Clinical trial NCT05410925: Efficacy and Safety of a Half-dose Bolus of r-SAK Prior to Primary PCI in ST-elevation Myocardial Infarction
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: ST Elevation Myocardial Infarction
Keywords: ST Elevation Myocardial Infarction
Recombinant Staphylokinase
Thrombolysis
Lead sponsor: The First Affiliated Hospital with Nanjing Medical University
Sponsor class: OTHER
First posted: 2022-06-08
Enrollment: 2260
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Age 18-75 years, weight ≥45 kg
2. Diagnosed as STEMI (meeting the following two conditions simultaneously)

   1. Ischemic chest pain lasts ≥ 30 minutes
   2. 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
3. Time from onset of persistent chest pain to randomization ≤12 hours
4. Primary PCI expected to be performed ≥30 minutes, and ≤120 minutes

Exclusion Criteria:

1. Cardiogenic shock
2. 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)
3. Ischemic stroke or TIA in the past 6 months
4. History of hemorrhagic stroke
5. Known intracranial aneurysm
6. Severe trauma, surgery or head injury within 1 month
7. Suspected aortic dissection or infective endocarditis
8. Puncture with difficult hemostasis by compression within 1 month (e.g., visceral biopsy, compartment puncture)
9. Currently taking anticoagulants
10. Poorly controlled hypertension ( ≥180/110 mmHg)
11. 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)
12. Known allergy to r-SAK
13. Pregnancy, lactation, or planning for pregnancy
14. History of chronic total occlusion, myocardial infarction or CABG
15. Having taken antiplatelet drugs other than aspirin and ticagrelor, such as clopidogrel, prasugrel or cilostazol after the symptom onset
16. Patients with other conditions that made them unsuitable to be recruited at the discretion of the investigators

Primary outcomes:
measure: MACE
timeFrame: Within 90 days
Secondary outcomes:
measure: Each of the following cardiac and cerebrovascular events
timeFrame: Within 90 days
measure: NT-proBNP
timeFrame: 1 day before discharge or day 7, day 90±3
measure: CMR indexes
timeFrame: Day 5
measure: LVEF assessed by echocardiogram
timeFrame: Day 90±3
measure: The percentage of TIMI flow grade 2 and 3 prior to PCI
timeFrame: Immediately prior to PCI
measure: The percentage of TIMI flow grade 3 prior to PCI
timeFrame: Immediately prior to PCI
measure: The percentage of TIMI flow grade 2 and 3 after PCI
timeFrame: Immediately after PCI
measure: The percentage of TIMI flow grade 3 after PCI
timeFrame: Immediately after PCI
measure: MACE
timeFrame: Within 360 days
measure: Each of the following cardiac and cerebrovascular events
timeFrame: Within 360 days
measure: NT-proBNP
timeFrame: Day 360±7
measure: LVEF assessed by echocardiogram
timeFrame: Day 360±7
Other outcomes:
measure: Major bleeding events during hospitalization or within 7 days (BARC 3, 5)
timeFrame: During hospitalization or within 7 days
measure: Minor bleeding events during hospitalization or within 7 days (BARC 2)
timeFrame: During hospitalization or within 7 days
measure: Major bleeding events within 90 days (BARC 3, 5)
timeFrame: Within 90 days
measure: Minor bleeding events within 90 days (BARC 2)
timeFrame: Within 90 days
Locations:
city: Nanjing
country: China
facility: The First Affiliated Hospital of Nanjing Medical University
state: Jiangsu
city: Changzhou
country: China
facility: Changzhou Second People's Hospital
city: Changzhou
country: China
facility: Changzhou Wujin People's Hospital
city: Changzhou
country: China
facility: The First People's Hospital of Changzhou
city: Chongqing
country: China
facility: Chongqing Hospital of Jiangsu Province Hospital
city: Dalian
country: China
facility: The second Affiliated Hospital of Dalian Medical University
city: Daqing
country: China
facility: Daqing Oilfield General Hospital
city: Dongguan
country: China
facility: Dongguan People's Hospital
city: Fengcheng
country: China
facility: Fengcheng People's Hospital
city: Guangzhou
country: China
facility: General Hospital of Southern Theatre Command
city: Hainan
country: China
facility: The Second Affiliated Hospital of Hainan Medical University
city: Hangzhou
country: China
facility: The Affiliated Hospital of Hangzhou Normal University
city: Hangzhou
country: China
facility: The Second Affiliated Hospital of Zhejiang University Medical College
city: Hefei
country: China
facility: The First Affiliated Hospital of Anhui Medical University
city: Huai'an
country: China
facility: Huai'an First People's Hospital
city: Huai'an
country: China
facility: Huai'an Second People's Hospital
city: Lianyungang
country: China
facility: Donghai Country People's Hospital
city: Lianyungang
country: China
facility: The First People's Hospital of Lianyungang
city: Lianyungang
country: China
facility: The Second People's Hospital of Lianyungang
city: Liyang
country: China
facility: Liyang Hospital of Jiangsu Province Hospital
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University
city: Nanjing
country: China
facility: Nanjing Tongren Hospital
city: Nanjing
country: China
facility: Sir Run Run Hospital Nanjing Medical University
city: Nanjing
country: China
facility: The Fourth Affiliated Hospital of Nanjing Medical University
city: Nanning
country: China
facility: Nanjing Qixia District Hospital
city: Nantong
country: China
facility: Affiliated Hospital of Nantong University
city: Nantong
country: China
facility: Nantong First People's Hospital
city: Neimeng
country: China
facility: The People's Hospital of Zhalaite
city: Qingdao
country: China
facility: Qingdao Municipal Hospital
city: Shandong
country: China
facility: Qilu Hospital of Shandong University
city: Shanghai
country: China
facility: Renji Hospital affiliated to Shanghai Jiaotong University
city: Shanghai
country: China
facility: Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
city: Shenyang
country: China
facility: The People's Hospital of Liaoning Province
city: Shenzhen
country: China
facility: Shenzhen People's Hospital
city: Suining
country: China
facility: Suining County People's Hospital
city: Suqian
country: China
facility: Nanjing Drum Tower Hospital Group Suqian Hospital
city: Suqian
country: China
facility: Suqian First Hospital
city: Suzhou
country: China
facility: Suzhou Dushu Lake Hospital
city: Suzhou
country: China
facility: Suzhou Municipal Hospital of Anhui Province
city: Suzhou
country: China
facility: Suzhou Municipal Hospital
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University
city: Suzhou
country: China
facility: Wanbei Coal-Electricity Group General Hospital
city: Taihe
country: China
facility: Taihe County Traditional Chinese Medicine Hospital
city: Taishan
country: China
facility: Taishan People&#39;s Hospital
city: Taizhou
country: China
facility: Taizhou People's Hospital
city: Wenzhou
country: China
facility: The First Affiliated Hospital of Wenzhou Medical University
city: Wenzhou
country: China
facility: The Second Affiliated Hospital of Wenzhou Medical University
city: Wuxi
country: China
facility: Affiliated Hospital of Jiangnan University
city: Wuxi
country: China
facility: Wuxi People's Hospital
city: Wuxi
country: China
facility: Wuxi Second People's Hospital
city: Xuzhou
country: China
facility: The Affiliated Hospital of Xuzhou Medical University
city: Xuzhou
country: China
facility: The People's Hospital of Jiawang District of Xuzhou City
city: Xuzhou
country: China
facility: Xuzhou Central Hospital
city: Yancheng
country: China
facility: Yancheng No.1 People's Hospital
city: Yangzhou
country: China
facility: Affiliated Hospital of Yangzhou University
city: Yangzhou
country: China
facility: Subei People's Hospital of Jiangsu province
city: Zhengzhou
country: China
facility: Fuwai Central China Cardiovascular Hospital
city: Zhengzhou
country: China
facility: The 7th People's Hospital of Zhengzhou
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
city: Zhenjiang
country: China
facility: Affiliated Hospital of Jiangsu University
city: Zhenjiang
country: China
facility: Zhenjiang First People's Hospital
Study officials:
affiliation: The First Affiliated Hospital with Nanjing Medical University
name: Chunjian Li, PHD
role: PRINCIPAL_INVESTIGATOR
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