Safety and Efficacy of Polymyxin B Hemoperfusion (PMX) for Endotoxemic Septic Shock in a Randomized, Open-Label Study

Study Overview
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Brief Summary
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Prospective, multicenter, randomized, open-label study of standard of care plus the PMX cartridge versus standard of care alone in patients with endotoxemic septic shock

Detailed Description
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This is a prospective, multicenter, randomized, open-label trial of standard medical care plus the PMX cartridge versus standard medical care alone, in subjects with endotoxemia and septic shock. Subjects in critical care areas will be assessed for septic shock using known or suspected infection, multiple organ failure, fluid resuscitation and hypotension requiring vasopressor support as primary criteria. Subjects will meet all entry criteria for study if endotoxin activity is within the range of ≥ 0.60 to <0.90. Eligible and consented subjects will be randomized to receive either the PMX cartridge (administered twice for 1½ to 2 hours per treatment session approximately 24 hours apart) plus standard medical care or standard medical care alone. For all randomized subjects, a follow-up visit (if they are still in the hospital) or a telephone call will be completed at Day 28 (or later) to determine their mortality status. In surviving subjects, a follow-up visit or telephone call to determine their mortality status will also take place at approximately three months (i.e. Day 90) and 12 months after the subject was randomized.

Official Title
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A Prospective, Multicenter, Randomized, Open-Label Study to Evaluate the Efficacy and Safety of PMX Cartridge in Addition to Standard Medical Care for Patients With Endotoxemic Septic Shock

Conditions
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Septic Shock, Endotoxemia

Intervention / Treatment
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* Device: Toraymyxin PMX 20R Extracorporeal Hemoperfusion Cartridge


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years of age Hypotension requiring vasopressor support: Requirement for at least one of the vasopressors listed below, at the dose shown below, for at least 2 continuous hours and no more than 30 hours Norepinephrine > 0.05mcg/kg/min Dopamine > 10 mcg/kg/min Phenylephrine > 0.4 mcg/kg/min Epinephrine > 0.05 mcg/kg/min Vasopressin > 0.03 units/min Vasopressin (any dose) in combination with another vasopressor listed above The subject must have received intravenous fluid resuscitation of a minimum of 30mL/kg administered within 24 hours of eligibility Documented or suspected infection defined as definitive or empiric intravenous antibiotic administration The subject must have a screening multi-organ dysfunction score (MODS) >9 OR a sequential organ failure assessment (SOFA) >11, in the event a complete MODS cannot be obtained due to missing measurements Endotoxin Activity Assay between ≥ 0.60 to <0.90 EA units Evidence of at least 1 of the following criteria for new onset organ dysfunction that is considered to be due to the acute illness: Requirement for positive pressure ventilation via an endotracheal tube or tracheostomy tube Thrombocytopenia defined as acute onset of platelet count <150,000µ/L or a reduction of 50% from prior known levels Acute oliguria defined as urine output <0.5mL/kg/hr for at least 6 hours despite adequate fluid resuscitation Exclusion Criteria: Inability to obtain an informed consent from the subject, family member or an authorized surrogate Lack of commitment for full medical support Inability to achieve or maintain a minimum mean arterial pressure (MAP) of ≥ 65mmHg despite vasopressor therapy and fluid resuscitation Subject has end-stage renal disease and requires chronic dialysis There is clinical support for non-septic shock such as: Acute pulmonary embolus Transfusion reaction Severe congestive heart failure (e.g. NYHA Class IV, ejection fraction < 35%) Subject has had chest compressions as part of CPR during this hospitalization without immediate return to communicative state Subject has had an acute myocardial infarction (AMI) within the past 4 weeks Subject has uncontrolled hemorrhage (acute blood loss requiring > 3 UPC in the past 24 hours) Major trauma within 36 hours of screening Subject has severe granulocytopenia (leukocyte count less than 500 cells/mm3) or severe thrombocytopenia (platelet count less than 30,000 cells/mm3) HIV infection in association with a last known or suspected CD4 count of <50/mm3 Subject's baseline state is non-communicative Subject has sustained extensive third-degree burns within the past 7 days Body weight < 35 kg (77 pounds) Known hypersensitivity to Polymyxin B Subject has known sensitivity or allergy to heparin or has a history of heparin associated thrombocytopenia (H.I.T.) Subject is currently enrolled in an investigational drug or device trial Subject has been previously enrolled in the current trial Any other condition, that in the opinion of the investigator, would preclude the subject from being a suitable candidate for enrollment, such as end-stage chronic illness (eg. lack of source control and bowel necrosis) with no reasonable expectation of survival to hospital discharge

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: The subjects will be randomized in a 2:1 ratio to the two groups (PMX cartridge plus standard of care: standard of care alone). A blocked randomization scheme will be used to provide approximately balanced ratio allocations to the two groups for each investigative site during the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PMX Treatment<br>Standard medical care for septic shock plus treatment with the PMX cartridge (twice approximately 24 hours apart) | Device: Toraymyxin PMX 20R Extracorporeal Hemoperfusion Cartridge<br>* TORAYMYXIN PMX-20R (PMX) is an extracorporeal hemoperfusion cartridge intended for the selective removal of endotoxin from circulating blood through direct hemoperfusion (DHP). Each treatment will target 2 hours with a minimum of 1 ½ hours, at a flow rate of approximately 100 mL/minute, (range of 80 to 120 mL/minute).<br>|
| No Intervention: Control<br>Standard medical care alone | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Day 28 mortality comparison | The primary objective is to compare the safety and efficacy of the PMX cartridge (Toraymyxin) based on mortality at 28 days in patients with septic shock and endotoxemia who are treated with standard medical care plus the use of the PMX cartridge, versus patients who receive standard medical care alone. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MAP comparison | compare changes in mean arterial blood pressure (MAP) from Day 0 to Day 3 in each group | 3 days | 
| Vasopressor dose comparison | compare the changes in vasopressor doses from Day 0 to Day 3 in each group | 3 days | 
| Survival time comparison | compare the survival time from baseline to death within 28 days in each group | 28 days | 
| Day 28 mortality comparison for patients on norepinephrine >0.1 mcg/kg/min | compare mortality at 28 days post baseline for patients with baseline norepinephrine dose >0.1 mcg/kg/min in each group | 28 days | 
| Day 14 mortality comparison | compare mortality at 14 days post baseline in each group | 14 days | 
| Vasopressor use comparison | compare total duration of vasopressor use from Day 0 to Day 3 in each group | 3 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, septic shock, severe sepsis, endotoxemia, endotoxemic, TIGRIS, PMX, Toraymyxin, EAA