Clinical Investigation of Safety and Performance of a Medical Device (ClearPlasma) for the Treatment of Patients With Acute Upper Gastrointestinal Hemorrhage.

Study Overview
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Brief Summary
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Pre-market, multi-center, international, double-blind, randomized, controlled, prospective, first-in-human clinical investigation of a Class IIb Investigational Medical Device, in which Patients presenting with acute upper gastrointestinal hemorrhage (AUGIH) and due to undergo a plasma transfusion, will be randomized to receive a one-time infusion (up to 8 hours) of up to two 250 mL units of plasminogen-depleted plasma (PDP) or fresh-frozen plasma (FFP). In case of transfusions needing more than two units, the third unit and above will consist in regular plasma for both treatment groups. Patients will be continuously monitored for 8 hours following the transfusion, and will be assessed between 8-12 hours after plasma transfusion or the following morning (the earlier of the two options), between 24-48 hours after plasma transfusion or at discharge (the earlier of the two options) and after 30+/-3 days after transfusion.

Detailed Description
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Upper gastrointestinal hemorrhage (UGIH) is one of the most common gastrointestinal emergencies, and is associated with significant morbidity and mortality. Acute upper gastrointestinal hemorrhage (AUGIH) management guidelines call for aggressive hemodynamic resuscitation, prevention and treatment of complications and treatment of bleeding, which generally includes endoscopic intervention and transfusion of appropriate blood components. However, in many cases, spontaneous hyperfibrinolysis occurs, jeopardizing pharmacological control of AUGIH. Antifibrinolytic drugs are considered effective in counteracting hyperfibrinolysis, but are associated with various side effects, such as neurotoxicity and accelerated fibrinolysis upon prolonged use. 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. PlasFree 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 re-bleeding in Patients undergoing plasma transfusions. The Primary Objective of this trial is to assess the safety profile of a one-time infusion of up to two units of PDP obtained through filtration with ClearPlasma in Patients presenting with acute upper gastrointestinal hemorrhage and to compare it to the same procedure carried out using FFP units. The Secondary Objective of this trial is to assess the efficacy of a one-time infusion of up to two units of PDP obtained through filtration with ClearPlasma in the reduction of re-bleeding in Patients presenting with acute upper gastrointestinal hemorrhage (as a measure of the performance of ClearPlasma) and to compare it to the same procedure carried out using FFP units.

Official Title
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MULTI-CENTER,DOUBLE-BLIND, RANDOMIZED, TWO-ARMS, CONTROLLED, PROSPECTIVE CLINICAL INVESTIGATION ASSESSING THE SAFETY AND PERFORMANCE OF A CLASS IIb MEDICAL DEVICE (CLEARPLASMATM) FOR THE TREATMENT OF PATIENTS WITH ACUTE UPPER GASTROINTESTINAL HEMORRHAGE.

Conditions
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Acute Upper Gastrointestinal Hemorrhage, Acute Upper Gastrointestinal Bleeding

Intervention / Treatment
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* Other: Plasma treated with ClearPlasma (Extra-corporeal plasma filtration device)
* Other: Regular fresh-frozen plasma (not treated)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female Patients. Patients aged ≥ 18 and ≤ 80 years old. Patients presenting with acute upper gastrointestinal hemorrhage (> 0.5 L), diagnosed by presence of blood in gastric lavage, hematemesis or melena within no longer than 24 h before enrolment. Patients presenting with acute upper gastrointestinal hemorrhage (< 24 h) for which fresh frozen plasma (FFP) has been ordered. 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. Patient on anticoagulant therapy at the time of enrolment. Patients with known renal failure (creatinine clearance < 30 mL/min) at the time of enrolment. Patients suffering of Hemophilia A or B. Patients suffering of venous and arterial thromboembolic events within 3 months before the enrolment. Patients with history of allergic reaction to plasma, polyethersyplone or polycarbonate. Patients suffering of IgA deficiency at the time of enrolment. Patients with history of hemorrhage while on anticoagulant treatment (warfarin, apixaban, rivaroxaban, dabigatran, low molecular weight heparin). 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 24 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, first-in-human clinical investigation, in which Patients presenting with acute upper gastrointestinal hemorrhage (AUGIH) and required plasma transfusion, will be randomized to receive a one-time infusion (up to 8 hours) of up to two 250 mL units of PDP (group A) or FFP (group B). The administration of Plasma needs to be in line with the clinical practice and doctor decision.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Plasminogen-Depleted Plasma Infusion<br>Patients presenting with acute upper gastrointestinal hemorrhage (AUGIH) and due to undergo a plasma transfusion, will be randomized to receive a one-time infusion (up to 8 hours) of up to two 250 mL units of PDP. In case of transfusions needing more than two units, the third unit and above will consist in regular plasma regardless of treatment group. Patients will be continuously monitored for 8 hours following the transfusion, and will be assessed between 8-12 hours after plasma transfusion or the following morning (the earlier of the two options), between 24-48 hours after plasma transfusion or at discharge (the earlier of the two options) and after 30±3 days after transfusion. | Other: Plasma treated with ClearPlasma (Extra-corporeal plasma filtration device)<br>* ClearPlasma is 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 that is indicated for use in conditions where massive bleeding situations exist.<br>|
| Other: Fresh-Frozen Plasma Infusion<br>Patients presenting with acute upper gastrointestinal hemorrhage (AUGIH) and due to undergo a plasma transfusion, will be randomized to receive a one-time infusion (up to 8 hours) of up to two 250 mL units of FFP. In case of transfusions needing more than two units, the third unit and above will consist in regular plasma regardless of treatment group. Patients will be continuously monitored for 8 hours following the transfusion, and will be assessed between 8-12 hours after plasma transfusion or the following morning (the earlier of the two options), between 24-48 hours after plasma transfusion or at discharge (the earlier of the two options) and after 30±3 days after transfusion. | Other: Regular fresh-frozen plasma (not treated)<br>* Regular fresh-frozen plasma (not treated)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Profile in Patients treated with PDP versus FFP. | Comparison of adverse events rate during the study period and within 30±3 days after transfusion with PDP (group A) or FFP (group B). All adverse occurrences (serious/non-serious or device-related/non-device related) will be recorded prospectively, categorized and evaluated for causality using defined criteria. | Entire Study Period (up to 1 month per patient). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of re-bleeding episodes in Patients treated with PDP versus FFP. | Comparison of the number of re-bleeding episodes occurring for the Patient throughout the study period and within 30±3 days after transfusion with PDP (group A) or FFP (group B). | Entire Study Period (up to 1 month per patient). | 
| Duration of hospital stay in Patients treated with PDP versus FFP. | Comparison of the duration of the hospital stay for the Patient up to 30±3 days after transfusion with PDP (group A) or FFP (group B). | Entire Study Period (up to 1 month per patient) or until patient discharge. | 
| CBC profile in Patients treated with PDP versus FFP. | Comparison of complete blood count (CBC) profiles between Patients who received transfusion with PDP (group A) or FFP (group B) at baseline (Screening Visit) versus T=8-12h, T=24-48h and End of Study Visit. | Entire Study Period (up to 1 month per patient). | 
| D-dimer profile in Patients treated with PDP versus FFP. | Comparison of D-dimer profiles between Patients who received transfusion with PDP (group A) or FFP (group B) at baseline (Screening Visit) versus T=8-12h, T=24-48h and End of Study Visit. | Entire Study Period (up to 1 month per patient). | 
| PT/INR (blood coagulation parameter) measurement in Patients treated with PDP versus FFP. | Comparison of Prothrombin Time and International Normalized Ratio (PT/INR) between Patients who received transfusion with PDP (group A) or FFP (group B) until Patient discharge from hospital. | Entire Study Period (up to 1 month per patient) or until patient discharge. | 
| aPTT (blood coagulation parameter) measurement in Patients treated with PDP versus FFP. | Comparison of Activated Partial Thromboplastin Time (aPTT) between Patients who received transfusion with PDP (group A) or FFP (group B) until Patient discharge from hospital. | Entire Study Period (up to 1 month per patient) or until patient discharge. | 
| Incidence of venous and arterial thromboembolic events in Patients treated with PDP versus FFP. | Comparison of the incidence of venous and arterial thromboembolic events during the study period and within 30±3 days after transfusion with PDP (group A) or FFP (group B). | Entire Study Period (up to 1 month per patient). | 
| Plasma transfusion-related mortality in Patients treated with PDP versus FFP. | Comparison of the plasma transfusion-related mortality during the study period and within 30±3 days after transfusion with PDP (group A) or FFP (group B). | Entire Study Period (up to 1 month per patient). | 
| Total blood loss from transfusion in Patients treated with PDP versus FFP. | Comparison of total blood loss from transfusion with PDP (group A) or FFP (group B) until Patient discharge from hospital, as measured by: Red blood cells (RBC) units transfused; Plasma units transfused; Platelet units transfused; Hemoglobin levels. | Entire Study Period (up to 1 month per patient) or until patient discharge. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Upper Gastrointestinal Hemorrhage, Gastrointestinal Hemorrhage, Gastrointestinal Bleeding, Acute Upper Gastrointestinal Bleeding, Plasminogen-Depleted Plasma, Plasma Transfusion