A Pre-market, Multi-center, International, Double-blind, Randomized, Two-arms, Controlled, Prospective Clinical Investigation Assessing the Safety and Performance of a Medical Device (ClearPlasma™) for the Treatment of Patients Undergoing Coronary Artery Bypass or Valve Replacement

Study Overview
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Brief Summary
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Bleeding is a significant complication in cardiac surgery, with 10-15% of open cardiac surgery patients experiencing major intra- or post-operative bleeding. To address this unmet need, PLAS-FREE LTD has developed ClearPlasma™, a single-use, extracorporeal plasma filtration device which extracts plasminogen from plasma to reduce fibrinolysis. The resulting plasminogen-depleted plasma (PDP) is expected to reduce risk of fibrinolysis and bleeding in patients undergoing plasma transfusions.

Detailed Description
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Bleeding is a significant complication in cardiac surgery, with 10-15% of open cardiac surgery patients experiencing major intra- or post-operative bleeding. Bleeding complications are associated with worse clinical outcomes, including a higher risk of infection, ischemic events attributable to hypo-perfusion (e.g., myocardial infarction, acute kidney injury), in-hospital mortality, and transfusion-related adverse events. Additionally, bleeding complications are an important driver of blood product utilization in cardiac surgery. Coagulopathy and bleeding after cardiac surgery are often a multifactorial problem, thus there is unmet need to find new technologies that can give better care to these bleeding patients. In 2016, it was estimated that one million people throughout the world undergo cardiac surgery each year. Most of these surgeries are Coronary artery bypass grafting and valves replacement. Coronary artery bypass grafting (CABG) is still the most commonly performed cardiac surgery procedure worldwide, representing annual volumes of approximately 200,000 isolated cases in the US and an average incidence rate of 62 per 100,000 inhabitants in western European countries. Aortic valve replacement is procedure that treat diseases affecting the aortic valve, one of four valves that control blood flow through the heart. In the United States, it is estimated that 2.5% of the general population, 8.5% of those 65-74 years of age and 13.2% of those ≥75 years of age have moderate to severe valvular diseases. These surgeries are commonly done in the western countries, however, the ability to halt the bleed remain challenge for most clinicians. Failed or delayed treatment of a massive bleeding can result in irreversible end-organ damage (e.g., renal failure), cardiovascular events (e.g., stroke, myocardial injury) or death, accompanied by significantly increased costs. Fibrin clot breakdown is actively mediated by plasmin, a serine protease which cleaves fibrin. Administration of plasma depleted of plasminogen, the precursor of plasmin, may shift the balance towards coagulation. PLAS-FREE LTD has developed ClearPlasma™, a single-use, extracorporeal plasma filtration device which extracts plasminogen from plasma to reduce fibrinolysis. The resulting plasminogen-depleted plasma (PDP) is expected to reduce risk of fibrinolysis and bleeding in patients undergoing plasma transfusions.

Official Title
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A Pre-market, Multi-center, International, Double-blind, Randomized, Two-arms, Controlled, Prospective Clinical Investigation Assessing the Safety and Performance of a Medical Device (ClearPlasma™) for the Treatment of Patients Undergoing Coronary Artery Bypass or Valve Replacement

Conditions
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Bleeding, Bypass Complication, Valve Replacement

Intervention / Treatment
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* Device: ClearPlasma


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged ≥ 18 years Patients undergoing isolated coronary artery bypass grafting or valve replacement surgeries with a cardiopulmonary bypass Patients that need at least 2 units of plasma transfusion according to the physician's decision. Patients understanding the nature of the study and providing their informed consent to participation; Patients willing and able to attend the follow-up visits and procedures foreseen by study protocol. - Exclusion Criteria: Patients who underwent a plasma infusion in the 30 days before enrolment; Patients in a life-threatening condition at the time of enrolment; Patients who are hemodynamically unstable and required pressor administration at the time of enrolment (i.e. hypovolemic shock, cardiogenic shock); Transfusion of cryoprecipitate during procedure. Patients suffering from Hemophilia A or B; Patients suffering from venous and arterial thromboembolic events within 3 months before the enrolment; Patients with increased risk of blood clotting, according to Investigator's judgement; Patients with fluid accumulation in the brain at the time of enrolment. Patients with retinal thrombosis at the time of enrolment; Patients with history of allergic reaction to plasma, polyethersyplone or polycarbonate; Patients suffering from known IgA deficiency at the time of enrolment; Patients identified by the Investigator to have any underlying medical conditions that may preclude conduct of study procedure (i.e. making the administration of study treatment hazardous) or obscure the interpretation of safety objectives; Patients who are participating or have participated in other clinical studies within the 30 days before the study enrolment. Women who are pregnant or breast-feeding or who wish to become pregnant during the period of the clinical investigation and for 3 months later; Female Patients of childbearing age (less than 12 months after the last menstrual cycle) who do not use adequate contraception*. Methods at low risk of contraceptive failure (less than 1% per year) when used consistently, including: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), some intra-uterine devices.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Multi-center, international, double-blind, randomized, controlled, prospective, clinical investigation, in which Patients undergoing Coronary Artery Bypass Grafting or valve replacement surgeries with a cardiopulmonary bypass, required plasma transfusion, will be randomized to receive a one-time infusion (up to 12 hours) of PDP (group A) or FFP (group B) with unlimited number of plasma units. The administration of plasma needs to be in line with the clinical practice and doctor decision. Furthermore, the main point is the patients with CABG/VRS that lost significant blood and need transfusion. Patients will be continuously monitored during transfusion and during stay in ICU. The assessment and additional test will be done at the admission to the ICU, 12 hours (±1) after procedure, 24 hours (±1) after procedure, 48 hours (±2) after procedure, at the discharge and 30±3 days after procedure.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ClearPlasma<br>Investigational Group (A): one-time infusion (up to 12 hours after surgery) of unlimited plasminogen depleted plasma PDP units generated by ClearPlasma™ device. | Device: ClearPlasma<br>* ClearPlasma ClearPlasma™ is an extra-corporeal plasma filtration device, designed to specifically extract plasminogen, a protein that drives fibrinolysis, from up to 250 mL of plasma. ClearPlasma™ is a non-pyrogenic, sterile, single-use medical device<br>|
| Placebo Comparator: Control<br>Control Group (B): one-time infusion (up to 12 hours) of unlimited regular plasma, Fresh frozen plasma (FFP) with mock ClearPlasma™ device. | Device: ClearPlasma<br>* ClearPlasma ClearPlasma™ is an extra-corporeal plasma filtration device, designed to specifically extract plasminogen, a protein that drives fibrinolysis, from up to 250 mL of plasma. ClearPlasma™ is a non-pyrogenic, sterile, single-use medical device<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ClearPlasma efficacy | Post-operative blood loss (mL) within 24 hours after surgery, defined as total output of mediastinal and pleural chest tubes. [time frame: up to 24 hours after procedure] | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transfusion- related SAE | Comparison of the number of transfusion- related SAEs between the groups. [time frame: discharge]obtained through filtration with ClearPlasma™ in patients after coronary artery bypass grafting or valve replacement surgery and to compare it to the same procedure carried out using FFP units. | 30 days | 
| Hemoglobin levels | Comparison of hemoglobin levels drop between the groups [time frame: measured at patient's departure from the operating room/admitting to the ICU and compared to the lowest hemoglobin value until discharge] | 30 days | 
| Post-operative blood loss | Post-operative blood loss (mL) within 12 hours after surgery, defined as total output of mediastinal and pleural chest tubes. [time frame: up to 12 hours after procedure] | 30 days | 
| Total blood loss | Total blood loss, defined as total output of chest tubes from insertion till removal [time frame: drain removal] | 30 days | 
| ClearPlasma | Ratio of bleeding events between the groups [time frame: discharge] | 30 days | 
| bleeding events- | Ratio of bleeding events requiring re-intervention up to discharge [time frame: discharge] | 30 days | 
| major bleeding | Ratio of major bleeding defined as blood loss greater than >1000 mL in first 12 h and/or need for surgical revision owing to bleeding; [time frame: discharge] | 30 days | 
| Mortality | All-cause mortality[time frame: 30 days] | 30 days | 
| In- hospital mortality | In- hospital mortality [time frame: discharge] | 30 days | 
| Number of blood units transfused | The number of units of allogeneic blood products transfused until discharge [time frame: discharge]: Red blood cells (RBC) units transfused; Plasma (PDP/FFP) units transfused; Platelet concentrates units transfused | 30 days | 
| Length of stay in the ICU | Length of stay in the ICU [Time Frame: discharge] | 30 days | 
| Hospitalization Duration | Total length of hospitalization [Time Frame: discharge] | 30 days | 
| Incidence of ischemic outcomes | Comparison of the incidence of ischemic outcomes defined as a composite of stroke, transient ischemic attack, acute myocardial infarction, PE and/or acute renal failure [time frame: discharge] Study Groups | 30 days |