* Intravenous injection of placebo is administered within 10 minutes after diagnosis of acute ST-segment elevation myocardial infarction<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MACE | Defined as a composite of all-cause death, reinfarction, unplanned target vessel revascularization, heart failure or cardiogenic shock, major ventricular arrhythmia | Within 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Each of the following cardiac and cerebrovascular events | Including all-cause death, cardiovascular death, reinfarction, stroke, unplanned target vessel revascularization, heart failure or cardiogenic shock, major ventricular arrhythmia, cardiogenic rehospitalization, ventricular septal rupture, papillary muscle rupture, cardiac rupture, ventricular aneurysm | Within 90 days | 
| NT-proBNP | The level of NT-proBNP | 1 day before discharge or day 7, day 90±3 | 
| CMR indexes | Including infarct size, left ventricular ejection fraction (LVEF), microvascular obstruction (MVO) and intramuscular hemorrhage (IMH), assessed by cardiac magnetic resonance (CMR) | Day 5 | 
| LVEF assessed by echocardiogram | LVEF assessed by echocardiogram | Day 90±3 | 
| The percentage of TIMI flow grade 2 and 3 prior to PCI | The percentage of thrombolysis in myocardial infarction (TIMI) flow grade 2 and 3 prior to PCI | Immediately prior to PCI | 
| The percentage of TIMI flow grade 3 prior to PCI | The percentage of TIMI flow grade 3 prior to PCI | Immediately prior to PCI | 
| The percentage of TIMI flow grade 2 and 3 after PCI | The percentage of TIMI flow grade 2 and 3 after PCI | Immediately after PCI | 
| The percentage of TIMI flow grade 3 after PCI | The percentage of TIMI flow grade 3 after PCI | Immediately after PCI | 
| MACE | Defined as a composite of all-cause death, reinfarction, unplanned target vessel revascularization, heart failure or cardiogenic shock, major ventricular arrhythmia | Within 360 days | 
| Each of the following cardiac and cerebrovascular events | Including all-cause death, cardiovascular death, reinfarction, ischemic stroke, unplanned target vessel revascularization, heart failure or cardiogenic shock, major ventricular arrhythmia, cardiogenic rehospitalization, ventricular septal rupture, papillary muscle rupture, cardiac rupture, ventricular aneurysm | Within 360 days | 
| NT-proBNP | The level of NT-proBNP | Day 360±7 | 
| LVEF assessed by echocardiogram | LVEF assessed by echocardiogram | Day 360±7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ST Elevation Myocardial Infarction, Recombinant Staphylokinase, Thrombolysis