PMX Hemoperfusion for Septic Shock

(TIGRIS Trial)

Recruiting at 20 trial locations

Overseen By Esha Kamaluddin

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Spectral Diagnostics (US) Inc.

Must be taking: Vasopressors, Antibiotics

Disqualifiers: End-stage renal disease, Severe heart failure, Recent AMI, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 30

Duration: 3 days

150 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests whether adding a blood-filtering device called the PMX cartridge to regular treatment helps patients with severe infections and organ failure. The device aims to remove harmful toxins from their blood.

Do I have to stop taking my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug Polymyxin B for treating infections?

Research shows that Polymyxin B is effective against various bacteria, including methicillin-resistant Staphylococcus and some multidrug-resistant Gram-negative bacteria, which suggests it could be useful in treating infections caused by these organisms. ^{1 2 3 4 5}

Is PMX Hemoperfusion with Polymyxin B safe for humans?

Polymyxin B has been used safely in various forms, including topical applications and intravenous treatments, for infections caused by resistant bacteria. It is generally well tolerated, but there can be side effects like nephrotoxicity (kidney damage) with improper use. Studies suggest that newer derivatives like SPR741 have reduced kidney toxicity and are well tolerated in healthy subjects. ^{6 7 8 9 10}

How is PMX hemoperfusion treatment different from other treatments for septic shock?

PMX hemoperfusion is unique because it uses a special cartridge to remove endotoxins (harmful substances from bacteria) from the blood, which can help stabilize blood circulation and improve organ function in septic shock patients. This approach is different from standard treatments that typically focus on antibiotics and supportive care, as it directly targets the toxins contributing to the condition. ^{11 12 13 14 15}

Eligibility Criteria

Adults with endotoxemic septic shock who have low platelet counts, reduced urine output despite fluids, need vasopressors to maintain blood pressure, and are suspected or confirmed to have an infection. They must also show signs of organ dysfunction and not be on chronic dialysis or suffering from conditions like severe heart failure, recent heart attack, uncontrolled bleeding, major trauma within the last 36 hours, extreme white cell or platelet depletion.

Inclusion Criteria

I am on a high dose of Phenylephrine.

I am taking vasopressin with another blood pressure medication.

I've received a fluid boost of at least 30mL/kg in the last day.

Exclusion Criteria

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

Major trauma within 36 hours of screening

Inability to obtain an informed consent from the subject, family member or an authorized surrogate

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive the PMX cartridge treatment twice, approximately 24 hours apart, in addition to standard medical care

3 days

2 treatment sessions (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up visits or calls to determine mortality status

12 months

Follow-up at Day 28, Day 90, and 12 months

Treatment Details

Interventions

• Polymyxin B

Trial Overview The trial is testing the safety and effectiveness of adding a Polymyxin B Hemoperfusion (PMX) cartridge treatment to standard care for patients with endotoxemic septic shock compared to standard care alone. It's a prospective study involving multiple centers where participants are randomly assigned to one of the two groups.

Participant Groups

Group I: PMX Treatment Experimental Treatment 1 Intervention

Standard medical care for septic shock plus treatment with the PMX cartridge (twice approximately 24 hours apart)

Group II: Control Active Control 1 Intervention

Standard medical care alone

Who Is Running the Clinical Trial?

Spectral Diagnostics (US) Inc.

Lead Sponsor

Trials

4

Recruited

600+

Findings from Research

Polymyxin B demonstrated significantly lower minimum inhibitory concentrations (MICs) compared to colistin against multidrug-resistant bacteria, including Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, suggesting it may be more effective in treating infections caused by these organisms.

The study indicates that while the differences in categorical interpretations of susceptibility were minimal, the lower MICs of polymyxin B could be crucial in clinical settings, especially for patients with co-morbidities where antibiotic toxicity is a concern.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of antibacterial activities of polymyxin B and colistin against multidrug resistant Gram negative bacteria. Doymaz, MZ., Karaaslan, E.[2020]

In a clinical trial involving 103 asymptomatic MRSA carriers, mupirocin was significantly more effective than Polysporin Triple (PT) ointment in eradicating MRSA, with 65% of mupirocin patients testing MRSA negative at 48 hours compared to only 31% in the PT group.

At the 12-week follow-up, mupirocin showed a 30.8% eradication rate at all sites, while only 2.8% of PT-treated patients achieved the same, indicating that mupirocin is a superior option for MRSA eradication when used with chlorhexidine body washes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind, randomized, controlled trial of topical polysporin triple compound versus topical mupirocin for the eradication of colonization with methicillin-resistant Staphylococcus aureus in a complex continuing care population. O'Grady, S., Hirji, Z., Pejcic-Karapetrovic, B., et al.[2021]

A comparative analysis of Staphylococcus aureus strains from patients with non-specific ulcerative colitis showed that biosporin was highly effective in inhibiting the growth of polyresistant S. aureus strains.

The study found that a therapeutic complex including biosporin was superior to conventional antibiotics in eliminating S. aureus from the large intestine, highlighting its potential as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparative evaluation of effectiveness of the effect of antibiotics and bacterial substances on clinical trains of Staphylococcus auerus isolated from patients with nonspecific ulcerative colitis]. Tropko, LV.[2006]

Polysporin First Aid Antibiotic Spray effectively inhibits the growth of all tested gram-positive bacteria, including methicillin-resistant Staphylococcus strains, indicating its potential for treating infections caused by these organisms.

The spray also shows effectiveness against many gram-negative bacteria, although it is not effective against Serratia marcescens, Morganella morganii, and Proteus mirabilis, suggesting it may be suitable for a wide range of wound infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy of Polysporin First Aid Antibiotic Spray (polymyxin B sulfate and bacitracin zinc) against clinical burn wound isolates. Walton, MA., Carino, E., Herndon, DN., et al.[2019]

The combination of polymyxin B (PMB) and vancomycin (VAN) showed a synergistic effect against six clinical isolates of Acinetobacter baumannii, including both PMB-susceptible and PMB-resistant strains, indicating its potential as an effective treatment option.

The PMB-VAN combination demonstrated a bactericidal effect within 24 hours against PMB-resistant isolates, suggesting it may help prevent hypermutation in these bacteria, which is crucial for overcoming antibiotic resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic activity of polymyxin B combined with vancomycin against carbapenem-resistant and polymyxin-resistant Acinetobacter baumannii: first in vitro study. Shinohara, DR., Menegucci, TC., Fedrigo, NH., et al.[2019]

Neomycin sulfate, when combined with bacitracin and polymyxin B, shows strong synergistic effects against common wound infection bacteria, suggesting its continued use in topical preparations despite safety concerns.

The study indicates that the three-drug combination can potentially allow for lower concentrations of antibiotics in formulations while maintaining efficacy, which could enhance safety and reduce the risk of sensitization associated with neomycin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro interactions of neomycin sulfate, bacitracin, and polymyxin B sulfate. Booth, JH., Benrimoj, SI., Nimmo, GR.[2019]

SPR741, a new derivative of polymyxin B, shows reduced nephrotoxicity and enhances the effectiveness of coadministered antibiotics against Gram-negative bacteria, making it a promising option for treating serious infections.

In clinical studies involving healthy adults, SPR741 was well tolerated at doses up to 1,800 mg/day, with a favorable pharmacokinetic profile that supports its further development for combating antibiotic-resistant infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, Pharmacokinetics, and Drug Interaction Potential of SPR741, an Intravenous Potentiator, after Single and Multiple Ascending Doses and When Combined with β-Lactam Antibiotics in Healthy Subjects. Eckburg, PB., Lister, T., Walpole, S., et al.[2020]

Topical application of a neomycin-bacitracin-polymyxin antibiotic preparation significantly reduces the risk of staphylococcal and streptococcal infections in minor skin injuries, based on recent double-blind controlled studies.

The combination is considered safe, with rare allergic reactions to neomycin and systemic side effects only occurring with excessive use, indicating its efficacy in preventing infections without major safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical antibiotics and minor skin trauma. Leyden, JJ., Sulzberger, MB.[2018]

A global survey of 284 healthcare experts revealed that colistin, an antibiotic used for multidrug-resistant Gram-negative infections, is often underdosed, with only 21.2% of respondents using a loading dose, which is crucial for effective treatment.

The survey highlighted the need for clear international guidelines on the indications and dosing of colistin to improve patient outcomes and prevent antibiotic resistance, as 20% of respondents reported colistin was unavailable when needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Global survey of polymyxin use: A call for international guidelines. Wertheim, H., Van Nguyen, K., Hara, GL., et al.[2021]

In a study of 259 patients with bloodstream infections caused by carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, treatment with polymyxin B did not significantly affect 30-day mortality compared to colistin.

Both polymyxin B and colistin showed similar outcomes in terms of mortality rates, indicating that neither drug provided a clear advantage in treating these infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison between Colistin and Polymyxin B in the Treatment of Bloodstream Infections Caused by Carbapenem-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii-calcoaceticus Complex. Garcia, RCL., Rodrigues, RD., Garcia, ECL., et al.[2023]

Prolonged direct hemoperfusion therapy with polymyxin B (PMX-DHP) for 12 hours resulted in significantly better blood pressure stabilization and reduced vasopressor dependency compared to the conventional 2-hour treatment in a study of 36 patients with septic shock.

Despite the improved circulatory stabilization with prolonged PMX-DHP, there was no difference in hospital mortality rates between the two treatment durations, indicating that while the therapy may enhance hemodynamic support, it does not necessarily lead to better survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged direct hemoperfusion using a polymyxin B immobilized fiber cartridge provides sustained circulatory stabilization in patients with septic shock: a retrospective observational before-after study. Miyamoto, K., Kawazoe, Y., Kato, S.[2020]

In a study of 69 septic shock patients, those treated with polymyxin B hemoperfusion (PMX-HP) showed a significant reduction in inotropic scores after 24 hours compared to those receiving conventional treatment, indicating improved hemodynamic stability.

PMX-HP was associated with a lower 28-day mortality rate (odds ratio 0.18), suggesting it may enhance survival outcomes for patients with septic shock due to intra-abdominal or gram-negative infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of polymyxin B hemoperfusion on hemodynamics and prognosis in septic shock patients. Lee, CT., Tu, YK., Yeh, YC., et al.[2018]

In a study of 30,731 septic shock patients, those treated with polymyxin B hemoperfusion (PMX) had a significantly higher 28-day survival rate of 77.9% compared to 71.1% in the control group, suggesting PMX may improve outcomes in septic shock.

Patients receiving PMX also experienced more days free from noradrenaline, ventilators, and continuous hemodiafiltration, indicating improved organ function and hemodynamics, particularly in those requiring lower doses of noradrenaline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Polymyxin B Hemoperfusion on Septic Shock Patients Requiring Noradrenaline: Analysis of a Nationwide Administrative Database in Japan. Fujimori, K., Tarasawa, K., Fushimi, K.[2022]

In a study involving critically ill patients with sepsis undergoing continuous venovenous hemofiltration, direct hemoperfusion with polymyxin B immobilized cartridge (DHP-PMX) did not significantly alter the pharmacokinetics of meropenem, a crucial antibiotic.

Key pharmacokinetic parameters such as the area under the curve (AUC), peak and trough concentrations, and half-life of meropenem remained comparable with and without DHP-PMX therapy, indicating that DHP-PMX does not clinically impact meropenem effectiveness in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of direct hemoperfusion with polymyxin B immobilized cartridge on meropenem in critically ill patients requiring renal support. Singhan, W., Vadcharavivad, S., Areepium, N., et al.[2020]

Polymyxin-B hemoperfusion has shown promising safety and potential efficacy in treating septic shock, particularly supported by studies from Japan and Europe, despite a lack of robust randomized controlled trials.

The EUPHRATES trial aims to address previous methodological flaws in studies of PMX-B, providing a significant opportunity to evaluate its effectiveness in removing endotoxins in critically ill patients with septic shock.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endotoxin removal: how far from the evidence? From EUPHAS to EUPHRATES. Rachoin, JS., Foster, D., Dellinger, RP.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Comparison of antibacterial activities of polymyxin B and colistin against multidrug resistant Gram negative bacteria. [2020]

2. Egypt pubmed.ncbi.nlm.nih.gov

A double-blind, randomized, controlled trial of topical polysporin triple compound versus topical mupirocin for the eradication of colonization with methicillin-resistant Staphylococcus aureus in a complex continuing care population. [2021]

3. Ukraine pubmed.ncbi.nlm.nih.gov

[Comparative evaluation of effectiveness of the effect of antibiotics and bacterial substances on clinical trains of Staphylococcus auerus isolated from patients with nonspecific ulcerative colitis]. [2006]

4. United States pubmed.ncbi.nlm.nih.gov

The efficacy of Polysporin First Aid Antibiotic Spray (polymyxin B sulfate and bacitracin zinc) against clinical burn wound isolates. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Synergistic activity of polymyxin B combined with vancomycin against carbapenem-resistant and polymyxin-resistant Acinetobacter baumannii: first in vitro study. [2019]

6. England pubmed.ncbi.nlm.nih.gov

In vitro interactions of neomycin sulfate, bacitracin, and polymyxin B sulfate. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, Pharmacokinetics, and Drug Interaction Potential of SPR741, an Intravenous Potentiator, after Single and Multiple Ascending Doses and When Combined with β-Lactam Antibiotics in Healthy Subjects. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Topical antibiotics and minor skin trauma. [2018]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Global survey of polymyxin use: A call for international guidelines. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Comparison between Colistin and Polymyxin B in the Treatment of Bloodstream Infections Caused by Carbapenem-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii-calcoaceticus Complex. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Prolonged direct hemoperfusion using a polymyxin B immobilized fiber cartridge provides sustained circulatory stabilization in patients with septic shock: a retrospective observational before-after study. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

Effects of polymyxin B hemoperfusion on hemodynamics and prognosis in septic shock patients. [2018]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Effects of Polymyxin B Hemoperfusion on Septic Shock Patients Requiring Noradrenaline: Analysis of a Nationwide Administrative Database in Japan. [2022]

14. United States pubmed.ncbi.nlm.nih.gov

The effect of direct hemoperfusion with polymyxin B immobilized cartridge on meropenem in critically ill patients requiring renal support. [2020]

15. Switzerland pubmed.ncbi.nlm.nih.gov

Endotoxin removal: how far from the evidence? From EUPHAS to EUPHRATES. [2019]