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

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

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

Study Overview

• Status: Recruiting
• Conditions: Septic Shock; Endotoxemia
• Intervention / Treatment: Device: Toraymyxin PMX 20R Extracorporeal Hemoperfusion Cartridge

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Not Applicable

Expanded Access

Temporarily not available outside the clinical trial. See expanded access record.

Contacts and Locations

• Study Contact: Name: Debra Foster; Phone Number: 2001 416-626-3233; Email: dfoster@spectraldx.com

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-0111
      • Not yet recruiting
      • University of Alabama at Birmingham
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Recruiting
      • University of Arkansas for Medical Sciences
  • California
    • Palo Alto, California, United States, 94305
      • Withdrawn
      • Stanford University
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California, San Francisco
  • Colorado
    • Boulder, Colorado, United States, 80909
      • Recruiting
      • Pulmonary Associates
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • Recruiting
      • George Washington University
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • Recruiting
      • Louisiana State University Health Shreveport
  • Massachusetts
    • Springfield, Massachusetts, United States, 01199
      • Recruiting
      • Baystate Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Withdrawn
      • Henry Ford Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Withdrawn
      • Washington University
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Terminated
      • Cooper Health System
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • Mt Sinai Hospital
    • Stony Brook, New York, United States, 11794
      • Recruiting
      • Stony Brook University
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • UPMC
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Recruiting
      • Medical University of South Carolina
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Recruiting
      • CHI Memorial
    • Chattanooga, Tennessee, United States, 37404
      • Recruiting
      • Parkridge Hospital
  • West Virginia
    • Morgantown, West Virginia, United States, 26505
      • Recruiting
      • West Virginia University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years of age

2. 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

   1. Norepinephrine > 0.05mcg/kg/min
   2. Dopamine > 10 mcg/kg/min
   3. Phenylephrine > 0.4 mcg/kg/min
   4. Epinephrine > 0.05 mcg/kg/min
   5. Vasopressin > 0.03 units/min
   6. Vasopressin (any dose) in combination with another vasopressor listed above
3. The subject must have received intravenous fluid resuscitation of a minimum of 30mL/kg administered within 24 hours of eligibility
4. Documented or suspected infection defined as definitive or empiric intravenous antibiotic administration
5. 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
6. Endotoxin Activity Assay between ≥ 0.60 to <0.90 EA units

7. Evidence of at least 1 of the following criteria for new onset organ dysfunction that is considered to be due to the acute illness:

   1. Requirement for positive pressure ventilation via an endotracheal tube or tracheostomy tube
   2. Thrombocytopenia defined as acute onset of platelet count <150,000µ/L or a reduction of 50% from prior known levels
   3. Acute oliguria defined as urine output <0.5mL/kg/hr for at least 6 hours despite adequate fluid resuscitation

Exclusion Criteria:

1. Inability to obtain an informed consent from the subject, family member or an authorized surrogate
2. Lack of commitment for full medical support
3. Inability to achieve or maintain a minimum mean arterial pressure (MAP) of ≥ 65mmHg despite vasopressor therapy and fluid resuscitation
4. Subject has end-stage renal disease and requires chronic dialysis

5. There is clinical support for non-septic shock such as:

   1. Acute pulmonary embolus
   2. Transfusion reaction
   3. Severe congestive heart failure (e.g. NYHA Class IV, ejection fraction < 35%)
6. Subject has had chest compressions as part of CPR during this hospitalization without immediate return to communicative state
7. Subject has had an acute myocardial infarction (AMI) within the past 4 weeks
8. Subject has uncontrolled hemorrhage (acute blood loss requiring > 3 UPC in the past 24 hours)
9. Major trauma within 36 hours of screening
10. Subject has severe granulocytopenia (leukocyte count less than 500 cells/mm3) or severe thrombocytopenia (platelet count less than 30,000 cells/mm3)
11. HIV infection in association with a last known or suspected CD4 count of <50/mm3
12. Subject's baseline state is non-communicative
13. Subject has sustained extensive third-degree burns within the past 7 days
14. Body weight < 35 kg (77 pounds)
15. Known hypersensitivity to Polymyxin B
16. Subject has known sensitivity or allergy to heparin or has a history of heparin associated thrombocytopenia (H.I.T.)
17. Subject is currently enrolled in an investigational drug or device trial
18. Subject has been previously enrolled in the current trial
19. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PMX Treatment; Standard medical care for septic shock plus treatment with the PMX cartridge (twice approximately 24 hours apart)	Device: Toraymyxin PMX 20R Extracorporeal Hemoperfusion Cartridge; 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).
No Intervention: Control; Standard medical care alone

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Spectral Diagnostics (US) Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 17, 2019
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): September 30, 2025

Study Registration Dates

• First Submitted: April 2, 2019
• First Submitted That Met QC Criteria: April 2, 2019
• First Posted (Actual): April 3, 2019

Study Record Updates

• Last Update Posted (Actual): June 9, 2023
• Last Update Submitted That Met QC Criteria: June 8, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: septic shock; sepsis; severe sepsis; endotoxemia; endotoxemic; TIGRIS; PMX; Toraymyxin; EAA
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Bacteremia; Toxemia; Shock, Septic; Shock; Endotoxemia
• Other Study ID Numbers: SDI-PMX-NA003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There are no plans for sharing IPD at this time.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes