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

ST Elevation Myocardial Infarction Clinical Trial

— OPTIMA-6  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05410925
• Other study ID #: 018
• Status: Recruiting
• Phase: Phase 4
• Start date: April 8, 2023
• Est. completion date: January 1, 2026

Study information

• Verified date: July 2023
• Source: The First Affiliated Hospital with Nanjing Medical University
• Contact: Chunjian Li, PHD
• Phone: +86 13701465229
• Email: lijay[@]njmu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2260
• Est. completion date: January 1, 2026
• Est. primary completion date: January 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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 ? or ? 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

Related Conditions & MeSH terms

• Infarction
• Myocardial Infarction
• ST Elevation Myocardial Infarction

Intervention

Drug:
• Recombinant staphylokinase
Intravenous injection of r-SAK is administered within 10 minutes after diagnosis of acute ST-segment elevation myocardial infarction
• Placebo
Intravenous injection of placebo is administered within 10 minutes after diagnosis of acute ST-segment elevation myocardial infarction

Locations

Country	Name	City	State
China	Changzhou Second People's Hospital	Changzhou
China	Chongqing Hospital of Jiangsu Province Hospital	Chongqing
China	The second Affiliated Hospital of Dalian Medical University	Dalian
China	The Second Affiliated Hospital of Zhejiang University Medical College	Hangzhou
China	Huai'an First People's Hospital	Huai'an
China	Huai'an Second People's Hospital	Huai'an
China	The First People's Hospital of Lianyungang	Lianyungang
China	The First Affiliated Hospital of Nanjing Medical University	Nanjing	Jiangsu
China	The Fourth Affiliated Hospital of Nanjing Medical University	Nanjing
China	Renji Hospital affiliated to Shanghai Jiaotong University	Shanghai
China	Taizhou People's Hospital	Taizhou
China	Affiliated Hospital of Jiangnan University	Wuxi
China	Wuxi Second People's Hospital	Wuxi
China	Xuzhou Central Hospital	Xuzhou
China	Yancheng No.1 People's Hospital	Yancheng

Sponsors (1)

Lead Sponsor	Collaborator
The First Affiliated Hospital with Nanjing Medical University

Country where clinical trial is conducted

China, 

References & Publications (18)

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* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Major bleeding events during hospitalization or within 7 days (BARC 3, 5)	Major bleeding events during hospitalization or within 7 days (BARC 3, 5)	During hospitalization or within 7 days
Other	Minor bleeding events during hospitalization or within 7 days (BARC 2)	Minor bleeding events during hospitalization or within 7 days (BARC 2)	During hospitalization or within 7 days
Other	Major bleeding events within 90 days (BARC 3, 5)	Major bleeding events within 90 days (BARC 3, 5)	Within 90 days
Other	Minor bleeding events within 90 days (BARC 2)	Minor bleeding events within 90 days (BARC 2)	Within 90 days
Primary	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	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
Secondary	NT-proBNP	The level of NT-proBNP	1 day before discharge or day 7, day 90±3
Secondary	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
Secondary	LVEF assessed by echocardiogram	LVEF assessed by echocardiogram	Day 90±3
Secondary	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
Secondary	The percentage of TIMI flow grade 3 prior to PCI	The percentage of TIMI flow grade 3 prior to PCI	Immediately prior to PCI
Secondary	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
Secondary	The percentage of TIMI flow grade 3 after PCI	The percentage of TIMI flow grade 3 after PCI	Immediately after PCI
Secondary	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
Secondary	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
Secondary	NT-proBNP	The level of NT-proBNP	Day 360±7
Secondary	LVEF assessed by echocardiogram	LVEF assessed by echocardiogram	Day 360±7