Clinical trial NCT05649696: Prolonged Clinical Follow-up of OPTIMA-5
Official title: A Single Bolus R-SAK Prior to Primary PCI for ST-elevation Myocardial Infarction (OPTIMA-5): 1-Year Follow-up
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: ST-segment Elevation Myocardial Infarction (STEMI)
Keywords: ST Elevation Myocardial Infarction
Recombinant Staphylokinase
Lead sponsor: The First Affiliated Hospital with Nanjing Medical University
Sponsor class: OTHER
First posted: 2022-12-14
Enrollment: 210
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: The OPTIMA-5 trial is a prospective, multi-center, randomized, patient blinded, controlled trial comparing a single bolus of half-dose recombinant staphylokinase (r-SAK) with normal saline (NS) in patients with ST-segment elevation myocardial infarction (STEMI) presenting ≤12 hours of symptom onset and expected to undergo primary percutaneous coronary intervention (PPCI) within 120 minutes. The results of OPTIMA-5 showed that a single bolus r-SAK prior to PPCI for STEMI improves infarct related artery (IRA) patency and reduces infarct size without increasing major bleeding. On this basis, this study was designed to investigate the effect of the novel reperfusion strategy on 1-year outcomes of patients with STEMI.

Detailed description: Acute myocardial infarction (AMI) is one of the leading causes of death all over the world, and accounted for more than 100 thousand deaths in the US in 2019. Early PPCI reduces mortality in patients with STEMI. If PPCI cannot be performed within 120 minutes of presentation, guidelines recommend the use of thrombolytic therapy. However, it remains uncertain whether adjunctive thrombolytic therapy administered immediately prior to PPCI improves outcomes in patients undergoing the procedure within 120 minutes.

SAK is a fibrin specific fibrinolytic agent produced by Staphylococcus aureus that was first discovered in 1948. A recombinant form of SAK was approved by China Food and Drug Administration (CFDA) for treatment of patients with STEMI. It has been demonstrated that r-SAK is more potent than urokinase and recombinant streptokinase in rabbit models.

The OPTIMA-5 trial is an investigator-initiated, prospective, multi-center, randomized, patient blinded, controlled trial comparing a single bolus of half-dose r-SAK with NS in patients with STEMI presenting ≤12 hours of symptom onset and expected to undergo PPCI within 120 minutes. Between October 29, 2021 and August 14, 2022, 283 STEMI patients were screened in 8 centers in China and 200 were randomized to r-SAK group or control in a 1:1 ratio using a computer-generated randomization sequence.

On this basis, this study was aimed to conduct a 1-year follow-up study to further confirm the efficacy and safety of this novel reperfusion strategy for patients with STEMI.

Eligibility criteria: Arm 1 and 2 inclusion and exclusion criteria

Inclusion Criteria:

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

   i. Ischemic chest pain lasts ≥30 minutes; ii. Electrocardiogram indicates that ST-segment elevation ≥2 mm in 2 or more contiguous precordial leads or ≥1 mm in 2 or more peripheral leads;
3. Time from onset of persistent chest pain to randomization \<12 hours;
4. Primary PCI expected to be performed within 120 minutes.

Exclusion Criteria:

1. Cardiogenic shock;
2. Active bleeding or 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. Platelet count \<100×109/L or hemoglobin \<100 g/L;
6. Known intracranial aneurysm;
7. Severe trauma, surgery or head injury within 1 month;
8. Suspected aortic dissection or infective endocarditis;
9. Recent puncture with difficult hemostasis by compression (eg, visceral biopsy, compartment puncture);
10. Currently taking anticoagulants;
11. Poorly controlled hypertension ( ≥180/110 mmHg);
12. Hepatic or renal impairment (glutamic-pyruvic transaminase, glutamic oxalacetic transaminase, or γ -glutamyl transferase \>2.5 times upper limit of normal value; creatinine \>1.5 times upper limit of normal value);
13. Known allergy to r-SAK;
14. Pregnancy, lactation, or planning for pregnancy;
15. History of myocardial infarction or CABG;
16. Having taken antiplatelet drugs other than aspirin and ticagrelor, such as clopidogrel, prasugrel or cilostazol after the symptom onset;
17. Patients with other conditions that made them unsuitable to be recruited at the discretion of the investigators.

Arm 3 inclusion and exclusion criteria Inclusion criteria

1. Age ≥18, ≤75 years old, weight ≥45kg, gender is not limited；
2. Taking maintenance dose of aspirin and ticagrelor for more than 3 days, or taking loading dose of aspirin (300mg) and ticagrelor (180mg);
3. Inpatients with suspected coronary atherosclerotic heart disease scheduled for coronary angiography or interventional therapy.

Exclusion criteria

1. Patients who had received r-SAK thrombolytic therapy before;
2. Previous diagnosis of Staphylococcus aureus infection;
3. Patients who were participating in other clinical trials;
4. Other patients considered unsuitable for inclusion by the investigators.

Primary outcomes:
measure: MACE
timeFrame: Within 360 days
Secondary outcomes:
measure: Adverse cardiac and cerebrovascular events
timeFrame: Within 360 days
Other outcomes:
measure: r-SAK antibody level in human serum
timeFrame: Day 90 ± 7, Day 180 ± 7, Day 360 ± 14
measure: In-vitro thrombolysis rate
timeFrame: 60 minutes after In-vitro thrombolysis
measure: r-SAK activity before and after in-vitro thrombolysis
timeFrame: Immediately before in-vitro thrombolysis and 60 minutes after In-vitro thrombolysis
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: Dalian
country: China
facility: The second Affiliated Hospital of Dalian Medical University
city: Huai'an
country: China
facility: Huai 'an Second People's Hospital affiliated to Nanjing Medical University
city: Lianyungang
country: China
facility: Lianyungang First People's Hospital
city: Taizhou
country: China
facility: Taizhou People's Hospital
city: Wuxi
country: China
facility: Affiliated Hospital of Jiangnan University
city: Zhejiang
country: China
facility: The Second Affiliated Hospital of Zhejiang University Medical College
Study officials:
References:
citation: Correction to: Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation. 2018 Mar 20;137(12):e493. doi: 10.1161/CIR.0000000000000573. No abstract available.
citation: Heusch G, Libby P, Gersh B, Yellon D, Bohm M, Lopaschuk G, Opie L. Cardiovascular remodelling in coronary artery disease and heart failure. Lancet. 2014 May 31;383(9932):1933-43. doi: 10.1016/S0140-6736(14)60107-0. Epub 2014 May 13.
citation: Agnoletti G, Cargnoni A, Agnoletti L, Di Marcello M, Balzarini P, Pasini E, Gitti G, Martina P, Ardesi R, Ferrari R. Experimental ischemic cardiomyopathy: insights into remodeling, physiological adaptation, and humoral response. Ann Clin Lab Sci. 2006 Summer;36(3):333-40.
citation: Townsend N, Wilson L, Bhatnagar P, Wickramasinghe K, Rayner M, Nichols M. Cardiovascular disease in Europe: epidemiological update 2016. Eur Heart J. 2016 Nov 7;37(42):3232-3245. doi: 10.1093/eurheartj/ehw334. Epub 2016 Aug 14. No abstract available.
citation: Collen D, Lijnen HR. Thrombolytic agents. Thromb Haemost. 2005 Apr;93(4):627-30. doi: 10.1160/TH04-11-0724.
citation: Pulicherla KK, Kumar A, Gadupudi GS, Kotra SR, Rao KR. In vitro characterization of a multifunctional staphylokinase variant with reduced reocclusion, produced from salt inducible E. coli GJ1158. Biomed Res Int. 2013;2013:297305. doi: 10.1155/2013/297305. Epub 2013 Aug 13.
citation: Ueshima S, Matsuo O. Development of new fibrinolytic agents. Curr Pharm Des. 2006;12(7):849-57. doi: 10.2174/138161206776056065.
citation: Yamamoto J, Kawano M, Hashimoto M, Sasaki Y, Yamashita T, Taka T, Watanabe S, Giddings JC. Adjuvant effect of antibodies against von Willebrand Factor, fibrinogen, and fibronectin on staphylokinase-induced thrombolysis as measured using mural thrombi formed in rat mesenteric venules. Thromb Res. 2000 Mar 1;97(5):327-33. doi: 10.1016/s0049-3848(99)00184-x.
citation: Szemraj J, Stankiewicz A, Rozmyslowicz-Szerminska W, Mogielnicki A, Gromotowicz A, Buczko W, Oszajca K, Bartkowiak J, Chabielska E. A new recombinant thrombolytic and antithrombotic agent with higher fibrin affinity - a staphylokinase variant. An in-vivo study. Thromb Haemost. 2007 Jun;97(6):1037-45. doi: 10.1160/th06-10-0562.
citation: Vakili B, Nezafat N, Negahdaripour M, Yari M, Zare B, Ghasemi Y. Staphylokinase Enzyme: An Overview of Structure, Function and Engineered Forms. Curr Pharm Biotechnol. 2017;18(13):1026-1037. doi: 10.2174/1389201019666180209121323.
citation: Li CJ, Huang J, Yang ZJ, Cao KJ. Thrombolytic efficacy of native recombinant staphylokinase on femoral artery thrombus of rabbits. Acta Pharmacol Sin. 2007 Jan;28(1):58-65. doi: 10.1111/j.1745-7254.2007.00455.x.
citation: Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. doi: 10.1161/CIRCULATIONAHA.110.009449. No abstract available.
citation: Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth Universal Definition of Myocardial Infarction (2018). Glob Heart. 2018 Dec;13(4):305-338. doi: 10.1016/j.gheart.2018.08.004. Epub 2018 Aug 25. No abstract available.
citation: Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007 May 1;115(17):2344-51. doi: 10.1161/CIRCULATIONAHA.106.685313.
citation: Halvorsen S, Storey RF, Rocca B, Sibbing D, Ten Berg J, Grove EL, Weiss TW, Collet JP, Andreotti F, Gulba DC, Lip GYH, Husted S, Vilahur G, Morais J, Verheugt FWA, Lanas A, Al-Shahi Salman R, Steg PG, Huber K; ESC Working Group on Thrombosis. Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J. 2017 May 14;38(19):1455-1462. doi: 10.1093/eurheartj/ehw454. No abstract available.